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HIV sequence database



Mutations in Retroviral Genes Associated with Drug Resistance

Jennifer Hammond,1 Brendan A. Larder,2 Raymond F. Schinazi 3 and John W. Mellors1

1 University of Pittsburgh, 603 Parran Hall, Pittsburgh, PA 15261.
2 Virco, UK, 162A Cambridge Science Park, Milton Road, Cambridge CB4 4GH.
3 Emory University/VAMC, 1670 Clairmont Road, Decatur, GA 30033.

 

Introduction

Drug resistance is the inevitable consequence of incomplete suppression of HIV replication. The rapid replication rate of HIV and its inherent genetic variation have led to the identification of many HIV variants that exhibit altered drug susceptibility. The growing number of drug resistance mutations listed in this revised table stands as a testimony to the genetic flexibility of HIV. This updated table lists 143 mutations occurring in the HIV Gag (3), Protease (44), Reverse Transcriptase (69), or Envelope (27) genes. Although the tables are quite comprehensive, the reader should be reminded that the mutations described are predominantly found in clade B virus and not in other HIV genotypes. The revised table includes for the first time drug resistance mutations that have been identified for SIV and FIV.

In the table the phrase "Enzyme resist." refers to inhibition assays done just with a mutated enzyme. Instead of introducing the mutations into a virus and testing the susceptibility of the mutant virus to a drug, researchers introduce the mutation(s) into the enzyme and determine their effect by running enzyme activity assays. These sort of assays don't take into account changes in other viral proteins (like gag) that would also help confer resistance, which is the reason for distinguishing enzyme resistance from whole virus resistance.

Acknowledgments

The authors would like to gratefully acknowledge their colleagues for assistance in assembling this table. This work was supported in part by the National Institutes of Health, the Department of Veterans Affairs, and the Georgia VA Research Center for AIDS and HIV Infections.

Mutations in HIV RT that confer drug resistance, ordered by position.

Amino Acid    Codon            Class of Drug                    Compound      In         In       -Fold      Cross-resistance         comments                             Refs
  Change     change                                                         vitro      Vivo   -resistance        (-fold)


  M 41  L   ATG to TTG/CTG    Nucleoside RTI                       AZT         ?          Y         4              -                M41L/T215Y: 60-70-fold;              (1, 2, 3)
                                                                                                                                    M41L/D67N/K70R/T215Y: 180-fold.

  A 62  V   GCC to GTC        Multiple Nucleoside Resistance                   N          Y        Nil             -                A62V alone has no effect, but in     (4, 5)
                                                                                                                                    combination with mutations at 75, 
                                                                                                                                    77, 116, 151 causes multi NRTI 
                                                                                                                                    resistance.

  K 65  R   AAA to AGA        Nucleoside RTI                       ddI         Y          Y        4-10       ddC; PMEA; 3TC(5)     Infrequently observed in patients     (6)
                                                                                                                                    receiving ddI or ddC

  K 65  R   AAA to AGA        Nucleoside RTI                       ddC         Y          Y        4-10              -                           -                        (6, 7)

  K 65  R   AAA to AGA        Nucleoside RTI                     1592U89       Y          N         3                -              K65R/L74V: 3.6-fold;  K65R/M184V:     (8)
                                                                                                                                    7-fold; K65R/L74V/M184V: 10.2-fold
 
  K 65  R   AAA to AGA        Nucleoside RTI                       DXG         Y          ?         8          other dioxolane      Reverses AZT resistance in            (9)
                                                                                                                 derivatives        D67N/K70R/T215Y/K219Q background

  K 65  R   AAA to AGA        Nucleoside RTI                       PMEA        Y          N       10-25               -                         -                         (10, 11)

  K 65  R   AAA to AGA        Nucleoside RTI                       PMPA        Y          ?        3.5                -                         -                         (12)

  D 67  N   GAC to AAC        Nucleoside RTI                        AZT        Y          Y         -                 -             D67N/K70R/T215Y/K219Q: 120-fold;      (1, 2, 3)
                                                                                                                                    M41L/D67N/K70R/T215Y: 180-fold.

  T 69  D   ACT to GAT        Nucleoside RTI                        ddC        N          Y         5                 -                         -                         (13)

  K 70  E   AAA to GAA        Nucleoside RTI                       PMEA        Y          Y         9         3TC (7); PFA: 2-fold              -                         (14, 15)
                                                                                                              hypersusceptibility

  K 70  R   AAA to AGA        Nucleoside RTI                       AZT         Y          Y         -                 -             D67N/K70R/T215Y/K219Q:                (1, 2, 3)
                                                                                                                                          120-fold

  L 74  I   TTA to ATA        HIV-1 Specific RTI                 HBY 097       Y          ?         -                 -                         -                         (16)

  L 74  V   TTA to GTA        Nucleoside RTI                      ddI          N          Y        5-10              ddC(4)         Can reverse effect of T215Y           (17)
                                                                                                                                      AZT resistance mutation

  L 74  V   TTA to GTA        Nucleoside RTI                    1592U89        Y          N         4                  -            K65R/L74V: 3.6-fold;                  (8)
                                                                                                                                    K65R/L74V/M184V: 10.2-fold 

  L 74  V   TTA to GTA        Nucleoside RTI                       DXG         Y          ?         4                  -                      -                           (9)

  L 74  V   TTA to GTA        HIV-1 Specific RTI                 HBY 097       Y          ?         -                  -                      -                           (16)

  V 75  I   GTA to TTA        HIV-1 Specific RTI                 HBY 097       Y          ?         -                  -            Compensates for negative effect 
                                                                                                                                    of G190E mutation on RT activity      (16)

  V 75  I   GTA to ATA        Multiple Nucleoside Resistance        -          N          Y        Nil                  -           V75I alone has no effect, but in      (4, 5)
                                                                                                                                    combination with mutations at 62, 
                                                                                                                                    77, 116, 151 causes multi NRTI 
                                                                                                                                    resistance.

  V 75  L   GTA to ATA        HIV-1 Specific RTI                  HBY 097       Y          ?         -                  -                           -                      (16)

  V 75  T   GTA to ACA        Nucleoside RTI                        d4T         Y          Y         7             ddI; ddC; d4C;   Observed with d4T selection in vitro,  (18, 19)
                                                                                                                      (-)-FTC         rarely in patients receiving d4T
                                                                                                                      
  F 77  L   TTC to CTC        Multiple Nucleoside Resistance         -          N          Y        Nil                 -           F77L alone has no effect, but in       (4, 5)
                                                                                                                                    combination with mutations at 62, 
                                                                                                                                    75, 116, 151 causes multi NRTI 
                                                                                                                                         resistance.

  W 88  G   TGG to GGG        Pyrophosphate Analogue RTI      Foscarnet (PFA)   Y          Y         5         Hypersusceptibility  Observed after selection with AZT      (20, 21, 22)
                                                                                                                      to AZT        and PFA; suppresses effects of AZT  
                                                                                                                                             mutations
                                                                                                                             
  W 88  S   TGG to TCG        Pyrophosphate Analogue RTI      Foscarnet (PFA)   N          Y        2-4        Wild-type suscep-    Partially suppresses effects           (20, 21, 22)
                                                                                                                 -tibility to AZT.

  E 89  G   GAA to GGA        Pyrophosphate Analogue RTI      Foscarnet (PFA)   Y          N        14                 -            Isolated by screening RT clones for    (23)
                                                                                                                                             ddGTP resistance

  E 89  K   GAA to GGA        Pyrophosphate Analogue RTI      Foscarnet (PFA)   Y          N        >16                -            Suppresses effects of AZT resistance   (21, 22)
                                                                                                                                                 mutations

  L 92  I   TTA to ATA        Pyrophosphate Analogue RTI      Foscarnet (PFA)   Y          N         8                 -            Partially suppresses effects of AZT   (21, 22)
                                                                                                                                        resistance mutations

  A 98  G   GCA to GGA          HIV-1 Specific RTI               L-697,661      N          Y         8                 -                             -                     (24)

  A 98  G   GCA to GGA          HIV-1 Specific RTI               Nevirapine     N          Y         -                 -                             -                     (25)

  L 100 I   TTA to ATA          HIV-1 Specific RTI             TIBO R82150      Y          ?       >100                -            suppresses effects of AZT resistance   (26, 27, 28)
                                                                                                                                    mutations

  L 100 I   TTA to ATA          HIV-1 Specific RTI             TIBO R82913      Y          ?         -                 -            Found in combination with E138K        (29)

  L 100 I   TTA to ATA          HIV-1 Specific RTI              L-697,661       Y          N         2                 -                             -                     (24)

  L 100 I   TTA to ATA          HIV-1 Specific RTI             Nevirapine       N          Y         -                 -                             -                     (30)

  L 100 I   TTA to ATA          HIV-1 Specific RTI         DMP 266 (L-743,726)  Y          ?       8-11                -            Combinations of mutations needed for   (31, 32)
                                                                                                                                    high-level resistance; L100I/V108I: 
                                                                                                                                    1,000-fold; L100I/V179D/Y181C: 
                                                                                                                                    1,000-fold

  L 100 I   TTA to ATA          HIV-1 Specific RTI            BHAP U-88204E     Y          ?        -                  -                            -                      (33, 34)

  L 100 I   TTA to ATA          HIV-1 Specific RTI           UC-68 (638532)     Y          ?        70                 -                            -                      (35)

  L 100 I   TTA to ATA          HIV-1 Specific RTI           UC-70 (638534)     Y          ?        758                -                            -                      (36)

  L 100 I   TTA to ATA          HIV-1 Specific RTI              UC-781          Y          ?        20                 -            Activity of UC-781 versus L100I,       (37, 38)
                                                                                                                                    K103N, V106A, E138K, Y181C and Y188L 
                                                                                                                                    reduced by 2-, 7-, 1.5-, 1.5-, 5- and 
                                                                                                                                    150-fold, respectively, compared to 
                                                                                                                                    wild type

  L 100 I   TTA to ATA          HIV-1 Specific RTI            UC-84 (615985)    Y          ?     >40, > 33             -                            -                      (36, 39)

  K 101 E   AAA to GAA          HIV-1 Specific RTI       8-Chloro-TIBO R091767  ?          Y        -                  -                            -                      (40)

  K 101 E   AAA to GAA          HIV-1 Specific RTI   BHAP U-87201E (atevirdine) N          Y        -                  -           K101E, Y188H, E233Y and K238T observed 
                                                                                                                                   with U-87201E/AZT combination therapy   (41)

  K 101 E   AAA to GAA          HIV-1 Specific RTI      DMP 266 (L-743,726)     Y          ?      1,000                -                            -                      (32)

  K 101 E   AAA to GAA          HIV-1 Specific RTI            L-697,661         N          Y        8                  -                            -                      (24)

  K 101 E   AAA to GAA          HIV-1 Specific RTI         UC-10 (645129)       Y          ?       12                  -                  K101E/Y181C: 200-fold            (36, 42, 43)

  K 101 E   AAA to GAA          HIV-1 Specific RTI         UC-38 (629243)       Y          N        -                  -                  K101E/G190E: >100-fold           (36)

  K 101 E   AAA to GAA          HIV-1 Specific RTI         UC-57 (647014)       Y          ?        -                  -                  K101E/Y181C: 58-fold             (36)

  K 101 E   AAA to GAA          HIV-1 Specific RTI             UC781            Y          ?        7     UC040(18);Nevirapine(15)      V108I/ Y181C: 55-fold; 
                                                                                                                                      K101E/ V108I/ Y181C: 500-fold.       (37, 43)

  K 101 I   AAA to ATA          HIV-1 Specific RTI             UC-16            Y          N       10                  -                 K101I/G141E: 10-fold              (36)

  K 101 Q   AAA to CAA          HIV-1 Specific RTI          Trovirdine          Y          ?        -                  -              Found in combination with V108I      (44, 45)

  K 103 N   AAA to AAC          HIV-1 Specific RTI     8-Chloro-TIBO R091767    ?          Y        -                  -                          -                        (40)

  K 103 N   AAA to AAC          HIV-1 Specific RTI  BHAP U-87201E (atevirdine)  N          Y        -                  -                K103N and Y181C observed with      (41)
                                                                                                                                               monotherapy

  K 103 N   AAA to AAC          HIV-1 Specific RTI  BHAP U-90152 (delavirdine)  ?          Y        -                  -            K103N/Y181C seen separately and in     (46)
                                                                                                                                         combination in patients

  K 103 N   AAA to AAC          HIV-1 Specific RTI      DMP 266 (L-743,726)     Y          Y        67                 -              Predominant mutation in vivo         (31)

  K 103 N   AAA to AAC          HIV-1 Specific RTI           L-697,593          Y          ?        20                 -               K103N/Y181C: > 1,000-fold           (47)

  K 103 N   AAA to AAC          HIV-1 Specific RTI           L-697,661          Y          Y         8                 -            K103N and Y181C most common with       (24, 48)
                                                                                                                                              monotherapy

  K 103 N   AAA to AAC          HIV-1 Specific RTI    Loviride (R89439, -APA)  Y          Y         -                 -                        -                          (49)

  K 103 N   AAA to AAC          HIV-1 Specific RTI          MKC442 (I-EBU)      Y          ?         -                 -             predominant mutation in vivo          (50)

  K 103 N   AAA to AAC          HIV-1 Specific RTI          Nevirapine          N          Y         -                 -                        -                          (30)

  K 103 N   AAA to AAC          HIV-1 Specific RTI          TIBO R82913         Y          ?       >100                -                K103N/Y181C: > 1,000-fold          (33)

  K 103 N   AAA to AAC          HIV-1 Specific RTI         UC-10 (645129)       Y          N         5                 -                        -                          (35)

  K 103 N   AAA to AAC          HIV-1 Specific RTI         UC-81 (615727)       Y          ?         40                -                        -     

  K 103 Q   AAA to CAA          HIV-1 Specific RTI           L-697,661          N          Y         8                 -                        -                          (48)

  K 103 R   AAA to AGA          HIV-1 Specific RTI          Trovirdine          Y          ?         -     Nevirapine; 9-chloro-TIBO    K103R/V179D: 500-fold; Found       (44, 45)
                                                                                                                                        in combination with V179D or 
                                                                                                                                               Y181C

  K 103 R   AAA to AGA          HIV-1 Specific RTI         MKC442(1-EBU)        Y          Y         -                 -                        -                          (51)

  K 103 T   AAA to ACA          HIV-1 Specific RTI  BHAP U-90152 (delavirdine)  ?          Y         -                 -                        -                          (46)

  K 103 T   AAA to ACA          HIV-1 Specific RTI           UC-42              Y          N        100                -                        -                          (36)

  V 106 A   GTA to GCA          HIV-1 Specific RTI         BHAP U-88204E        Y          ?         -                 -                        -                          (34)

  V 106 A   GTA to GCA          HIV-1 Specific RTI           E-EBU-dM           Y          ?         -                 -                        -                          (52)

  V 106 A   GTA to GCA          HIV-1 Specific RTI          Nevirapine          Y          Y       ~100                -                No effect on AZT resistance        (25, 29, 30, 33)

  V 106 A   GTA to GCA          HIV-1 Specific RTI         TIBO R82913          Y          ?       ~100                -                        -                          (29)

  V 106 A   GTA to GCA          HIV-1 Specific RTI       UC-69 (646989)         Y          ?         -                 -                  V106A/V181C: 166-fold            (36)

  V 106 A   GTA to GCA          HIV-1 Specific RTI            UC-82             Y          ?        13                 -                Activity of UC-82 versus L100I,    (37, 38)
                                                                                                                                        K103N, V106A, E138K, Y181C and 
                                                                                                                                        Y188L reduced by 2-, 6-, 1.5-, 
                                                                                                                                        2-, 4- and 200-fold, respectively, 
                                                                                                                                          compared to wild type

  V 106 A   GTA to GCA          HIV-1 Specific RTI     S-2720 (Quinoxaline)     Y          ?         -                 -                P225H follows V106A.  Also seen    (53)
                                                                                                                                        with L101I and Y181C.  Double and 
                                                                                                                                        triple mutants highly resistant to 
                                                                                                                                        other NNRTI's, including MKC442

  V 106 I   GTA to ATA          HIV-1 Specific RTI          HBY 097            -           -         -                 -                   Appears under lowered drug      (54)
                                                                                                                                            concentration selection

  V 108 I   GTA to ATA          HIV-1 Specific RTI     DMP 266 (L-743,726)     Y           ?         -                 -                  L100I/V108I: 1,000-fold          (31)

  V 108 I   GTA to GCA          HIV-1 Specific RTI         L-697,661           Y           Y         4                 -                        -                          (24)

  V 108 I   GTA to ATA          HIV-1 Specific RTI   Loviride (R89439, -APA)  Y           ?         -                 -                        -                          (49)

  V 108 I   GTA to GCA          HIV-1 Specific RTI        MKC442 (I-EBU)       Y           ?         -                 -                        -                          (50)

  V 108 I   GTA to ATA          HIV-1 Specific RTI         Nevirapine          N           Y         -                 -                        -                          (30)

  V 108 I   GTT to GAT          HIV-1 Specific RTI        TIBO R82913          N           Y       >100          R82150 (> 100)                 -                          (55)

  V 108 I   GTA to ATA          HIV-1 Specific RTI         Trovirdine          Y           ?         -                 -               Found in combination with K101Q     (44, 45)

  V 108 I   GTA tO ATA          HIV-1 Specific RTI           UC781             Y           ?         -                 -               V108I/Y181C:  55 fold.  K101E/V108I (43)
                                                                                                                                           /Y181C: 500 fold.

  Y 115 F   TAT to TTT           Nucleoside RTI             1592U89            Y           N         2                 -               K65R/L74V and/or Y115F with M184V:  (8)
                                                                                                                                      10 fold; L74V/Y115F/M184V: 11-fold

  F 116 Y   TTT to TAT     Multiple Nucleoside Resistance      -               N           Y        Nil                -               F116Y alone has no effect, but in   (4, 5)
                                                                                                                                       combination with mutations at 62, 
                                                                                                                                       75, 77, 151 causes multi NRTI 
                                                                                                                                                  resistance.

  P 119 S   CCC to TCC         Nucleoside RTI                F-ddA             Y           ?         4                 -               Found with V179D and/or L214F,      (56)
                                                                                                                                       which are possibly compensatory

  E 138 K   GAG to AAG         HIV-1 Specific RTI             TSAO             Y           ?       >100                -               E138A (GAG to GCG) in TSAO-naive    (57, 58, 59)
                                                                                                                                       patients confers TSAO viral 
                                                                                                                                              resistance
  E 138 K   GAG to AAG         HIV-1 Specific RTI          MKC442 (I-EBU)      Y           N         -                 -              Obtained in the concomitant presence (60)
                                                                                                                                          of low 3TC concentrations

  E 138 K   GAG to AAG         HIV-1 Specific RTI           TIBO R82913        Y           ?         -                 -              Found in combination with L100I      (27)

  E 138 K   GAG to AAG         HIV-1 Specific RTI            UC-82             Y           ?         5                 -              Activity of UC-82 versus L100I,      (37, 38)
                                                                                                                                      K103N, V106A, E138K, Y181C and Y188L 
                                                                                                                                      reduced by 2-, 6-, 1.5-, 2-, 4- and 
                                                                                                                                      200-fold, respectively, compared to 
                                                                                                                                           wild type

  E 138 K   GAG to AAG         HIV-1 Specific RTI          UC-84 (615985)      Y           ?        >100             TSAOs                            -                    (35, 61)

  T 139 I   ACA to ATA         HIV-1 Specific RTI           Calanolide A       Y           ?        >70          Not other NNRTIs                     -                    (39)

  G 141 E   GGG to GAG         HIV-1 Specific RTI            UC-16             Y           N         -                 -                 K101I/G141E: 10-fold              (35)

  Q 151 M   CAG to ATG   Multiple Nucleoside Resistance        -               N           Y  AZT: 10; ddI/  ddC: 5    -                Pivotal multi nucleoside RTI       (4, 5, 62)
                                                                                                                                      resistance mutation (first to occur), 
                                                                                                                                          found in association with 
                                                                                                                                      combinations of four other mutations:  
                                                                                                                                       A62V/ V75I/ F77L/ F116Y/Q151M:  AZT 
                                                                                                                                      190-fold; ddI 50-fold; ddC 20-fold; 
                                                                                                                                            d4T > 10-fold

  S 156 A   TCA to GCA      Pyrophosphate Analogue RTI      Foscarnet (PFA)    Y           N         4.5               -                            -                      (21)

  Q 161 L   CAA to CTA      Pyrophosphate Analogue RTI      Foscarnet (PFA)    Y           Y          5                -               Q161L/H208Y: 9-fold; Q161L/H208Y    (20)
                                                                                                                                     suppresses effects of AZT mutations

  V 179 D   GTT to GAT         HIV-1 Specific RTI        DMP 266 (L-743,726)   Y           ?          -                -                L100I/V179D/Y181C: 1,000-fold      (31)

  V 179 D   GTT to GAT         HIV-1 Specific RTI            L-697,661         N           Y          4                -                            -                      (24)

  V 179 D   GTT to GAT         HIV-1 Specific RTI           TIBO R82913        N           Y         20           R82150 (20)                       -                      (63)

  V 179 D   GTT to GAT         HIV-1 Specific RTI          Trovirdine          Y           ?          -                -             Found in combination with K103R or    (44, 45)
                                                                                                                                     Y181C; V179D/Y181C: > 1,000-fold

  V 179 D   GTT to GAT         HIV-1 Specific RTI          UC-10 (645129)      Y           ?         16                -                            -                      (35)

  V 179 E   GTT to GAG         HIV-1 Specific RTI         L-697,661            N           Y          8                -                            -                      (23)

  Y 181 C   TAT to TGT         HIV-1 Specific RTI    -APA R18893 (loviride-   Y           ?          -                -                            -                      (64)
                                                          -analogue)

  Y 181 C   TAT to TGT         HIV-1 Specific RTI  BHAP U-87201E (atevirdine)  N           Y          -                -       K103N and Y181C observed with monotherapy   (46)

  Y 181 C   TAT to TGT         HIV-1 Specific RTI        BHAP U-88204E         Y           ?          -                -                        -                          (34)

  Y 181 C   TAT to TGT         HIV-1 Specific RTI  BHAP U-90152 (delavirdine)  ?           Y          -                -          K103N/Y181C seen separately and in       (46)
                                                                                                                                      combination in vivo

  Y 181 C   TAT to TGT         HIV-1 Specific RTI       BM+51.0836             Y           ?          -                -                            -                      (65)

  Y 181 C   TAT to TGT         HIV-1 Specific RTI     DMP 266 (L-743,726)      Y           ?          4                -        L100I/V179D/Y181C: 1,000-fold; uncommon    (31, 32)
                                                                                                                                            in vivo

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         E-EBU                Y           ?          -                -                           -                       (52)

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         E-EPSeU              Y           ?          >50              -      Y188C confers greater resistance than Y181C  (66)

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         E-EPU                Y           ?          >95              -      Y188C confers greater resistance than Y181C  (66) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         MKC442 (1-EBU)       ?           Y          -                -                           -                       (51) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         L-697,593            Y           ?          >100             -      K103N/Y181C: > 1,000-fold                    (47) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         L-697,661            Y           Y          >30              -      K103N and Y181C most common 
                                                                                                                              with monotherapy                             (24, 48) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         Loviride 
                                                          (R89439, -APA)      ?           Y          -                -                           -                       (67) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         Nevirapine           Y           Y          >100       Other NNRTIs Can suppress 
                                                                                                                              effects of AZT mutations                     (25, 68, 69) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         NSC 648400 
                                                          (E-BPTU)             Y           ?          160        Other NNRTIs                      -                       (70) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         TIBO R82913          Y           ?          >100             -      K103N/Y181C:> 1,000-fold                     (29) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         Trovirdine           Y           ?          -          Nevirapine; 
 n                                                                                                               9-chloro-
                                                                                                                 TIBO         V179D/Y181C:> 1,000-fold; 
                                                                                                                              Found in combination with K103R or V179D     (44, 45) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         UC-10 
                                                          (645129)             Y           ?          6                -      K101E/Y181C: 200-fold                        (36, 42) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         UC-32 
                                                          (645542)             Y           ?          3                -                           -                       (36) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         UC-38 
                                                          (629243)             Y           ?         8-149       Other NNRTIs                      -                       (36, 71) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         UC-040               Y           ?         16                -                           -                       (42) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         UC-57 
                                                          (647014)             Y           ?         -                 -      K101E/Y181C: 58-fold                         (36) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         UC-68 
                                                          (638532)             Y           ?         5                 -                            -                      (36) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         UC-69 
                                                          (646989)             Y           ?         -                 -      V106A/V181C: 166-fold                        (36) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         UC-80 
                                                          (639475)             Y           ?         1                 -                            -                      (36) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         UC-81 
                                                          (615727)             Y	   ?         53                -                            -                      (35, 72) 

  Y 181 C   TAT to TGT	       HIV-1 Specific RTI	  UC-82		       Y	   ?         5                 -                            -                      (42) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         UC-84 
                                                          (615985)             Y	   ?         >11               -                            -                      (36) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         UC781                Y           ?         13                -     V108/ Y181C:  55 fold; K101E/ 
                                                                                                                             V108I/ Y181C: 500 fold.                       (42) 

  Y 181 C   TAT to TGT         HIV-1 Specific RTI         1737 
                                                     (Tetrahydronaphthalene 
                                                     derivative)               Y           ?         20                -     Y181C also confers resistance 
                                                                                                                             to numerous other 
                                                                                                                             tetrahydronaphthalene derivative              (73)

  Y 181 I    TGT to ATT        HIV-1 Specific RTI         BHAP U-88204E        Y           Y          -                -     Appeared after treatment of Y181C-
                                                                                                                             mutated virus with BHAP; high-level 
                                                                                                                             resistance to BHAP, nevirapine and 
                                                                                                                             TIBO; observed in one nevirapine-
                                                                                                                             treated patient                               (74) 

  Y 181 I    TAT to ATT        HIV-1 Specific RTI     MKC442 (I-EBU)           Y           N       1,000              -                    -                               (60) 

  Y 181 I    TGT to ATT        HIV-1 Specific RTI     Nevirapine               N           Y       High-level         -      Observed in one patient                       (75) 

  M 184 I    ATG to ATA        Nucleoside RTI         3TC (lamivudine)         Y           Y        -                 -      M184V and M184I can suppress 
                                                                                                                             effects of AZT resistance mutations           (76, 77, 78)   

  M 184 T        -             Nucleoside RTI         3TC (lamivudine)         Y           ?        -                 -      Reduced replication capacity and RT 
                                                                                                                             activity                                      (79, 80) 

  M 184 V    ATG to GTG        Nucleoside RTI         3TC (lamivudine)         Y           Y      >100          ddI; ddC; 
                                                                                                                (-)-FTC      M184V and M184I can suppress effects 
                                                                                                                             of AZT resistance mutations; GTA seen 
                                                                                                                             in cell culture                               (76, 77, 78) 

  M 184 V    ATG to GTG        Nucleoside RTI         (-)-FTC                  Y           ?      >100               -       M184V can suppress effects of AZT 
                                                                                                                             mutations                                     (76, 77) 

  M 184 V    ATG to GTG        Nucleoside RTI         1592U89                  Y           N      3                  -       K65R/L74V and/or Y115F with M184V: 
                                                                                                                             10-fold; K65R/M184V: 8-fold; L74V/
                                                                                                                             M184V: 9-fold resistance; L74V/Y115F
                                                                                                                             /M184V: 11-fold                               (8) 

  M 184 V    ATG to GTG        Nucleoside RTI           ddC                    Y           Y      2-5                -                  -                                 (81) 

  M 184 V    ATG to GTG        Nucleoside RTI           ddI                    Y           Y      2-5                -      Rarely observed in patients receiving ddI      (81) 

  M 184 V    ATG to GTG        Nucleoside RTI         L-FddC                   Y           ?      >100               -                 -                                   (82) 

  Y 188 C    TAT to TGT        HIV-1 Specific RTI     E-EPSeU                  Y           ?      >250               -      Y188C is the predominant mutation for 
                                                                                                                            E-EPSeU; Y188C confers greater resistance 
                                                                                                                            than Y181C                                     (66) 

  Y 188 C    TAT to TGT        HIV-1 Specific RTI     E-EPU                    Y           ?      >250               -      Y188C confers greater resistance 
                                                                                                                            than Y181C                                     (66) 

  Y 188 C    TAT to TGT        HIV-1 Specific RTI     HEPT                     Y           ?       -                 -                  -                                  (52) 

  Y 188 C    TAT to TGT        HIV-1 Specific RTI     Nevirapine               N           Y       -                 -                  -                                  (30) 

  Y 188 H    TAT to CAT        HIV-1 Specific RTI     BHAP U-87201E 
                                                      (atevirdine)             N           Y       -                 -      K101E, Y188H, E233Y and K238T 
                                                                                                                            observed with U-87201E/AZT 
                                                                                                                            combination therapy                            (41) 

  Y 188 H    TAT to CAT        HIV-1 Specific RTI     TIBO R82913              Y           ?       -                 -                  -                                  (27) 

  Y 188 H/L  TAT to CAT/CTT    HIV-1 Specific RTI     Loviride (R89439,  
                                                      -APA)                   ?           Y       -                 -                  -                                  (67) 
  Y 188 L    TAT to TTA        HIV-1 Specific RTI     DMP 266 (L-743,726)      Y           ?     1,000               -                  -                                  (31) 

  Y 188 L    TAT to TTA        HIV-1 Specific RTI     TIBO R82913              N           Y       -                 -                  -                                  (63) 

  V 189 I    GTA to ATA        HIV-1 Specific RTI     HBY 097                  Y           ?      2         Other NNRTIs 
                                                                                                                (2-6)                   -                                  (16) 
  
  G 190 A    GGA to GCA        HIV-1 Specific RTI     Loviride (R89439, 
                                                      -APA)                   ?           Y      -                 -                   -                                  (83) 
  G 190 A    GGA to GCA        HIV-1 Specific RTI     Nevirapine               N           Y      -                 -                   -                                  (25) 

  G 190 E    GGA to GAA        HIV-1 Specific RTI     AAP-BHAP (U-104489)      Y           ?     >100               -       T139I/ G190E/ T200A/ L214F:  
                                                                                                                            >100.  Additional mutations possibly 
                                                                                                                            restore the replication capacity of 
                                                                                                                            the G190E mutant                               (84) 

  G 190 E    GGA to GAA        HIV-1 Specific RTI     HBY 097                  Y           ?      -        Other NNRTIs     Reduces enzymatic activity of RT 
                                                                                                                            and viral replication competency               (85) 

  G 190 E    GGA to GAA        HIV-1 Specific RTI     S-2720                   Y           ?      -                -                   -                                   (86) 

  G 190 E    GGA to GAA        HIV-1 Specific RTI     UC-38 (629243)           Y           N      -                         K101E/G190E: >100-fold; cross resistance 
                                                                                                                            to: TSAO-m3T, Nev, TIBO R82913, BHAP 
                                                                                                                            U88204; susceptible to L697,661                (35, 43) 

  G 190 E    GGA to GAA        HIV-1 Specific RTI     AAP-BHAP (U-95133)       Y           ?    >100               -        T139I/ G190Q/ T200A/ L214F:  >100-fold.  
                                                                                                                            Additional mutations possibly restore 
                                                                                                                            the replication competency of the G190E 
                                                                                                                            mutant.                                        (84) 

  G 190 Q    GGA to CAA        HIV-1 Specific RTI     HBY 097                  Y           ?     -        Other NNRTIs      Appears exclusively in connection with V179D   (16) 

  G 190 T    GGA to ?          HIV-1 Specific RTI     HBY 097                  -           -     -                 -        Appears under lowered drug concentration 
                                                                                                                            selection                                      (54) 

  H 208 Y    CAT to TAT        Pyrophosphate 
                               Analogue RTI           Foscarnet (PFA)          Y           Y     -                 2        Q161L/H208Y: 9-fold; increased susceptibility 
                                                                                                                            to AZT (100-fold), nevirapine (20-fold) 
                                                                                                                            and TIBO R82150 (30-fold); Q161L/H208Y 
                                                                                                                            suppresses effects of AZT mutations            (20) 

  H 208 Y    CAT to TAT        Multiple Nucleoside 
                               Resistance             AZT + 3TC                ?           Y     -                 -        Polymorphism facilitating AZT+3TC dual 
                                                                                                                            resistance                                     (87) 

  L 210 W    TTG to TGG        Nucleoside RTI         AZT                      Y           Y     -                 -        210W/215Y:  42-fold 41L/210W/215Y:  
                                                                                                                            49-fold  41L/67N/70R/210W/215Y:  
                                                                                                                            366-fold Mutation arises after prolonged 
                                                                                                                            AZT therapy.                                   (88, 89, 90) 

  R 211 K    AGG to AAG        Multiple 
                               Nucleoside Resistance  AZT + 3TC                ?           Y     -                 -        Polymorphism facilitating AZT+3TC dual 
                                                                                                                            resistance in association with M184V and 
                                                                                                                            other AZT resistance mutations.                (87) 

  L 214 F    CTT to TTT        Multiple 
                               Nucleoside Resistance  AZT + 3TC                ?           Y     -                 -        Polymorphism facilitating AZT+3TC dual 
                                                                                                                            resistance in association with  M184V and 
                                                                                                                            other AZT resistance mutations.                (87, 91) 

  T 215 F    ACC to TTC        Nucleoside RTI         AZT                      ?           Y     -                 -        K67N/K70R/T215Y/K219Q: 120-fold                (1, 2, 3) 

  T 215 Y    ACC to TAC        Nucleoside RTI         AZT                      Y           Y     -                 -        M41L/T215Y: 60-70-fold; K67N/K70R/
                                                                                                                            T215Y/K219Q: 120-fold.  Effect of T215Y 
                                                                                                                            is reversed by a ddI mutation (L74V), 
                                                                                                                            NNRTI mutations (L100I;Y181C) or 
                                                                                                                            (-)-FTC/3TC mutations (M184I/V)                (1, 2, 3) 

  Y 215 C    TTC to TGC        Nucleoside RTI         ddC                      N           Y     4                -         Arises on background of T215Y 
                                                                                                                            AZT resistance                                 (92) 

  K 219 E    AAA to GAA        Nucleoside RTI         AZT                      Y           N     -                -                       -                                (1, 2, 3)  

  K 219 Q    AAA to CAA        Nucleoside RTI         AZT                      ?           Y     -                -         K67N/K70R/T215Y/K219Q: 120-fold                (1, 2, 3) 

  P 225 H    CCT to CAT        HIV-1 Specific RTI     S-2720 (Quinoxaline)     Y           ?     -                -         P225H follows V106A.  Also seen with 
                                                                                                                            L101I and Y181C.  Double and triple 
                                                                                                                            mutants highly resistant to other 
                                                                                                                            NNRTI's, including MKC442.                     (53) 
  E 233 V    GAA to GTA        HIV-1 Specific RTI     BHAP U-87201E 
                                                      (atevirdine)             N           Y     -                -         K101E, Y188H, E233Y and K238T observed 
                                                                                                                            with U-87201E/AZT combination therapy          (41) 

  P 236 L    CCT to CTT        HIV-1 Specific RTI     BHAP U-87201E 
                                                      (atevirdine)             Y           N     -                -                      -                                 (93) 

  P 236 L    CCT to CTT        HIV-1 Specific RTI     BHAP U-90152 
                                                      (delavirdine)            Y           Y     -                -         Sensitizes RT ~10-fold to nevirapine, 
                                                                                                                            TIBO R82913 and L-697,661                      (93) 

  P 236 L    CCT to CTT        HIV-1 Specific RTI     HEPT                     Y           ?     -                -                      -                                 (70) 

  K 238 T    AAA to ACA        HIV-1 Specific RTI     BHAP U-87201E 
                                                      (atevirdine)             N           Y     -                -         K101E, Y188H, E233Y and K238T observed 
                                                                                                                            with U-87201E/AZT combination therapy          (41) 

  G 333 D    GGC to GAC        Multiple Nucleosides   AZT+3TC                  Y           Y     -                -         Facilitates dual resistance to AZT+3TC 
                                                                                                                            in association with M184V and standard 
                                                                                                                            AZT resistance mutations.                      (87) 

  G 333 E    GGC to GAG        Multiple Nucleosides   AZT + 3TC                Y           Y     -                -         Facilitates dual resistance to AZT+3TC 
                                                                                                                            in association with M184V and standard 
                                                                                                                            AZT resistance mutations.                      (87) 

Mutations in Protease and Drug Resistance
  K 65 R    AAA to AGA        Nucleoside RTI              ddC                  Y          Y        4-10              -                           -                        (6, 7)

  R 8  K    CGA to AAA        Protease Inhibitor        A-77003                Y          ?         10               -               R8K/  M46I/  G48V: 20-fold           (94, 95)
 
  R 8  Q    CGA to CAA        Protease Inhibitor        A-77003                Y          ?         10               -               M46I improves replication 
                                                                                                                                     competency of R8Q mutant             (94, 96) 
  
  L 10 F    CTC to TTC        Protease Inhibitor        DMP 450                Y          ?         -                -               Probably compensatory                (97, 98) 
  
  L 10 F    CTC to GGC        Protease Inhibitor        VB 11,328              Y          ?         -                -               L10F/I84V: 8-fold                    (99) 
  
  L 10 F    CTC to CGC        Protease Inhibitor        VX-478 (141W94)        Y          ?         -                -                     -                              (100) 
  
  L 10 F    CTC to CGC        Protease Inhibitor         XM323                 -          -         -        L10F/  V82A: 2-fold;    L10F/  K45I/  I84V: 50-fold          (101)
    
  L 10 F    CTC to CGC        Protease Inhibitor        SC-55389A              Y          ?         2.8      Not SC-52151            N88S/L10F: 25-fold                   (102, 103, 104) 
 
  L 10 F    CTC to TTC        Protease Inhibitor        BILA 2185 BS           Y          ?         -        BILA 1906 BS (360)      L10F/ L23I/ V32I/ M46I/ I47V/ 
                                                                                                                                     I54M/ A71V/ I84V:  1,500-fold.  
                                                                                                                                     Associated Gag mutations:  p1/p6 
                                                                                                                                     cleavage site (L to F (CTT to 
                                                                                                                                     TTT at P1'); p7/p1 cleavage site 
                                                                                                                                     (Q to R (CAG to CGG) at P3', 
                                                                                                                                     A to V (GCT to CTT) at P2'.      (106) 
 
  L 10 I    CTC to ATC        Protease Inhibitor        MK-639 (L-735
                                                        ,524, indinavir)       ?          Y        -         -                                                        (105) 

  L 10 I       -              Protease Inhibitor        Ro 31-8959
                                                        (saquinavir)           -          Y        -         -                       Found in combination with 
                                                                                                                                     G48V in vivo                     (107) 

  L 10 R    CTC to CGC        Protease Inhibitor        MK-639 (L-735,524, 
                                                        indinavir)             -          N        Y        XM-323 (15)              L10R/  M46I/  L63P/  V82T: 
                                                                                                                                     4-fold; L10R/  M46I/  L63P/  
                                                                                                                                     V82T/  I84V: 8-fold              (105) 

  L 10 V    CTC to GTC        Protease Inhibitor        MK-639 (L-735,524, 
                                                        indinavir)             ?          Y        -        A-80987 (4)                       -                       (105) 

  K 20 M    AAG to ATG        Protease Inhibitor        MK-639 (L-735,524, 
                                                        indinavir)             ?          Y        -        VX-478 (8)                        -                       (105) 

  K 20 R    AAG to AAA        Protease Inhibitor        ABT-538 (ritonavir)    N          Y        -          -                      K20R/M36I/I54V/V82A: 41-fold     (108) 

  K 20 R    AAG to AAA        Protease Inhibitor        MK-639 (L-735,524, 
                                                        indinavir)             ?          Y        -        Ro-31-8959 (8);                  -                        (105) 

  L 23 I    CTA to ATA        Protease Inhibitor        BILA 2185 BS           Y          ?        -        Ro 31-8959 (50);L-735,
                                                                                                            524 (80); BILA 1906 
                                                                                                            BS (360)                 L10F/ L23I/ V32I/ M46I/ I47V/ 
                                                                                                                                     I54M/ A71V/ I84V:  1,500-fold.  
                                                                                                                                     Associated Gag mutations:  p1/p6                
                                                                                                                                     cleavage site (L to F (CTT to 
                                                                                                                                     TTT at P1'); p7/p1 cleavage site 
                                                                                                                                     (Q to R (CAG to CGG) at P3', 
                                                                                                                                     A to V (GCT to CTT) at P2'.      (106, 109) 

  L 24 I    TTA to ATA        Protease Inhibitor        MK-639 (L-735,524, 
                                                        indinavir)             ?          Y        -        SC-52151 (8)             -                                (105)  

  L 24 V    TTA to GTA        Protease Inhibitor        SC-52151               Y          ?      10-20      SC55389A                 L24V/  G48V/  A71V/  
                                                                                                                                     V75I/  P81T: 1000-fold           (102, 103) 

  D 30 N    GAT to AAT        Protease Inhibitor        AG1343 
                                                        (nelfinavir)           Y          Y        -           -                     D30N/A71V: 7-fold; D30N
                                                                                                                                     and N88D are most common 
                                                                                                                                     in vivo after 24 weeks of 
                                                                                                                                     therapy; they do not cause 
                                                                                                                                     cross-resistance to other
                                                                                                                                     protease inhibitors              (110, 111) 
 
  V 32 I    GTA to ATA        Protease Inhibitor        ABT-538 (ritonavir)    Y          ?        40          -                     V32I and V82I are synergistic 
                                                                                                                                     mutations yielding 20-fold 
                                                                                                                                     enzyme resistance                (108) 
 
  V 32 I    GTA to ATA        Protease Inhibitor        A-77003                Y          ?        7 
                                                                                              (enzyme resist.) -                     V32I appears first; progression 
                                                                                                                                     to V32I/  M46V and V32I/  /  
                                                                                                                                     M46V/  A71V/  V82A occurs even 
                                                                                                                                     in the absence of drug           (96) 

  V 32 I    GTA to ATA        Protease Inhibitor        BILA 1906 BS           Y          ?       -            -                     V32I/  A71V: 3-fold; V32I/  
                                                                                                                                     M46I,L/ A71V/  I84V: 5-fold; 
                                                                                                                                     V32I/ M46I,L/ A71V/ I84A:  
                                                                                                                                     520-fold.  32I/ 46L/ 71V/ 
                                                                                                                                     84A are functionally impaired.  
                                                                                                                                     Associated Gag mutations:  
                                                                                                                                     p1/p6 cleavage 
                                                                                                                                     site (L to F 
                                                                                                                                     (CTT to TTT at P1')              (112, 106) 

  V 32 I    GTA to ATA        Protease Inhibitor        BILA 2011 
                                                        (palinavir)            Y          ?      1200         BILA 1906 (1400)       Other mutations found in 
                                                                                                                                     p1/  p6 cleavage site            (113) 

  V 32 I    GTA to ATA        Protease Inhibitor        KNI-272                Y          ?       2                 -                V32I/  M46I/  I84V: 37-fold;
                                                                                                                                     V32I/  L33F/  K45I/  F53L/  
                                                                                                                                     A71V/  I84V/  L89M: 130-fold     (114) 

  V 32 I    GTA to ATA        Protease Inhibitor        MK-639 (L-735, 
                                                        524, indinavir)        Y          Y       -                 -                V32I/  M46L/  V82A: 3-fold;
                                                                                                                                       V32I/  M46L/  A71V/  V82A:
                                                                                                                                      14-fold                         (105) 

  V 32 I    GTA to ATA        Protease Inhibitor        BILA 2185 BS           Y          ?       -          BILA 1906 (360)         L10F/ L23I/ V32I/ M46I/ I47V/ 
                                                                                                                                     I54M/ A71V/ I84V:  1,500-fold.  
                                                                                                                                     Associated Gag mutations:  
                                                                                                                                     p1/p6 cleavage site (L to F 
                                                                                                                                     (CTT to TTT at P1'); p7/ p1 
                                                                                                                                     cleavage site (Q to R 
                                                                                                                                     (CAG to CGG) at P3', A to V 
                                                                                                                                     (GCT to CTT) at P2'.             (106) 

  L 33 F    TTA to TTC        Protease Inhibitor        ABT-538 (ritonavir)    N          Y       -                -                 M36I/I54V/A71V/V82I: 8-fold; 
                                                                                                                                     K20R/M36I/I54V/V82A: 41-fold. 
                                                                                                                                     In vivo, V82A/F/T/S occurs first,
                                                                                                                                     often followed by changes at 
                                                                                                                                     54,71 and 36                     (108) 

  M 36 I    ATG to ATA        Protease Inhibitor        ABT-538 (ritonavir)    N          Y       -                -                 In vivo, V82 occurs first, 
                                                                                                                                     often followed by changes at 
                                                                                                                                     54, 71 and 36                    (108) 

  M 36 I         -            Protease Inhibitor        AG1343 (nelfinavir)    -          Y       -                -                            -                     (110) 

  K 45 I    AAA to ATA        Protease Inhibitor        XM323                  -          -       -                -                 L10F/  K45I/  I84V: 
                                                                                                                                     50-fold                          (95) 

  M 46 F    ATG to TTC        Protease Inhibitor        A-77003                Y          ?       4 
                                                                                               (enzyme resist.)    -                 Seen with V82A                   (96) 

  M 46 I    ATG to ATA        Protease Inhibitor        A-77003                Y          ?       -                -                 No effect on susceptibility 
                                                                                                                                     but improves replication 
                                                                                                                                     competency of R8Q mutant; 
                                                                                                                                     R8K/  M46I/  G48V: 20-fold       (94, 96) 

  M 46 I    ATG to ATA        Protease Inhibitor        ABT-538 (ritonavir)    Y          Y       -                -                 M46I/  L63P/  A71V/  V82F/  
                                                                                                                                     I84V: 27-fold                    (108) 

  M 46 I    ATG to ATA        Protease Inhibitor        AG1343 (nelfinavir)    Y          Y       -                -                          -                       (110) 

  M 46 I    ATG to ATA        Protease Inhibitor        BILA 1906 BS           Y          ?       -                -                 L 735,524 (60)&V32I/  A71V: 
                                                                                                                                     3-fold; V32I/  M46I,L/ A71V/  
                                                                                                                                     I84V: 5-fold; V32I/ M46I,L/ 
                                                                                                                                     A71V/ I84A:  520-fold.  V32I/
                                                                                                                                     M46L/A71V/I84A is functionally 
                                                                                                                                     impaired.  Associated Gag 
                                                                                                                                     mutations:  p1/p6 cleavage site 
                                                                                                                                     (L to F (CTT to TTT at P1')     (106, 109, 112, 113) 

  M 46 I    ATG to ATA        Protease Inhibitor        BILA 2185 BS           Y          ?      -             BILA 1906 (360)       L10F/ L23I/ V32I/ M46I/ I47V/ 
                                                                                                                                     I54M/ A71V/ I84V:  1,500-fold.  
                                                                                                                                     Associated Gag mutations:  
                                                                                                                                     p1/p6 cleavage site (L to F 
                                                                                                                                     (CTT to TTT at P1'); p7/p1 
                                                                                                                                     cleavage site (Q to R 
                                                                                                                                     (CAG to CGG) at P3', A to V 
                                                                                                                                     (GCT to CTT) at P2'.            (106) 
        
  M 46 I    ATG to ATA        Protease Inhibitor        DMP 450                Y          ?      -                 -                 Probably compensatory           (97, 98)


  M 46 I    ATG to ATA        Protease Inhibitor        MK-639 (L-735,524,
                                                         indinavir)            N          Y      -                 -                 M46I/  L63P/  V82T: 4-fold; 
                                                                                                                                     L10R/  M46I/  L63P/  V82T: 
                                                                                                                                     4-fold; L10R/  M46I/  L63P/  
                                                                                                                                     V82T/  I84V: 8-fold            (105, 115) 

  M 46 I    ATG to ATA        Protease Inhibitor        VB 11,32               Y          ?     -                  -                 I50V/  M46I/  I47V: 
                                                                                                                                     20-fold                        (95, 99) 

  M 46 I    ATG to ATA        Protease Inhibitor        VX-478 (141W94)        Y          ?    Nil                 -                            -                       - 

  M 46 L    ATG to TTC        Protease Inhibitor        A-77003                Y          ?    2-3 
                                                                                            (enzyme resist.)       -                            -                   (96)
     
  M 46 L    ATG to TTG        Protease Inhibitor        BILA 1906 BS           Y          ?     -                  -                Associated p1/  p6 cleavage 
                                                                                                                                    site mutation (L to F 
                                                                                                                                    (CTT to TTT) at P1'             (106, 109, 112, 113) 

  M 46 L    ATG to TTG        Protease Inhibitor        MK-639 (L-735,524,
                                                         indinavir)            Y          Y     -                  -                V32I/  M46L/  A71V/  V82A: 
                                                                                                                                    14-fold; V32I/  M46L/  
                                                                                                                                    V82A: 3-fold&(95)\cr

  M 46 L    ATG to CTG        Protease Inhibitor        XM323                  Y          ?     -                  -                V82A/  M46L: 7-fold; V82A/
                                                                                                                                    M46L/  L97V: 11-fold            (101) 

  M 46 V        -             Protease Inhibitor        A-77003                Y          ?     -                  -                V32I appears first; progression 
                                                                                                                                    to V32I/  M46V and V32I/  /  
                                                                                                                                    M46V/  A71V/  V82A occurs even 
                                                                                                                                    in the absence of drug          (95) 

  I 47 V    ATA to CTA        Protease Inhibitor        VB 11,328              Y          ?     -                  -                I50V/  M46I/  I47V: 20-fold      -

  I 47 V    ATA to CTA        Protease Inhibitor        VX-478 (141W94)        Y          ?    Nil                 -                             -                   - 

  I 47 V    ATA to CTA        Protease Inhibitor        BILA 2185 BS           Y          ?     -             BILA 1906 (360)       L10F/ L23I/ V32I/ M46I/ I47V/ 
                                                                                                                                    I54M/ A71V/ I84V:  1,500-fold.  
                                                                                                                                    Associated Gag mutations:  
                                                                                                                                    p1/p6 cleavage site (L to F 
                                                                                                                                    (CTT to TTT at P1'); p7/p1 
                                                                                                                                    cleavage site (Q to R (CAG 
                                                                                                                                    to CGG) at P3', A to V 
                                                                                                                                    (GCT to CTT) at P2'.            (106) 

  G 48 V    GGG to GTG        Protease Inhibitor        A-77003                Y          ?    -                  -                 R8K/  M46I/  G48V: 20-fold; 
                                                                                                                                    G48V/  I82T: 100-fold           (116) 

  G 48 V    GGG to GTG        Protease Inhibitor        Ro 31-8959 
                                                        (saquinavir)           Y          Y    -                  -                 Found in comb. with L10I in 
                                                                                                                                    vivo; G48V/  I84V/  L90M: 
                                                                                                                                    30-fold; G48V/  L90M: >100-fold 
                                                                                                                                    enzyme resistance; G48V/  L90M/  
                                                                                                                                    I54V: > 50-fold 
                                                                                                                                    (subtype B or O)                (117, 118) 

  G 48 V    GGG to GTG        Protease Inhibitor        SC-52151               Y          ?    -                  -                 Ro 31-8959&G48V/  V82A, G48V/  
                                                                                                                                    L63P/  V82A or I54T: 10- to 
                                                                                                                                    20-fold; L24V/  G48V/  A71V/  
                                                                                                                                    V75I/  P81T: 1000-fold          (102, 103) 

  G 48 V    GGG to GTG        Protease Inhibitor        MP-167                 Y          ?   20            MP-134(5) SC-52151
                                                                                                            (16) Ro31-8959(5)  
                                                                                                            (Fold increase in 
                                                                                                            IC90s).                 L10F/G48V:20-fold               (119) 
 
  G 48 V    GGG to GTG        Protease Inhibitor        MK-639 (L-735,524,
                                                         Indinavir)            ?          Y    -                  -                         -                       (120) 

  I 50 V    ATT to GTT        Protease Inhibitor        VB 11,328              Y          ?    3                  -                 I50V/  M46I/  I47V: 
                                                                                                                                    20-fold                         (95) 

  I 50 V    ATT to GTT        Protease Inhibitor        VX-478 (141W94)        Y          ?    3                  -                        -                        (121) 

  I 54 M    ATT to ATG        Protease Inhibitor        BILA 2185 BS           Y          ?    -           BILA 1906 (360)          L10F/ L23I/ V32I/ M46I
                                                                                                                                    / I47V/ I54M/ A71V/ I84V:  
                                                                                                                                    1,500-fold.  Associated 
                                                                                                                                    Gag mutations:  p1/p6 
                                                                                                                                    cleavage site (L to F 
                                                                                                                                    (CTT to TTT at P1'); 
                                                                                                                                    p7/p1 cleavage site 
                                                                                                                                    (Q to R (CAG to CGG) at 
                                                                                                                                    P3'; A to V (GCT to CTT) 
                                                                                                                                    at P2'.                         (106) 

  I&54 V    ATC to GTC        Protease Inhibitor        ABT-538 (ritonavir)    N          Y    -                 -                  I54V/V82T: 9-fold; 
                                                                                                                                    K20R/M36I/I54V/V82A: 
                                                                                                                                    41-fold; M36I/I54V/A71V/
                                                                                                                                    V82T: 8-fold; I54V/A71V/
                                                                                                                                    V82A/L90N: 7-fold; In vivo, 
                                                                                                                                    V82A/F/T/S occurs first, 
                                                                                                                                    followed by changes at 
                                                                                                                                    54, 71 and 36                   (108) 

  I 54 V    ATC to GTC        Protease Inhibitor        MK-639 (L-735,524, 
                                                        indinavir)             ?          Y    -                 -                          -                       (112) 

  I 54 V    ATA to GTA        Protease Inhibitor        Ro 31-8959 
                                                        (saquinavir)           Y          -    -                 -                  In subtype O                      -

  I 54 V    ATC to GTC        Protease Inhibitor        Ro 31-8959 
                                                        (saquinavir)           Y          -    -                 -                  In subtype B                    (117, 118) 

  D 60 E    GAT to GAA        Protease Inhibitor        DMP 450                Y          ?    -                 -                  Probably compensatory           (97, 98) 

  L 63 P    CTC to CCC        Protease Inhibitor        MK-639 (L-735,524,
                                                         indinavir)            N          Y    -                 -                  M46I/  L63P/  V82T: 
                                                                                                                                    4-fold; L10R/  M46I/  
                                                                                                                                    L63P/  V82T/  I84V: 
                                                                                                                                    8-fold; L10R/  M46I/  
                                                                                                                                    L63P/  V82T: 4-fold             (105)  

  A 71 T    GCT to ACT        Protease Inhibitor        BMS 186,318            Y          ?    -                 -                  A71T/  V82A: 15-fold            (122, 123) 

  A 71 T    GCT to ACT        Protease Inhibitor        MK-639 (L-735,524,
                                                         indinavir)            ?          Y    -                 -                          -                       (105) 

  A 71 V         -            Protease Inhibitor        A-77003                Y          ?    -                 -                  V32I appears first; 
                                                                                                                                    progression to V32I/  
                                                                                                                                    M46V and V32I/  /  M46V/  
                                                                                                                                    A71V/  V82A occurs even 
                                                                                                                                    in the absence of drug; 
                                                                                                                                    M46I/  L63P/  A71V/  V82F/  
                                                                                                                                    I84V: 27-fold                   (95, 101) 

  A 71 V    GCT to GTT        Protease Inhibitor        ABT-538 (ritonavir)    Y          Y   -                 -                          -                        (108) 

  A 71 V    GCT to GTT        Protease Inhibitor        AG1343 (nelfinavir)    Y          ?   5                 -                   D30N/  A71V: 7-fold; 
                                                                                                                                    M46I/  L63P/  A71V/  
                                                                                                                                    I84V: 30-fold                     -

  A 71 V    GCT to GTT        Protease Inhibitor        BILA 1906 BS           Y          ?  -                  -                   V32I/  A71V: 3-fold; V32I/  
                                                                                                                                    M46I,L/ A71V/  I84V: 5-fold; 
                                                                                                                                    V32I/ M46I,L/ A71V/ I84A:  
                                                                                                                                    520-fold.  32I/ 46L/ 71V/ 
                                                                                                                                    84A are functionally impaired.  
                                                                                                                                    Associated Gag mutations:  
                                                                                                                                    p1/p6 cleavage site (L to F 
                                                                                                                                    (CTT to TTT at P1')             (106, 109, 112, 113) 

  A 71 V    GCT to GTT        Protease Inhibitor        BILA 2011 (palinavir)  Y          ? -              BILA 2185: 30-fold                -                      (112) 

  A 71 V    GCT to GTT        Protease Inhibitor        MK-639 (L-735,524,
                                                         indinavir)            Y          Y -                  -                   V32I/  M46L/  A71V/  V82A: 
                                                                                                                                   14-fold                          (95) 

  A 71 V    GCT to GTT        Protease Inhibitor        SC-52151               Y          ? -             Not L-735,524            A71V/  V75I/  P81T: 20- to 
m                                                                                                                                  30-fold; L24V/  G48V/  A71V/  
                                                                                                                                   V75I/  P81T: 1000-fold; N88D 
                                                                                                                                   or I11V/  M46I/  F53L/  A71V/  
                                                                                                                                   N88D:10- to 20-fold              (102, 103) 

  A 71 V    GCT to GTT        Protease Inhibitor        BILA 2185 BS           Y          ? -             BILA 1906 (360)          L10F/ L23I/ V32I/ M46I/ I47V/ 
                                                                                                                                   I54M/ A71V/ I84V:  1,500-fold.  
                                                                                                                                   Associated Gag mutations:  
                                                                                                                                   p1/p6 cleavage site (L to F 
                                                                                                                                   (CTT to TTT at P1'); p7/p1 
                                                                                                                                   cleavage site (Q to R 
                                                                                                                                   (CAG to CGG) at P3'; A to V 
                                                                                                                                   (GCT to CTT) at P2'.             (106) 

    G 73 S    GGT to GCT        Protease Inhibitor        MK-639 (L-735,524,
                                                         indinavir)            ?          Y -                                      Emerges following a switch 
                                                                                                                                   from saquinavir to indinavir.    (124) 
  
  V 75 I    GTA to ATA        Protease Inhibitor        SC-52151               Y          ? -                -                     L24V/  G48V/  A71V/  V75I/  
                                                                                                                                   P81T: 1000-fold; A71V/  V75I/  
                                                                                                                                   P81T: 20- to 30-fold; L24V/  
                                                                                                                                   G48V/  A71V/  V75I/  P81T: 
                                                                                                                                   1000-fold                        (102, 103) 

  V 77 I        -             Protease Inhibitor        AG1343 (nelfinavir)    Y          Y -                -                         -                               - 

  P 81 T    CCT to ACT        Protease Inhibitor        SC-52151               Y          ? -                -                     A71V/  V75I/  P81T: 20- to 
                                                                                                                                   30-fold; L24V/  G48V/  A71V/  
                                                                                                                                   V75I/  P81T: 1000-fold           (102, 103) 

  I 82 T    ATC to ACC        Protease Inhibitor        A-77003                Y          ? -                -                     G48V/  I82T: 100-fold 
                                                                                                                                   (82T was derived from in 
                                                                                                                                   vitro passage of 82I)            (125) 

  V 82 A    GTC to GCC        Protease Inhibitor        A-77003                Y          ? -                -                     Rare; seen with M46F; 
                                                                                                                                   V32I appears first; 
                                                                                                                                   progression to V32I/  M46V 
                                                                                                                                   and V32I/  /  M46V/  A71V/  
                                                                                                                                   V82A occurs even in the 
                                                                                                                                   absence of drug                 (95, 116, 125) 

  V 82 A    GTC to GCC        Protease Inhibitor        ABT-538 (ritonavir)    N          Y 2               -                      In vivo, V82 occurs first, 
                                                                                                                                   often followed by changes 
                                                                                                                                   at I54, A71 and M36             (108) 

  V 82 A    GTC to GCC        Protease Inhibitor        BMS 186,318            Y          ? -            A-77003 (4)               A71T/  V82A: 15-fold            (122, 123) 

  V 82 A    GTC to GCC        Protease Inhibitor        MK-639 (L-735,524,
                                                         indinavir)            Y          Y -              -                       V32I/  M46L/  V82A: 3-fold; 
                                                                                                                                   V32I/  M46L/  A71V/  V82A: 
                                                                                                                                   14-fold                         (105) 

  V 82 A    GTC to GCC        Protease Inhibitor        P9941                  Y          ? 6-8            -                               -                       (126) 

  V 82 A    GTC to GCC        Protease Inhibitor        SC-52151               Y          ? -              -                       G48V/  V82A, G48V/  L63P/  
                                                                                                                                   V82A or I54T: 10- to 
                                                                                                                                   20-fold                         -

  V 82 A         -            Protease Inhibitor        SKF108922              Y          ?               -                                -                       -  

  V 82 A    GTC to GCC        Protease Inhibitor        XM323                  Y          ? -             -                        V82A/  M46L: 7-fold; V82A/  
                                                                                                                                   M46L/  L97V: 11-fold; L10F/  
                                                                                                                                   V82A: 2-fold; ; V82A/  
                                                                                                                                   L97V: 3-fold                   (101) 

  V 82 A    GTC to GCC        Protease Inhibitor        Ro 31-8959 
                                                        (saquinavir)           ?          Y -             -                        Follows G48V during 
                                                                                                                                   saquinavir therapy or 
                                                                                                                                   after a switch to nelfinavir  
                                                                                                                                   or indinavir.                  (127, 128, 129) 
  
  V 82 F    GTC to TTC        Protease Inhibitor        ABT-538 (ritonavir)    Y          Y -             -                        V82F/  I84V: 8- to 10-fold; 
                                                                                                                                   M46I/  L63P/  A71V/  V82F/  
                                                                                                                                   I84V: 27-fold                  (108) 

  V 82 F    GTC to TTC        Protease Inhibitor        MK-639 (L-735,524,
                                                         indinavir)            ?          Y -             -                                -                      (99) 

  V 82 F    GTC to TTC        Protease Inhibitor        XM323                  Y          ? -             -                        V82F/  I84V: 92-fold           (101)  

  V 82 I    GTC to ATC        Protease Inhibitor        A-77003                Y          ? -             -                        No resistance alone but 
                                                                                                                                   V32I and V82I are synergistic 
                                                                                                                                   mutations yielding 20-fold 
                                                                                                                                   enzyme resistance (82T was 
                                                                                                                                   derived from in vitro passage 
                                                                                                                                   of 82I)                        (96) 

  V 82 I    GTC to ATC        Protease Inhibitor        XM323                  Y          ? <2            -                               -                       (101) 

  V 82 S    GTC to TCC        Protease Inhibitor        ABT-538 (ritonavir)    N          Y 6             -                        In vivo, V82 occurs first, 
                                                                                                                                   often followed by changes 
                                                                                                                                   at I54, A71 and M36            (108) 

  V 82 T    GTC to ACC        Protease Inhibitor        ABT-538 (ritonavir)    N          Y 3             -                        In vivo, V82 occurs first, 
                                                                                                                                   often followed by changes 
                                                                                                                                   at I54, A71 and M36; V82T 
                                                                                                                                   has reduced replication 
                                                                                                                                   efficacy in natural 
                                                                                                                                   background                     (108) 

  V 82 T    GTC to ACC        Protease Inhibitor        MK-639 (L-735,524,
                                                         indinavir)            N          Y -             -                        M46I/  L63P/  V82T: 4-fold; 
                                                                                                                                   L10R/  M46I/  L63P/  V82T: 
                                                                                                                                   4-fold; L10R/  M46I/  L63P/  
                                                                                                                                   V82T/  I84V: 8-fold            (105) 

  V 82 T         -            Protease Inhibitor        SKF108842              Y          ? -             -                                -                      (130) 

  V 82 T         -            Protease Inhibitor        SKF108922              Y          ? -             -                                -                      -

  I 84 A    ATA to GCA        Protease Inhibitor        BILA 1906 BS           Y          ? -       BILA 2185 BS (200)             V32I/  A71V: 3-fold; V32I/  
                                                                                                                                   M46I,L/ A71V/  I84V: 5-fold; 
                                                                                                                                   V32I/ M46I,L/ A71V/ I84A:  
                                                                                                                                   520-fold.  32I/ 46L/ 71V/ 
                                                                                                                                   84A are functionally 
 m                                                                                                                                 impaired.  Associated Gag 
                                                                                                                                   mutations:  p1/p6 cleavage 
                                                                                                                                   site (L to F (CTT to TTT 
                                                                                                                                   at P1')                        (106, 109, 112, 113) 

  I 84 A    ATG to ATA        Protease Inhibitor        BILA 2011 (palinavir)  Y          ? -       Ro 31-8959 (400);              I84A is the most 
                                                                                                                                   common mutation                (112) 

  I 84 V    ATA to GTA        Protease Inhibitor        ABT-538 (ritonavir)    Y          Y -            -                         M46I/  L63P/  A71V/  
                                                                                                                                   V82F/  I84V: 27-fold; 
                                                                                                                                   V82F/  I84V: 8- to 
                                                                                                                                   10-fold; M46I/  L63P/  
                                                                                                                                   A71V/  V82F/  I84V: 
                                                                                                                                   27-fold                        (108) 

  I 84 V    ATA to GTA        Protease Inhibitor        AG1343 (nelfinavir)    -          ? -            -                         M46I/  L63P/  A71V/  
                                                                                                                                   I84V: 30-fold                  (110) 

  I 84 V    ATA to GTA        Protease Inhibitor        BILA 1906 BS           Y          ? -       BILA 2185 BS(200)              V32I/  A71V: 3-fold; 
                                                                                                                                   V32I/  M46I,L / A71V/  
                                                                                                                                   I84V: 5-fold; V32I/ M46I,
                                                                                                                                   L/ A71V/ I84A:  520-fold.  
                                                                                                                                   32I/ 46L/ 71V/ 84A are 
                                                                                                                                   functionally impaired.  
                                                                                                                                   Associated Gag mutations:  
                                                                                                                                   p1/p6 cleavage site (L 
                                                                                                                                   to F (CTT to TTT at P1')       (106, 109, 112, 113) 

  I 84 V    ATA to GTA        Protease Inhibitor        BILA 2185 BS           Y          ? -      BILA 1906 BS(360)               L10F/ L23I/ V32I/ M46I/ 
                                                                                                                                   I47V/ I54M/ A71V/ I84V:  
                                                                                                                                   1,500-fold.  Associated 
                                                                                                                                   Gag mutations:  p1/p6 
                                                                                                                                   cleavage site (L to F 
                                                                                                                                   (CTT to TTT at P1'); 
                                                                                                                                   p7/p1 cleavage site 
                                                                                                                                   (Q to R (CAG to CGG) at 
                                                                                                                                   P3', A to V (GCT to CTT) 
                                                                                                                                   at P2'.                        (106) 

  I 84 V    ATA to GTA        Protease Inhibitor        DMP 450                Y          ? -            -                                     -                  (97, 98) 

  I 84 V    ATA to CTA        Protease Inhibitor        MK-639 (L-735,524,
                                                         indinavir)            N          Y -            -                         G48V/  I84V/  L90M: 30-fold; 
                                                                                                                                   L10R/  M46I/  L63P/  V82T/  
                                                                                                                                   I84V: 8-fold                   (105) 

  I 84 V    ATA to GTA        Protease Inhibitor        Ro 31-8959 
                                                        (saquinavir)           Y          ? -            -                                     -              (95) 

  I 84 V    ATA to GTA        Protease Inhibitor        RPI-312                Y          ? 5            -                                     -              (131) 

  I 84 V         -            Protease Inhibitor        SKF108842              Y          ? -            -                                     -                - 

  I 84 V    ATA to GTA        Protease Inhibitor        VB 11,328              Y          ? -            -                         L10F/  I84V: 8-fold          -

  I 84 V    ATA to GTA        Protease Inhibitor        VX-478 (141W94)        Y          ? -            -                                     -                - 

  I 84 V    ATA to GTA        Protease Inhibitor        XM323                  Y          ? 12     P9941; not A-77003 
                                                                                                   or Ro 31-8959                  V82F/  I84V: 92-fold;L10F/  
                                                                                                                                  K45I/  I84V:50-fold         (95, 101) 

  I 84 V    ATA to GTA        Protease Inhibitor        MP-134                 Y          ? 10     MP-167(5) ABT-
                                                                                                   538(10) MK-639(8) 
                                                                                                   SC-52151(8) Ro31-895(2) 
                                                                                                   (IC90 data)                               -                (132) 

  N 88 D         -            Protease Inhibitor        AG1343 (nelfinavir)    Y          Y -           -                         D30N and N88D are most 
                                                                                                                                  common in vivo after 24 
                                                                                                                                  weeks of therapy; they 
                                                                                                                                  do not cause cross-
                                                                                                                                  resistance to other 
                                                                                                                                  protease inhibitors         (110) 

  N 88 D    AAT to GAT        Protease Inhibitor        SC-52151               Y          ? -           -                         N88D compensatory, 
                                                                                                                                  no resistance alone         (132) 

  N 88 S    AAT to AGT        Protease Inhibitor        SC-55389A              Y          ? 20    L735,524 (3); 
                                                                                                  not SC-52151                    N88S/L10F:  25              (104) 

  L 90 M    TTG to ATG        Protease Inhibitor        ABT-538 (ritonavir)    N          Y -           -                         82A/   54V/  I/   71V/   
                                                                                                                                  90L/  M: 7-fold             (108) 

  L 90 M    TTG to ATG        Protease Inhibitor        AG1343 (nelfinavir)    N          Y -           -                         Rare in patients            (110) 

  L 90 M    TTG to ATG        Protease Inhibitor        MK-639 (L-735,524,
                                                         indinavir)            ?          Y -           -                                   -                 (105) 

  L 90 M    TTG to ATG        Protease Inhibitor        Ro 31-8959 
                                                        (saquinavir)           Y          Y -           -                         G48V/  L90M: >100-fold 
                                                                                                                                  enzyme resistance; double 
                                                                                                                                  mutant rare in vivo; L90M 
                                                                                                                                  most common in vivo; 
                                                                                                                                  G48V/  I84V/  L90M: 
                                                                                                                                  30-fold                     (117) 

  L 97 V    TTA to GTA        Protease Inhibitor        XM323                  Y          ? -           -                         No resistance alone;
                                                                                                                                  V82A/L97V: 3-fold; 
                                                                                                                                  V82A/  M46L/  L97V: 
                                                                                                                                  11-fold                     (101)
Mutations in Envelope and Drug Resistance
Amino Acid    Codon            Class of Drug                    Compound      In         In       -Fold      Cross-resistance         comments                Refs
  Change     channge                                                         vitro      Vivo   -resistance        (-fold)

  R 22 A    AGG to AGA         Fusion/ Binding Inhibitor     RPR103611         Y          ?         -              -                     -                    (132)

  I 84 S    ATC to AGC         Fusion/ Binding Inhibitor     RPR103611         Y          ?         -              -                     -                    (132) 

  S 113 N   AGT to AAT         Fusion/  Binding Inhibitor    Dextran sulphate 
                                                                (DS)           Y          ?         -              -            S113N/  S134N/  K269E/  
                                                                                                                                Q278E/  N293D/  
                                                                                                                                N323S/  R387I: 250-fold; 
                                                                                                                                113 is in the V1 loop region (132, 133)

  S 134 N   AGC to AAC         Fusion/  Binding Inhibitor    Dextran sulphate 
                                                                (DS)           Y         ?          -              -            V2 loop region; S113N/  
                                                                                                                                S134N/  K269E/  
                                                                                                                                Q278E/  N293D/  N323S/  
                                                                                                                                R387I: 250-fold               (133, 134)

  F 145 L   TTC to TTA         Fusion/  Binding Inhibitor    JM-3100           Y         ?          -              -            Combination of mutations: 
                                                                                                                                2- to 100-fold                (135, 136) 

  N 188 K   AAT to AAA         Fusion/  Binding Inhibitor    Siamycin I        Y         ?          -              -            N188K/  G332E/  N351D/  
                                                                                                                                A550T/  N633D/  L762S: 
                                                                                                                                 9-fold                       (137)

  I 228 V   ATA to GTA         Fusion/  Binding Inhibitor    JM-2763           Y         ?          -              -            Combination of mutations          -

  K 269 E   AAA to GAA         Fusion/  Binding Inhibitor    Dextran sulphate 
                                                                (DS)           Y         ?          -              -            V3 loop region; S113N/  
                                                                                                                                S134N/  K269E/  
                                                                                                                                Q278E/  N293D/  N323S/  
                                                                                                                                R387I: 250-fold               (133, 134)

  N 270 S   AAT to AGT         Fusion/  Binding Inhibitor    JM-3100           Y         ?          -              -                      -                      - 

  R 272 T   AGA to ACA Fusion/  Binding Inhibitor            JM-3100           Y         ?          -              -                      -                      -                       

  S 274 R   AGT to AGA Fusion/  Binding Inhibitor            JM-2763           Y         ?          -              -            Combination of mutations: 
                                                                                                                                95- to 792-fold                (135, 136) 

  S 274 R   AGT to AGA Fusion/  Binding Inhibitor            JM-3100           Y         ?    DS (> 7 to 6,667)    -                

  Q 278 H   CAG to CAT Fusion/  Binding Inhibitor            Dextran sulphate 
                                                             (DS)              Y         ?          -              -            V3 loop region; S113N/  
                                                                                                                                S134N/  K269E/  
                                                                                                                                Q 278E/   N293D/  N323S/  
                                                                                                                                R387I: 250-fold                (133, 134)

  Q 278 H   CAG to CAT Fusion/  Binding Inhibitor            JM-2763           Y         ?          -              -                     -

  Q 278 H   CAG to CAC Fusion/  Binding Inhibitor            JM-3100           Y         ?          -              -                     - 

  I 288 V   ATA to GTA Fusion/  Binding Inhibitor            JM-3100           Y         ?          -              -                     - 

  N 293 D   AAT to GAT Fusion/  Binding Inhibitor            Dextran sulphate 
                                                             (DS)              Y         ?          -              -           V3 loop region; S113N/  
                                                                                                                               S134N/  K269E/  Q278E/  
                                                                                                                               N293D/  N323S/  R387I: 
                                                                                                                               250-fold                       (133, 134) 

  N 293 H  AAT to CAT Fusion/  Binding Inhibitor             JM-3100           Y         ?          -               -                   - 

  A 297 T  GCA to ACA Fusion/  Binding Inhibitor             JM-2763           Y         ?          -               -                   -                        -

  A 297 T  GCA to ACA Fusion/  Binding Inhibitor             JM-3100           Y         ?          -               -                   -                        - 

  N 323 S  AAT to AGT Fusion/  Binding Inhibitor             Dextran sulphate 
                                                             (DS)              Y         ?          -               -          C3 region; S113N/  
                                                                                                                               S134N/  K269E/  Q278E/  
                                                                                                                               N293D/  N323S/  R387I: 
                                                                                                                               250-fold                       (133, 134)

  G 332 E  GGA to GAA Fusion/  Binding Inhibitor             Siamycin I        Y         ?          -               -          N188K/  G332E/  N351D/  
                                                                                                                               A550T/  N633D/  L762S: 
                                                                                                                               9-fold                         (137) 

  N 351 D  AAT to GAT Fusion/  Binding Inhibitor             Siamycin I        Y         ?          -               -          N188K/  G332E/  N351D/  
                                                                                                                               A550T/  N633D/  L762S: 
                                                                                                                               9-fold                         (137) 

  P 385 L  CCA to CTA Fusion/  Binding Inhibitor             JM-2763           Y         ?          -               -                   -

  P 385 L  CCA to CTA Fusion/  Binding Inhibitor             JM-3100           Y         ?          -               -                   -

  R 387 I  AGA to ACA Fusion/  Binding Inhibitor            Dextran sulphate 
                                                            (DS)               Y         ?          -               -          CD4 binding region; 
                                                                                                                               S113N/  S134N/  K269E/  
                                                                                                                               Q278E/  N293D/  N323S/  
                                                                                                                               R387I: 250-fold               (133, 134)

  Q 410 E  CAA to GAA Fusion/  Binding Inhibitor            JM-3100            Y         ?          -               -                   - 

  S 433 P  TCC to CCC Fusion/  Binding Inhibitor            JM-3100            Y         ?          -               -                   - 

  V 457 I  GTA to ATA Fusion/  Binding Inhibitor            JM-3100            Y         ?          -               -                   -

  A 550 T  GCC to ACC Fusion/  Binding Inhibitor            Siamycin I         Y         ?          -               -          N188K/  G332E/  N351D/  
                                                                                                                               A550T/  N633D/  L762S: 
                                                                                                                               9-fold                         (137) 

  N 633 D  AAT to GAT Fusion/  Binding Inhibitor            Siamycin I         Y         ?          -               -          N188K/  G332E/  N351D/  
                                                                                                                               A550T/  N633D/  L762S: 
                                                                                                                               9-fold                         (137) 

  L 762 S  TTG to TCG Fusion/  Binding Inhibitor            Siamycin I         Y         ?          -               -          N188K/  G332E/  N351D/  
                                                                                                                               A550T/  N633D/  L762S: 
                                                                                                                               9-fold                         (137) 

Mutations in SIV Reverse Transccriptase and Drug Resistance
Amino Acid    Codon            Class of Drug                    Compound      In         In       -Fold      Cross-resistance                 comments                        Refs
  Change     channge                                                         vitro      Vivo   -resistance        (-fold)

  K 65 R    AAA to AGA        SIV Nucleoside RT Inhibitor        PMPA          ?          Y         5        3TC (80); ddI; ddC; d4T;  K65R appears first, followed by       (138, 139, 140)
                                                                                                                     PMEA              N69S and I118V. Observed changes 
                                                                                                                                       at N69S and I118V do not result 
                                                                                                                                       in increased resistance.

  Q 151 M   CAG to ATG        SIV Nucleoside RT Inhibitor         AZT          ?          Y        >100       ddI; ddC; d4T; 3TC                 -                           (141)

  M 184 V   ATG to GTG        SIV Nucleoside RT Inhibitor       (-)-FTC        Y          ?         -              -                             -                           (82)
Mutations in FIV Reverse Transcriptase and Drug Resistance
Amino Acid    Codon            Class of Drug                    Compound      In         In       -Fold       Cross-resistance                comments                         Refs
  Change     channge                                                         vitro      Vivo   -resistance        (-fold)

  L 74  I   TTA to ATA        HIV-1 Specific RTI                 HBY 097       Y          ?         -                -                          -                             (16)

  D 3   H   GAT to CAT        FIV Nucleoside RT Inhibitor          ddC         Y          ?         4            ddI; PFA                       -                             (142, 143)
  
  V 47  I   GTA to ATA        FIV Nucleoside RT Inhibitor          d4T         Y          ?        4-6      PFA (>50); AZT; ddI; PMEA           -                             (144)

  P 156 S   CCA to TCA        FIV Nucleoside RT Inhibitor          3TC         Y          ?         7       AZT (4), AZT + 3TC (6)              -                             (145)

  M 183 T   ATG to ACG        FIV Nucleoside RT Inhibitor        (-)-FTC       Y          ?        10             ddC                   Corresponds to 184 in HIV; M183V      (146)
                                                                                                                                        recombinant displays 10-fold 
                                                                                                                                        resistance to 3TC or (-)-FTC.
Abbreviations

Amino acids

     A                       alanine
     C                       cysteine
     D                       aspartate
     E                       glutamate
     F                       phenyalanine
     G                       glycine
     H                       histidine
     I                       isoleucine
     K                       lysine
     L                       leucine
     M                       methionine
     N                       asparagine
     P                       proline
     Q                       glutamine
     R                       arginine
     S                       serine
     T                       threonine
     V                       valine
     W                       tryptophan
     Y                       tyrosine
Compounds
     1592U89             (1S,4R)-4-[2-amino-6-cyclopropyl-amino)-9H-purin-9-yl]-2-cyclopentene-1-methanol succinate (a carbovir analogue, Glaxo Wellcome)
     3TC                 (-)--L-2',3'-dideoxy-3'-thiacytidine (Glaxo Wellcome)
     1737                Tetrahydronapthalene lignan derivative
     -APA R18893        -nitro-anilino-phenylacetamide
     A-77003, A-75925    C2 symmetry-based protease inhibitors (Abbott Laboratories)
        and A-80987
     AAP-BHAP            bisheteroarylpiperazine analogue (Pharmacia & Upjohn)
     ABT-538             C2 symmetry-based protease inhibitor (Abbott Laboratories)
     AZdU                3'-azido-2',3'-dideoxyuridine
     AZT                 3'-azido-3'-deoxythymidine (Glaxo Wellcome)
     AZT-p-ddI           3'-azido-3'-deoxythymidilyl-(5',5')-2',3'-dideoxyinosinic acid (Ivax)
     BHAP                bisheteroarylpiperazine
     BILA 1906           N-1S-[[[3-[2S-(1,1-dimethylethyl)amino]carbonyl-4R-]3-pyridinylmethyl)thio]-1-piperidinyl]-2R-hydroxy-1S-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl}-2-quinolinecarboxamide (Bio-Mega/Boehringer Ingelheim)
     BILA 2185           N-(1,1-dimethylethyl)-1-[2S-[[2-2,6-dimethyphenoxy)-1-oxoethyl]amino]-2R-hydroxy-4-phenylbutyl]4R-pyridinylthio)-2-piperidine-carboxamide (Bio-Mega/Boehringer Ingelheim)
     BM+51.0836          thiazolo-isoindolinone derivative
     BMS 186,318         aminodiol derivative HIV-1 protease inhibitor (Bristol-Myers Squibb)
     d4API               9-[2,5-dihydro-5-(phosphonomethoxy)-2-furanel]adenine (Gilead Sciences)
     d4C                 2',3'-didehydro-2',3'-dideoxycytidine
     d4T                 2',3'-didehydro-3'-deoxythymidine (Bristol-Myers Squibb)
     ddC                 2',3'-dideoxycytidine (Roche)
     ddI                 2',3'-dideoxyinosine (Bristol-Myers Squibb)
     DMP 266             a 1,4-dihydro-2H-3,1-benzoxazin-2-one
     DMP 450             [4R-(4-,5-,6-,7-)]-hexahydro-5,6-bis(hydroxy)-1,3-bis(3-amino)phenyl]methyl)-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one-bismesylate (Avid Therapeutics)
     DXG                 (-)--D-dioxolane-guanosine
     EBU-dM              5-ethyl-1-ethoxymethyl-6-(3,5-dimethylbenzyl)uracil
     E-EBU               5-ethyl-1-ethoxymethyl-6-benzyluracil
     DS                  dextran sulphate
     E-EPSeU             1-(ethoxymethyl)-(6-phenylselenyl)-5-ethyluracil
     E-EPU               1-(ethoxymethyl)-(6-phenyl-thio)-5-ethyluracil
     F-ddA               2'-fluoro-2',3'-dideoxyadenosine
     (-)-FTC             (-)--L-2',3'-dideoxy-5-fluoro-3'-thiacytidine (Triangle Pharmaceuticals)
     HBY 097             (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthio-methyl)-3,4-dihydroquinoxalin-2(1H)-thione
     HEPT                1-[(2-hydroxyethoxy)methyl]6-(phenylthio)thymine
     JM2763              1,1'-(1,3-propanediyl)-bis-1,4,8,11-tetraazacyclo-tetradecane (Johnson Matthey)
     JM3100              1,1'-[1,4-phenylenebis-(methylene)]bis-(1,4,8,11-tetra\-azacyclo\-tetra\-decane) octa\-hydro\-chloride dihydrate (Johnson Matthey)
     KNI-272             (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid-containing tripeptide
     L-697,593           5-ethyl-6-methyl-3-(2-phthalimido-ethyl)pyridin-2(1H)-one
     L-697,661           3-[(-4,7-dichloro-1,3-benzoxazol-2-yl)methyl]amino-5-ethyl-6-methylpyridin-2(1H)-one
     L-FDDC              (-)--L-5-fluoro-2',3'-dideoxy-cytidine
     L-FDOC              (-)--L-5-fluoro-dioxolane cytosine
     MK-639              hydroxy-aminopentane amide HIV-1 protease inhibitor (Merck \              Co)
     MKC442              6-benzyl-1-ethoxymethyl-5-isopropyluracil (I-EBU, Triangle Pharmaceuticals/Mitsubishi)
     MP-134              C2 symmetry-based protease inhibitor
     MP-167              C2 symmetry-based protease inhibitor	
     nevirapine          11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyridol[3,2-b:2',3'-e] diazepin-6-one (Boehringer Ingelheim)
     NNRTI               non-nucleoside reverse transcriptase inhibitor
     NSC648400           1-benzyloxymethyl-5-ethyl-6-(-pyridylthio)uracil (E-BPTU)
     P9941               [2-pyridylacetyl-IIePheAla-y(CHOH)]\sub2 (Dupont Merck)
     PFA                 phosphonoformate (foscarnet, Astra)
     PMEA                9-(2 phosphonylmethoxyethyl)adenine (Gilead Sciences)
     PMPA                (R)-9-(2-phosphonyl-methoxypropyl)adenine (Gilead Sciences)
     Ro 31-8959          hydroxyethylamine derivative HIV-1 protease inhibitor (Roche)
     RPI-312             1-[(3S)-3-(n--benzyloxycarbonyl)-l-asparginyl)-amino-2-hydroxy-4-phenyl-butyryl]-n-tert-butyl-l-proline amide (peptidyl protease inhibitor)
     RPR103611
     RT                  reverse transcriptase
     S-2720              6-chloro-3,3-dimethyl-4-(isopropenyl-oxycarbonyl)-3,4-dihydro-quinoxalin-2(1H)thione
     SC-52151            hydroxyethylurea isostere protease inhibitor (Searle)
     SC-55389A           hydroxyethyl-urea isostere protease inhibitor (Searle)
     TIBO R82150         (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione (Janssen)
     TIBO 82913          (+)-(5S)-4,5,6,7,-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)-imidazo-[4,5,1-jk]-[1,4]benzo-diazepin-2(1it\ H)-thione (Janssen)
     TSAO-m$^3$T         [2',5'-bis-O-(tert-butyl-dimethylsilyl)-3'-spiro-5'-(4'-amino-1',2'-oxathiole-2',2'-dioxide)]--D-pentofuranosyl-N$^3$-methylthymine
     U-90152             1-[3-[(1-methylethyl)-amino]-2-pyridinyl]-4-[[5-[(methylsulphonyl)-amino]-lH-indol-2yl]carbonyl]-piperazine
     U-95133             (Alkylamino)piperidine bis(heteroaryl)piperazine analog
     U-104489            (Alkylamino)piperidine bis(heteroaryl)piperazine analog
     UC-040              thiocarboxanilide derivative (Uniroyal Chemical Co)
     UC                  thiocarboxanilide derivatives (Uniroyal Chemical Co)
     UC-781              N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furan-carbothioamide
     UC-82               N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-thiophene-carbothioamide
     VB 11,328           hydroxyethyl-sulphonamide protease inhibitor (Vertex Pharmaceuticals)
     VX-478              hydroxyethylsulphonamide protease inhibitor (Vertex Pharmaceuticals)
     XM 323              cyclic urea protease inhibitor (Dupont Merck)
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96. Kaplan AH, Michael SF, Wehbie RS, Knigge MF, Paul DA, Everitt L, Kempf DJ, Norbeck DW, Erickson JW and Swanstrom R. Selection of multiple human immunodeficiency virus type 1 variants that encode viral proteases with decreased sensitivity to an inhibitor of the viral protease. Proceedings of the National Academy of Sciences, USA 1994; 91:5597-5601.

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102. Potts KE, Smidt ML, Stallings WC, Clare M, Pillay D, Richman DD and Bryant ML. In vitro selection and characterization of human immunodeficiency virus type 1 (HIV-1) variants with decreased sensitivity to hydroxyethylurea isostere containing protease inhibitors. Third International Workshop on HIV Drug Resistance, Kauai, Hawaii, USA, 2-5 August, 1994. Abstract 4.

103. Pillay D, Smidt ML, Potts KE, Bryant ML and Richman DD. In vitro selection of protease inhibitors resistant human immunodeficiency virus type 1 (HIV-1) strains. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, FL, USA, 2-5 October, 1996. Abstract 7.

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105. Condra JH, Holder DJ, Schleif WA, Blahy OM, Danovich RM, Gabryelski LJ, Graham DJ, Laird D, Quintero JC, Rhodes A, Robbins HL, Roth E, Shivaprakash M, Yang T, Chodakewitz JA, Deutsch PJ, Leavitt RY, Massari FE, Mellors JW, Squires KE, Steigbigel RT, Teppler H and Emini EA. Genetic correlates of in vivo viral resistance to the HIV-1 protease indinavir. Journal of Virology 1996; 70(12): 8270-8276.

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108. Molla A, Korneyeva M, Gao Q, Vasavanonda S, Schipper PJ, Mo HM, Markowitz M, Chernyavskiy T, Niu P, Lyons N, Hsu A, Granneman R, Ho DD, Boucher CAB, Leonard JM, Norbeck DW and Kempf DJ. Ordered accumulation for mutation in HIV protease confers resistance to ritonavir. Nature Medicine 1996; 2(7):760-766.

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110. Patick AK, Mo H, Markowitz M, Appelt K, Wu B, Musick L, Kalish V, Kaldor S, Reich S, Ho D and Webber S. Antiviral and resistance studies of AG1343, an orally bioavailable inhibitor of human immunodeficiency virus protease. Antimicrobial Agents and Chemotherapy 1996; 40(2):292-297; 40(6):1575 (erratum).

111. Patick AK, Kuritzkes D, Johnson VA, Shugarts D, Bakhtiari M, Potts KE, Farnsworth A, Anderson R, Koel JL, Hazelwood JD, Nail CD, Duran M, Markowitz M, Ho D, Richman D. Genotypic and phenotypic analyses of HIV-1 variants isolated from patients treated with nelfinavir and other HIV-1 protease inhibitors. 6th International Workshop on HIV Drug Resistance, 25-28 June 1997; St. Petersburg, USA: Abstract 18.

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126. Otto MJ, Garber S, Winslow DL, Reid CD, Aldrich P, Jadhav PK, Patterson CE, Hodge CN and Cheng YS. In vitro isolation and identification of human immunodeficiency virus (HIV) variants with reduced sensitivity to C-2 symmetrical inhibitors of HIV type 1 protease. Proceedings of the National Academy of Sciences, USA 1993; 90(16):7543-7.

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142. Medlin HK, Zhu Y, Remington KM, Phillips TR, North TW. Selection and characterization of a mutant of feline immunodeficiency virus resistant to 2',3'-dideoxycytidine. Antimicrob Agents Chemother 1996; 40:953-957.

143. Zhu Y-Q, Remington KM, North TW. Mutants of feline immunodeficiency resistance to 2',3'-dideoxy-2',3'-didehydrothymidine. Antimicrob Agents Chemother 1996; 40:1983-1987.

144. Smith RA, Reminton KM, Lloyd RM Jr., Schinazi RF, North TW. A novel point mutation at position 156 of reverse transcriptase from feline immunodeficiency virus confers resistance to the combination of (-)--L-2',3'-dideoxy-3'-thiacytidine and 3'-azido-3'-deoxythymidine. J Virol 1997; submitted for publication.

145. Smith R, Remington K, Lloyd R, Schinazi R, North T. Mutants of feline immunodeficiency virus resistant to FTC and 3TC. Third International Feline Retrovirus Research Symposium, 1996, Ft. Collins, CO: Abstract 41.

146. Smith RA, Remington K, Lloyd RM Jr, Schinazi RF, North TW. A novel met to thr mutation in the YMDD motif of reverse transcriptase from feline immunodeficiency virus confers resistance to oxathiolane nucleosides. J Virol 1997; 71:2357-2362.

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