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A Comparison of HIV-1 Group M and Group O Functional and Immunogenic Domains in the Gag p24 Protein and the C2V3 Region of the Envelope Protein

Bette Korber1 Ibtissam Loussert-Ajakai2 John Blouin1 and Sentob Saragosti3

1T10 Los Alamos National Lab, Los Alamos, NM 87545, USA
2Laboratoire de Virologie, Hopital Bichat-Claude Bernard, 75877 Paris cedex 18, France
3I.C.G.M. Cochin Hospital 75014 Paris, France

The major focus of the sequencing effort of group O viruses to date has been on the p24 Gag and C2V3 gp120 env regions. A total of 42 p24 sequences and 45 C2V3 sequences derived from group O isolates have either been published or provided to the Los Alamos database prior to publication. The primary goals of this review are:
i. to provide a brief summary of the accumulating knowledge concerning HIV-1 group O serology and epidemiology;
ii. to outline differences and similarities group M and O HIV-1 viruses in the the heavily sequenced 24 Gag and C2V3 gp120 regions, with an emphasis on well-defined functional domains and
iii. to provide an alignment of the region of gp41 that harbors an immunodominant domain important for diagnostics. Only published sequences will be shown in alignments (Table 1), but complete sets of unpublished and published sequences currently in the database were used to generate the consensus sequences for group O sequences shown in the accompanying alignment figures.

Introduction

Group O characterization: After the discovery of the virus ANT70 by a group in Belgium [DeLeys 90],10 and the further characterization of this isolate, as well as the MVP5180 and VAU isolates (VAU was isolated from a French woman with no ties to Africa) in 1994 [vanden-Haesevelde 94,Gurtler 94,Charneau 94],64;25;2 it became clear that a new group of viruses, distinct from the HIV-1 Major (M) group, was present in the human population. This group was named the HIV-1 group O for "Outlier" group. The group O, group M, and chimpanzee viruses are genetically quite distant from one another, but these three groups share a distinct lineage relative to other primate lentiviruses (Figure 1). It is notable that four years separated the publications concerning the first and second of these outlier viruses.

Since the isolation of these first highly unusual HIV-1 strains, a second Caucasian patient was found in France [Cohen 95],7 and a quite large number of viruses of this group have been isolated, especially from Cameroonian patients [Loussert-Ajakai 95].37 The main method for identifying group O viral infections is obtaining a paradoxical pattern of positive and negative serological reactivity using a set of HIV-1 enzyme-linked immunosorbent assay detection kits [Simon 94].57 A variety of Western blot reactivity patterns can occur with group O serum. Phenotypic differences between group O and M have also been detected. HIV-1 group O isolates exhibited a high level of resistance to non-nucleoside inhibitors [Descamps 95],12 and Descamps et al., manuscript in preparation), and group M, but not group O viruses, require the incorporation of cyclophilin A for the production of infectious virions [Braaten 96].1

Sequence analysis of env and gag regions of the first ten group O isolates revealed a peculiar feature of this group relative to group M isolates - limited phylogenetic clustering patterns with only a few sequences grouping into clades in both the p24 and C2V3 regions [Loussert-Ajakai 95].37 This is in marked contrast to the clear phylogenetic subtypes that emerge in phylogenetic analysis of the group M sequences. The original ten group O isolates are a subset of the 40-plus sequences currently stored in the Los Alamos database, and the observation of limited subtype structure among O group sequences[Loussert-Ajakai 95]37 is consistent with the additional data now available. The nucleotide sequences of the envelope gene fragments spanning the C2V3 region have been shown to be particularly phylogenetically informative [Leitner 96a]35 and to give accurate phylogenetic reconstructions of the M group clades using a variety of phylogenetic tree reconstruction methods [Korber 94,Leitner 96b].33;36 Despite this, very little clear phylogenetic structure can be resolved among the group O sequences, in either the region encoding C2V3 of envelope or p24 (analysis was conducted on all sequences available, data not shown). This lack of clearly defined phylogenetic branching patterns in group O could be due to one or a combination of the following three possibilities.
i. An artifact of sample size; accumulation of sequences from new isolates should help us to evaluate this hypothesis.
ii. The length of the sequences in the regions studied not being adequate to reveal phylogenetic associations in group O, although the subtypes are clearly distinguishable using these regions for group M.
iii. A distinct evolutionary history of the two groups, such that the epidemiological history and biology of group M virus yields geographically and phylogenetically distinct subtypes, whereas the group O isolates had a different natural history and simply radiated out from an original ancestral virus [Loussert-Ajakai 95].37 Interestingly, the first case of AIDS documented in Europe was a Norwegian sailor infected with a group O virus [Jonassen 97]32. He developed clinical manifestations of HIV infection in 1966, his wife in 1967, and daughter in 1969. All of them died in the 1970s [Froland 88]19.

Figure 1. A maximum likelihood tree illustrating the phylogenetic relationship between HIV-1 Group M, HIV-1 Group O, and chimpanzee viral sequences relative to other primate lentiviral sequences. This tree was created using PHYLIP DNAML 4.0. (J. Felsenstein, http://evolution\ab.genetics\ab.washington\ab.edu\ab/phylip), with a series of optimization tests performed to select the parameters of three rate categories (1 3 and 9 with frequencies of 0.25, 0.50 and 0.25, respectively) and a transition/transversion ratio of 1.3. The sequences used were the group M isolates subtypes A-G from the alignments in Figure 1 and 2; the full length envelope group O sequences (MVP50, ANT70, VAU); AGMTYO; HIV-2/SIV sequences BEN, D205, ROD, and SIVMNE and SIVSTM; and the chimpanzee viral sequences CPZGAB and CPZANT70. There were 1866 positions spanning gp160 included in the alignment after gapstripping. The taxa included in this comparison were aligned using a Hidden Markov Model (HMMER version 1.8 http:\ab//genome\ab.wustl\ab.edu/eddy\ab/HMMER\ab/main\ab.html}) [Myers 96,Eddy 95].43;13 The clade including the HIV-1 and chimpanzee viral sequences is also seen in 100/100 PHYLIP Neighbor Joining bootstrap replicates using a p24 region alignment. The chimpanzee sequences are sometimes linked in phylogenetic reconstructions, and other times are separated as is seen is this tree, with CPZGAB branching with the Group M isolates. The associations of the CPZ sequences depend upon the region of HIV-1 used to construct the tree (data not shown), and may reflect an early recombination event.

Geographical distribution: Group O isolates can be identified genetically or serologically. Group O isolates that have been genetically characterized originated in Norway [Jonassen 97],32 Belgium [DeLeys 90],10 France [Loussert-Ajakai 95],37 Germany [Hampl 95],26 Spain [Soriano 96],59 the United States [Rayfield 96],52 and, of course, Cameroon [Mauclere 97],41. Group O infections have been serologically characterized using sera originating in Cameroon and Gabon [Nkengasong 94],46 Equatorial Guinea [Hunt 96],28 Benin [Heyndrickx 96],27 and Kenya [Songok 96].58 In Cameroon, 7 group O infections were found among 332 sera tested (7/332), Gabon (2/213), Niger (5/1459), Nigeria (2/183), Senegal (1/1283), Chad (2/619), and Togo (1/670) [Peeters 97]49.

Cameroon has the highest known prevalence of group O infections. Epidemiology studies conducted in Cameroon indicate a prevalence of HIV-1 group O infection of 2% [Zekeng 94],65 and more recently, Mauclere et al. found prevalence of group O infections ranging from 1% in the northern part of the country, to 6.3% in the capitol; overall, 82 group O infections were found among 2458 HIV-1 samples [Mauclere 97].41 Among the 19 cases found in France, 17 were from patients originally from Cameroon, and of the two French Caucasian patients, one acknowledged having a Cameroonian sexual partner.

The algorithm developed to characterize group O viruses [Gurtler 96, Mauclere 97]24;41 has proven to be very effective. The development of new tools (for example, new peptides used in combination, LIA (Innogenetics) has allowed the easy serological characterization of group O isolates and the screening of large numbers of samples. Alternatively, group O infections can be detected by genetic methods, including PCR using group O and group M specific primers and restriction analysis of a POL fragment[Janssens 95,Heyndrickx 96].67;68;

The gag capsid (p24) protein


Background: The gag precursor poly-protein is initially incorporated into the budding viral particle, and is cleaved into the structural proteins of the mature virion by viral protease. The Gag precursor self-assembles into virion like proteins even in the absence of other viral proteins; it binds and packages viral RNA, and interacts with other viral proteins and envelope lipid to assemble the viral particles (for a review of Gag proteins, see [Gorelick & Henderson 94]. 22) The capsid antigen (CA) is the p24 protein of HIV-1, and forms the viral core.

The major homology region: The major homology region (MHR) is a part of the capsid protein which is well conserved among lentiviruses of primates, cats, and ungulates [Ottenken 92,Matsuo 92,Grund 94,Gorelick 94]. 47;40;23;22 This region plays a role in viral particle formation and is critical for viral replication. Four highly conserved positions among all retroviruses (human, simian, caprine, bovine, equine, and feline) [Mammano 94]39 are indicated by asterisks in the alignment shown in Figure 2, on the following two pages, and in the consensus MHR alignment (Figure 3). The first three of these positions are critical for HIV-1 particle production, and mutations in forth residue result in aberrant particle size and inappropriate viral cores [Mammano 94].39

The MHR is conserved among group O viral sequences, as expected, although slightly greater variation is apparent in the group O viruses than the M group viruses. The conserved arginine (R) is present in most retroviral sequences, but it is substituted with a serine (S) in two of the group O viral sequences (data not shown).

Figure 2. Alignment of the p24 protein. The group M consensus is based on the sequences shown, so each M subtype is equally represented, by two sequences. Upper case letters signify invariant amino acids, and lower case indicate the most common amino acid in a position with some variation. The group O consensus was constructed from all 42 sequences available, but only those published or released are shown. A dash indicates identity with the consensus, a period indicates a insertion made to maintain the alignment. Hu Epitope 1 and 2 are immunodominant linear B cell epitopes that have been identified in group M [Janvier 96],30 and are highly conserved between groups M and O. The MHR is the major homology region and the Cypa region is the cyclophilin A binding domain. Asterisks in the MHR mark highly conserved, functionally important residues, and in the CyPa region mark prolines critical for group M viral replication. The plus signs over the O~group consensus indicate prolines that are common among O group sequences, but not perfectly conserved.


CONSENSUS-M  PIVQNlQGQmvHQaisPRTLNAWVKViEEKaFSPEvIPMFsALSEGATPQDLNtMLNtVGGHQAAMQmLKdTINEEAAEW
DRlHPvhAGPipPGQmRePRGSDIAGTTSTlQEQI?WMT.    118
A_KE_K88      -----A----I--TL--------------------------------------M---I----------------------------------------------------P----G---.    119
A_ZR_VI57     -----A----I---V--------------------------------------M---I----------------------------------------------------P----G---.    119
B_DE_D31      -------------P------------V-------------------------------------------E--------------------A-----------------------G---.    119
B_FR_LAI      -----I--------------------V-------------------------------------------E-----------V--------A-----------------------G---.    119
C_SO_SM145    -----------------------------------I----T---------------------------------------------Q---VA-----D-----------------A---.    119
C_ZR_VI313    -------------PM-------------------------T---------------------------------------------Q---VA---I-------------------A---.    119
D_ZR_ELI      ----------------------------------------------------------------------E--------------------A-----------------------A---.    119
D_ZR_Z2Z6     ----------------------------------------------------------------------E--------------------A-----------------------A---.    119
F_BR_BZ162    -------------S-----------------------------------------------------------------------AQ--------I-------------------Q---.    119
F_ZR_VI174    --------------------------------------------------------------------------------------Q--------I-------------------Q---.    119
G_GA_LBV217   -----A-------P------------V-------------------------------------------------------I--QQ--------I-D-----------------R---.    119
G_ZR_VI191    -----A-------PLT--------------N---------------------------------------------------I--PQ--------I-------------------R---.    119
H_GA_VI525    -----A--------------------V--------------------------A-------------I-----------------------------------------------A---.    119
H_ZR_VI557    -----A---P----------------V--------------------------A---I------------------------V--------------------------------A---.    119

CONSENSUS-O PIV?NAQGQM?HQalsprtlnaWvkAVeEkAFnpeiIPMFMALSEGaipYDiNtMLNaIGgHQGAlQVLKeVINeeAadWDRtHpppvGplpPgqiRePtGSDIAgTTstqqEqvhWtt. 117 O_CM.ANT70 ---S------V---I---------------------------------S----------------------------VE-----------------------------------I----. 119 O_DE.HAM112 -------------------------G-----------------------------------V--Y-S-------F---------------------D------. 103 O_CM.MVP51 ---T------V---I--------------------------------V------------------------------E-------AM--------------------------II---. 119 O_CM.CA9 --------------------------------------------------A--------------------------------. 83 O_FR.BCF01 -I-----------------------------------------------------------D---------T--------------------------------I-. 106 O_FR.BCF02 PI--------------------------------V------------E----------------LE--------I---------D-------------------V-. 106 O_FR.BCF03 P---------------------------------------------------------------S---------I-------------------------------. 106 O_FR.BCF06 ----------------------------------V------------------------------E-------AM-------L-D----------------IN-I-. 106 O_FR.BCF07 -----------------------------------S-----------------------------E------I-----------D---------------------. 106 O_FR.BCF08 P-------------------------------------------------------------------------I-----------------------------I-. 106 O_FR.BCF11 -----------I----------------------V------------------------------------------------------------------I--I-. 106 O_FR.RUD -I-----YV-------------------------V-----V--------------------D-------A--QQA--------------------------IL---. 106 O_FR.LT -------------------------------------------------------------D------------------------------------------I-. 106 O_FR.NF1 PI---------------------------------S-----------------------------E------V-----------D-------------------M-. 106 O_FR.VAU P---------------------------------T---V----------------------D-----------V-----------------------L---I----. 106

CONSENSUS-cpz P????A?G???HQ???PRTLNAWVK?VEEK?F?PEVIPMFSALSEGA?P?D?NTMLNAVG?HQGAMQVLKEVINEEAAEWDRLHPTHAGP???GQLREP?GSDIAGTTST?QEQ??W??? 92 CPZGAB -LVQN-Q-QMV--AIS---------V----A-S--------------L-Q-V--------G-----------------------------IAP------R----------L---IG-TT. 119 CPZANT -IIVD-G-IAR--PLT---------C----N-N--------------T-H-L--------D-----------------------------VQA------T----------V---MQ-MST 120

CONSENSUS-M ..sNPpiPVG?IYKRWIIlGLNKIVRMYSPvSILDirQGPKEPFRDYVDRFfKtLRAEQAtQeVKnWMTdTLLVQNANPDCKtILkALGpgAtlEEMMTACQGVGGPgHKArVL 229 A_KE_K88 ..--------D------------------------VK----------------------------G---E------------S--R---T------------------------ 231 A_ZR_VI57 ..--------D-------------------------K----------------V------S-D------E------------S--R---T-----------------S------ 231 B_DE_D31 ..N-------E-------------------T--------------------Y-----------------E--------------------A----------------------- 231 B_FR_LAI ..N-------E-------------------T--------------------Y--------S--------E--------------------A----------------------- 231 C_SO_SM145 ..--------D-------------------------K-------------------------D----------------------R------S--------------A------ 231 C_ZR_VI313 ..N-------D-------------------------K-------------------------D----------------------R------S--------------------- 231 D_ZR_ELI ..--------E-------V--------------------------------Y--------S-D------E--------------------Q----------------S------ 231 D_ZR_Z2Z6 ..--------E----------------------------------------Y--------S----G---E--------------------Q----------------S------ 231 F_BR_BZ162 ..----V---E------------------------------------------------------G------------------------------------------------ 231 F_ZR_VI174 ..N---V---E------------------------------------------------------G------------------------------------------------ 231 G_GA_LBV217 ..--------E---------------------------------------------------D--------------------------------------------S------ 231 G_ZR_VI191 ..--------D------------------------------------------------------G-------------------R---------------------------- 231 H_GA_VI525 ..G--A----D-------------------------K-------------------------D-------------------N------T--SI-------------S------ 231 H_ZR_VI557 ..--------D------------------------------------------A-----------G-------------------R---Q--SI-----------------K-- 231

CONSENSUS-O .r?nnpiPvGDIYrkWIVlgLnkmVkmyspvsiLDIkQGPKePFrDYvDrfyKTLRAEQAtQEVKNWMTETLLVQNaNPDCKQILKsLGPgAtLEEMMVACQGVGGPTHKa??L 226 O_CM.ANT70 .-P-Q----------------------------------------------------------------------------------------------------------RV- 232 O_DE.HAM112 .-A-Q-V---------------------HS 132 O_CM.MVP51 .-GA-S------------------------------R---------------------------------------S---------A---E--------------------KI- 232 O_CM.CA9 .-A-H------------------L------------K-------K------------ 139 O_FR.BCF01 .-P------------------------- 133 O_FR.BCF02 .-NP---------W----F----L---- 133 O_FR.BCF03 .-P-Q----------------------- 133 O_FR.BCF06 .-P---V-------------------L- 133 O_FR.BCF07 .-P------------------------- 133 O_FR.BCF08 .-A-QS---------------------- 133 O_FR.BCF11 .-GG-S---------------------- 133 O_FR.RUD .-AG------------------------ 133 O_FR.LT .-A------------------------- 133 O_FR.NF1 .-A------------------------- 133 O_FR.VAU .-A-Q-------------I--------- 133

CONSENSUS-cpz ???N???PVGD?Y?RW?I?GLNKVVR?Y?PVSIL?I?QGPKEPFRDYVDRFYKT?RAEQASQ?VK?WMT?TLL?QNANPDCK?ILKALG?GA?LEEM?TACQGVGGP?HKARVL 182 CPZGAB ..A-PPI----V-R--V-L-------M-C-----D-R-----------------L-------E--N---D---V--------Q------P--T----M---------S------ 231 CPZANT PQQ-GGV----I-K--I-M-------X-S-----E-K-----------------I-------P--A---E---I--------H------T--S----L---------A------ 234

Figure 3. A comparison of the consensus sequences across the MHR of gag p24. Highly conserved amino acids essential for group viral particle formation are marked with asterisks.


                           *   *    *  *          
     M group consensus:  irQGPKEPFRDYVDRFfKtLRAEQA
     group O consensus:  -k----e--r--v-rfy--------
         cpz consensus:  -?--------------Y--?-----

There is an immunodominant region within the MHR that can stimulate both human and murine antibodies (see [Korber 96]34 for a summary). One of the immunodominant linear epitopes defined for HIV-1 M group viruses is located within this region, defined as: GPKEPFRDYVDRFYK, (called Hu Epitope 2 in Figure 2) [Janvier 96]30. Only a single amino acid differs in this epitope between the group O consensus the M group consensuses. The tyrosine (Y) in the second to last position of the epitope matches the consensus of group O sequences, and is found in all B and D clade sequences, as well as among the Thai A subtypes. But in all other clades in the M group, this position is most commonly occupied by a phenylalanine (F). It is not clear whether this substitution would influence the antigenic specificity of the peptide, though it is very likely that the antigenic peptide studied by Janvier et al. would react with sera from individuals infected with group O strains of HIV-1, because the group M subtype B derived peptide perfectly matches the group O consensus. 9/20 sera from HIV-1 infected individuals reacted with this peptide [Janvier 96]30. Among HIV-2 and SIV sequences, the immunogenic region is conserved except for two substitutions: the central RD in positions six and seven become QS (see the Gag protein alignments in this compendium). These substitutions may not be critical for binding, as murine monoclonal antibodies that bind to this region have been shown to be cross-reactive with HIV-1, HIV-2, and SIVmac and SIVagm strains [Matsuo 92, Robert-Hebmann 92a, Niedrig 89].40;53;44 Therefore, this immunodominant domain could potentially be useful for serological identification of all primate lentiviral infections, by sequence analogy, including those of group O.

Cyclophilin A binding region: Cyclophilin A (CyPa) is a human protein that binds to a proline rich region in the HIV-1 p55 Gag precursor protein, and is incorporated into group M HIV-1 viral particles, (). Group M HIV-1 viral particles that lack cyclophilin A are not infectious, in contrast to other retroviruses [Luban 93, Thali 94, Franke 94]38;61;18. Cyclophilins are a family of proteins that catalyze protein folding and are protective against heat shock [Fisher & Schmid 90, Gething 92, Sykes 93]15;20;60. In contrast to HIV M group virus and the SIVcpz GAB strain, and the group O viruses do not have to bind and incorporate CyPa to produce infectious virions; this is one of the first major biological differences between group M and group O to be documented [Braaten 96]1.

Three of the prolines in the highly conserved CyPa binding region of p24 are required for the production of infectious virions in M group strains. These prolines are marked with an asterisk in Figures 2 and 4. The proline at position 222 (AGP) was required for CyPa binding and incorporation into virions, and was required for replication. The proline at position 225 ( PGQ) was not essential for replication, and so is not marked. Mutations in prolines 217 (lHP) and 231 (PRG) decreased particle yield and the mutant virus did not replicate [Franke 94].18 Proline 222 was highly, but not perfectly, conserved among group O viruses, in spite of the lack of a requirement for cyclophilin A binding. Proline 231 was perfectly preserved among group M, group O, and SIVcpz. Proline 217 is perfectly preserved among group M and SIVcpz viruses, but varies somewhat in group O viruses. Two additional prolines are present in group O viruses proximal to position 217 (Figure 2).

There are many murine monoclonal antibodies that bind to the CyPa binding domain [Korber 96].34 One particular epitope that has been defined by peptide reactivity (ETINEEAAEWDRVHP) was cross-reactive with sera from HIV-1, HIV-2 and SIV infections [Niedrig 88].45 While there are frequent substitutions among group O isolates in this region, most are conservative aspartic acid (D) to glutamic acid (E) substitutions, and there are some O strains that are identical to the M consensus sequence in this region. Thus it is likely that group O sera would react with this peptide.

Figure 4. A comparison of the consensus sequences across the Cyclophilin A binding region in gag p24. Highly conserved prolines essential for group M viral replication are marked with asterisks.


                                         *    *        * 
         M group consensus:  INEEAAEWDRlHPvhAGPipPGQmRePRGSDIAGTTS 
         group O consensus:  --ee-ad---t-pppv-plp-gqi-e-t-----g--s 
             cpz consensus:  ----------L--TH---???--L-E-?---------

Additional immunogenic domains in p24: A peptide covering positions 178-192 (HIV-1 IIIB) was recognized by sera from 8/20 HIV-1 positive people (Hu Epitope 1 in Figure 2) [Janvier 96].30 The linear immunodominant antigenic regions (Hu Epitope 1 and 2) in p24 group M viruses are conserved in group O as well, particularly human epitope 2, suggesting that they may provide broadly cross-reactive antigenic peptides recognized by sera of individuals with O and M group infections.

Through studies involving M group strains, HIV-1 epitopes have been defined for both helper and cytotoxic T cells across the p24 protein. The p24 T-cell epitopes that have been defined in M group tend to cluster, some near the C-terminal region, and some crossing the CyPa binding site and the MHR [Korber 96].34 Because of the conservation of p24, it is highly probably that some cross-reactivity between M and group O would be observed. For example, there is an HLA-A25 restricted CTL epitope, (ETINEEAAEW) that has been defined using CTL clones from long term survivors [van Baalen 96].63 This epitope is conserved in viruses of the B and D subtypes, but the form DTINEEAAEW is commonly in other clades, and this variant was not recognized by CTL specific for the index peptide. While group O sequences show some variation in this epitope, some are very similar to the reactive M group epitope, and may be cross-reactive: e.g. MVP51: EVINEEAAEW).

The C2V3 Region

Variation and immunogenicity of the V3 loop: The variation in the V3 loop has been the focus of extensive international research efforts, originally because it was noted in the late 1980s that antibodies directed against the tip of V3 loop could potently neutralize laboratory strains of HIV-1 in a type-specific manner [Javaherian 89, Palker 88, Rusche 88]38;48;55. More recently, anti-V3 monoclonal antibodies have been shown in general to be potent neutralizing agents when directed against HIV-1 laboratory-adapted strains, but far less so when directed against primary isolates. This presumably is due to distinct conformations of envelope, such that the V3 loop of primary isolates is inaccessible (see [Moore & Ho 95, Poignard 96] for review).42;51 Most anti-V3 monoclonal antibodies are type-specific, and monoclonals directed against one strain can be completely unreactive even with closely related viral strains, due to the hypervariable nature and high rate of amino acid substitution in the immunogenic tip of the V3 loop [Korber 96].34 Other neutralizing epitopes, both continuous and discontinuous, have been identified in envelope [Poignard 96, Moore 95].51;42 Many neutralizing antibodies (but not all, e. g. [Trkola 95a])62 share the property of reduced neutralization of primary isolates relative to laboratory adapted strains [Moore & Ho 95].42.

The turn at the tip of the loop is the focus of most anti-V3 neutralizing antibodies, and is most often found to be GPGR or GPGQ among M group viruses [Foley 96].16 These two motifs are not found among group O strains. With the exception of some common amino acids flanking the cysteines at the base of the V3 loop, group O and group M V3 loops are very different from each other. Helper and cytotoxic T cell epitopes, as well as antibody binding sites, have been identified within the V3 loop of M group viruses. Because group O and M viruses are highly variable in the C2V3 region within a group, and because the extent of the substitutions found between group O and M is so great, it is highly unlikely that there would be antigenic O and M cross-reactivity for either B or T cell epitopes in the V3 loop.

Phenotypic determinants in the V3 loop: The V3 loop has been shown to have a critical functional role in determining the phenotype of the virus [Hwang 91, Chesebro 92, deJong 92B].29;3;9 Positively charged amino acids in certain positions in the V3 loop are correlated with a syncytium-inducing (SI), T-cell-tropic viral phenotype among group M subtype B viruses [Fouchier 92]17 (the two most critical positions are indicated in Figure 5. The observations concerning these two positions, and a correlation between net positive charge on the loop and rapid high and slow low phenotypes, were extended beyond subtype B to other group M subtypes [de Wolf 94, Rubsamen-Waigmann 94].11;54Recently, a correlation between positive charge and phenotype was shown for the group O viruses [de Jong 96].8 Because of the length variation between different strains and the diversity found in this region, it is difficult to be certain the alignment of V3 loop shown in Figure 5 is biologically appropriate. Despite this, in a best estimate the two critical sites in the V3 loop associated with group M SI/NSI phenotype switching display a similar pattern of variation among group O strains and group M sequences. Both are highly variable positions, and the first position alternates between neutral and positively charged amino acids, and the second position alternates between negative, neutral and positively charged amino acids.

Figure 5. Alignment of the C2V3 region of gp120. The boundaries of the V3 loop are shown, and the positions that are associated with viral phenotype (SI phenotype and positive charge) are marked with asterisks. 45 group O sequences were used to generate the consensus, but only those published or released are shown.


CONSENSUS-M   kPVVSTQLLLNGSlAEeeiiiRSen?tnNaK?IIvqln?s..v?InCtRp?nnntrksi?i??gpgqafy?tg???iIG...dirqAhCnis???Wn..?tlqqv??k.l????                               
A_U455        ----------------R--R-----F-----T-----VNP..-K---S--Y-TRKNIRRYS.I-S-----V--K..---...--------V-RRD--..R-I---AEQ.-KK                                
A_KENYA       ----------------G-VM-----I-----N----FAEP..-K------.-----M--R-..-------A--D..---...N-------V-RAE--..T---K-VT-.-RE                                
B_D31         R-----------------VV---D-F-D---T-----KE-..-E------.--Y-S-R-R-..-ARR---TK-K..---...----------GAK-D..S--R-IVK-.-RE                                 
B_LAI         R-----------------VV---A-F-D---T------Q-..-E------.--------R-QR---R--VTI-K...--...NM--------RAK--..A--K-IAS-.-RE                                
C_SM145A      ----------------G--M-----L-----T---H--Q-..-E-R---Y.A------VR-..----T--TN.D..---...----------GDK--..R-----GK-.-AE                                 
C_DJ373A      -------------T---D-------L-----I------Q-..-E------.-----Q--R-..----T--A--D..---...----------RQK-K..E-----KG-.-KEHF                              
D_Z2Z6        R------------------------L-----I------E-..-A------.YR-I-QRTS-..-L---L-T-KTRS---......--Y----KNE--..K-----AI-.-GNLL                              
D_ELI         R-----------------V------L-----N--AH--E-..-K-T-A--.YQ---QRTP-..-L--SL-T-RSRS---......-------RAQ-S..K-----AR-.-GTLL                              
E_TN235       -------------------------L-----T---H--K-..-E------.S----T--P-..-------R--D..---...---K-Y-E-NGTK--..EV-T--TE-.-KE                                 
E_CM240X      ------------------------DL-----T---H--K-..-E------.S----T--T-..----V--R--D..---...N--K-Y-E-NGTK--..KV-K--TE-.-KEHF                              
F_BZ163A      -----------------D-----Q-ISD---T---HF-E-..-Q------.------G-H-..---R---A--D..---...---K----V-GTQ--..K--E--R...AKLK                                
F_93BR020.17  ----------------G--V---Q-ISD---I---H--E-..-Q------.------R-SL..---RV--TA-E..---...---K----V-GTQ-S..K--AR-RAR.-KT                                 
G_LBV217      -------------------M-----F-----N----F-K-..ID-V----.--------H-..-----L-A--A..---...--------V-ETD-R..DM--K-KAQ.-QG                                 
G_92RU131.9   --------------------V----F-D---V------K-..-E-T----.--------TF..A----L-A--E..---...--------V-RKD--..EM--N-TT-.-KGIF                              
H_CA13                        -KVM-----I-D-T-N-----KNP..-V------.-----R-MR-..-I-RGQTFHAIGA---...----------GAK--..DM-TK-ATQ.-GKHL                               
H_VI557                       NHV----K-I-D-T-N-----KSP..-P------.--------S-..-------A--D..---...---K-Y---TRED-K..R--HE-VQQ.-R                                  

CONSENSUS-O kptvsTqlilngtls?gkirimgknis??g?nIivtlnst??inmtC?Rpg?n??vqei?i.?gpmawysm?l??????????sr?AyC?yn?t?W?..?tlkqtaerylelv O_FR_BCF01 ---------------EKG---------KT-E-------VS..--I--H---.-LS---MK-..--LS----G-AA...NSSIK--V---N-ST-E-T O_FR_BCF02 ---------------E----M-A----DS-Q-------T-..-----Q---.HQT----R-..--------G-AA...GNGSE--R---E--T-N-I O_FR_BCF06 ---------M-----R-------R--TDNTK-------TS..-----M-K-.RGKI-R-AT..--LR-V--AAKT..ESQNTG--I---M--N-E-I..N--------- O_FR_BCF08 ------H------I-E-E--------RENAK---------..-----E--EG-LTI---HS..-------LG-KR...NTTVR--S-H-K--T-N-E O_FR_BCF11 --A------------E-------Q---DS-K-------K-VNM-I--T-D-.DQK----G-..--LS----SIAE...DSAKNT-A---N-SASS-K..N---NI-- O_FR_BCF03 --A------------K------A---TNT-N---------..--I--N---.RG.IKQ-G-..---SV--GS-AD..LGGNNN--I---D-DI-K-N O_FR_BCF07 ---------------K----L-A----DS-Q-----x-T-..-x---H---.-LK----K-..--------GIEN..ENIP.D--K---x--x-x-V O_CM_MVP51 ---------------RE---------TESAK-------TP..-----I-E-.IAE--D-YT..---R-R--T-KR.SNNTSPR--V---T--K-V-E..NA-Q---I---N-- O_CM_CA9 -------T--TDSAK-------Y-..VDI--E---.-HT----R-..--L-----GIER...NSKNS--L---N--T-D-K..RA-----------I O_FR_RUD ------H--F---I-ER----------SNSG--L------..-----V---.-NS----K-..--------QIER..EGKGAN--T-F-T--A-D-R..K--QGI-------- O_GA_VI686 ---------------KE----------DS-K--------S..-S---E---.-HT---MK-..--------G-EE...NKT.N--R---R--A-D-E..KA---MT------- O_CM_ANT70 R--------------K----M-A-D-LEG-K---------..L----E--Q.ID.I--MR-..--------GIGG...TAGNS--A---K--A-D-G..KI------------ O_DE_HAM112 -GV------GG-K------S-D..-EI--V---N-NN---MK-..--------A-GT....GSNR--V---Q--T-E-E..KA--N--------I O_FR_VAU ---------------K-N-T-------DS-E--LI---TN..-TIA-E---.-QTI-K-MA..--------A-SN....TKGDT-A---N-SA-D-N..KA--NIT------- O_CM_YBF22 R--------------K--L-------KTTAN--------SSAL-I--R--A.-IE--K-H-..--L--L--DIKG....AYNN--V---E--A-N-E..KA--E--------- O_CM_YBF26 R--------F-----E-----------NS-P---------..-----R-E-.DQK--QMQ-..--------SFKE....VSNN--I---K--TSD-V..KA------------ O_CM_YBF28 ---------------E-------Q---AT-K-------DI..VKI--E---.-IT----R-..---S----GIAE....GSNN--K-H-K--T-K-V..KA-----------M O_CM_YBF32 ---------------E-E---------NS-N---------..V----E---.-LT---MR-..--------A-EQ..EGKGNS--V---N-ST-A-E..EA--N-V-K--K-M O_CM_YBF35 --A------------EE----------DSAK------KDP..-KIK-T-E-.-QT--D-GV..---V-R-IQ-AQ....GDNRT-A---I--T-D-E..KA-EE--------L O_CM_YBF37 ---------------K-N-L----D--DT-K--L-S---S..-----E--Y.-QTI--VW-.GS-------A-DR..EQNKTIT-M-F-R--G-G-K..E----I-G------

CONSENSUS-cpz ?P?V?T?LL?N????????T??V?N??KN??V??????E???????C?RP.GN?T????QI..GPGMTFYN?E?..??G...DTR?A?C??N?T?W???R???E???A.?????VD CPZGAB K-V-T-Q--I-GSLAEGNI-VR-E-KS--TD-WIVQLV-A..VSLN-H--.--N-RGEV--..--------I-N..VV-...---S-Y-KI-G-T-N..-TVE-VKK-.LATSS CPZANT S-M-A-W--L-..GTYQTN-SV-M-GR--ES-LVRFGK-FENLTIT-I--.--R-VRNL--..--------V-I..AT-...---K-F-TV-K-L-EQA-NKT-HVL-.EHWKK--

Recently it has been shown that chemokine second receptor usage for HIV entry into CD4-positive immune cells is associated with the phenotype of the virus, and not with the genetically defined HIV-1 group or subtype [Zhang 96,Choe 96].66;4 CXCR4 (fusin) usage is associated with viruses of with T-cell tropic, SI phenotypes; CCR5 usage is associated with a macrophage tropic, non-SI (NSI) phenotype; and some SI viruses are able to use both CXCR4 and CCR5 [Zhang 96]66. The group O viruses, similar to the M group, have both patterns of second receptor usage [Zhang 96].66 The two group O isolates for which second receptor usage has been determined are CA9, with an NSI phenotype and second receptor usage restricted to CCR5; and MVP5180, with an SI phenotype and the ability to use both CCR5 and CXCR4. The pattern of positive charge substitutions in the V3 loop, at least in these two group O isolates, is consistent with what has been observed in the M group. The SI isolate MVP5180 has greater positive charge overall, and in particular, in the second of the two sites associated with the SI phenotype in the M group is positively charged in O\_CM\_MVP51 and negatively charged in O_CM_CA9 (Figure 6). The C-C chemokines RANTES, MIP-1 alpha, and MIP-1 beta produced by CD8 cells, can inhibit HIV-1 infection of primary and macrophage-tropic group M HIV-1 isolates, whereas T-cell tropic isolates tend to be resistant to the C-C chemokine suppressive effects [Cocchi 95].5 The V3 loop was shown to be a critical region for determining the susceptibility to chemokine-mediated suppression using chimeric gp120 proteins [Cocchi 96].6 It will be interesting to see if SI group O viruses, like MVP5180, will have a similar pattern of resistance.

Figure 6: The V3 loop sequences of SI strain MVP51 and NSI strain CA9. The positions that have been associated with viral phenotype are marked with asterisks. The positively charged amino acids arginine (R) and lysine (K) near the tip of the loop V3 found in SI isolate MVP51 are marked with a plus (+). The dashes (-) indicated insertions made to maintain the alignment.


                        *             * 
                               + +    ++ 
O_CM_MVP51  CIREGIAEVQDIYTGPMRWRSMTLKRSNNTSPRSRVAYC
  O_CM_CA9  CERPGNHTVQEIRIGPLAWYSMGIERNSKNSSR--LAYC

Immunodominant domain in gp41

The immunodominant region in gp41 is conserved between different group M strains, and is reactive with sera from individuals infected with a variety of group M subtypes [Engelbrecht 94, Petrov 90, Shafferman 89, Gnann 87].14;50;56;21 Although only a limited number of sequences are available in the database across this region, because of its importance for diagnostics, a comparison of the and group M and O consensus sequences in this region is shown in Figure 7.

Acknowledgments

With thanks to Lutz Gurtler, Sushil Devare, Francois Simon, Philippe Mauclere, J. Cohen, Marie Laure Chaix, Guido Van der Groen and Wouter Janssens for their history of graciously providing sequences to the Los Alamos Database prior to publication of the primary articles introducing the sequences, for sharing their knowledge concerning group O viruses, and for contributions of sequences used to build the consensuses provided in this manuscript.

Figure 7. Alignment of amino acids from gp41 spanning the immunodominant domain of gp41. This alignment starts at 50 amino acids from the start of gp41 and continues for the next 100 amino acids. The M consensus is based on the set of sequences shown. The group O consensus is based on the 9 sequences currently available at the Los Alamos database covering this region; the five that have been published or made public are shown in the alignment.


CONSENSUS-M  EaqQHlLqLTVWGIKQLqaRvLAvErYLkDQqlLGiWGCSGKlICtT?VPwNssWS.Nks?eeIW?NmTwmeWerEisnYt??iy?l?eeSQnQQekneqd                        
A_U455       -------K--------------------Q------------------T--------.---Q-D--N----LQ--K---S--GI--Q-I-----------L-                       
A_KENYA      -------K--------------------R-------------I----N--------.---QS---E----LQ-DK------DI--N-L-------------                       
B_D31        ----------------------------R------------------A----A---.---MDM--N-----------D---SL--T-I------------E                       
B_LAI        --------------------I--------------------------A----A---.---L-Q--N-------D---N---SL-HS-I------------E                       
C_SM145A     -----M-----------R-----I----E------------------A--------.-RTQ----E-L---Q-DK------DT--R-L-V---------K-                       
C_DJ373A     -VH--M------------T----I-----------------------A--------.---Q----D-----Q-D---N---ET--R-L-V--T---Q--K-                       
D_Z2Z6       --------------------I--------------------------T--------.-R-LND--Q-----------D---GL--R-I----T-------E                       
D_ELI        --------------------I---------------------H----N--------.-R-LN---Q-----------D---GL--S-I----T------KE                       
E_TN235      -------------------------------KF--L------I----A--$--T--.-R-Y----N----I----------NQ--EILT------DR--K-                        
E_CM240X     -------------------------------KF--L------I----A-----T--.-R-F----N---RI----------NQ--EILT------DR--K-                       
F_BZ163A     ----------------------------Q------L-----------N--------.---Q----E-------QK-----SNEV-R-I-K----------G                       
F_93BR020.17 -----------------------------------L-----------N--------.---L----G--------K-V---SKE--R-I-D--------K-E                       
G_LBV217     ----------------------------Q------------------N----T---.---FN---D----I------N---HQ--S-L----I--------                       
G_92RU131.9  -------------------------K-------------------P-N----T---.---FN---D----I------N---YQ--N-L---------D---                       

CONSENSUS-O QAQQqLLRlSVWGIRQLRARLlALETliQNQQlLnLWGCkgklvCYTSVkWN?tW?G?ds...IWd?LTWQeWDqqi?NiSs?IydeIQ?AQvQQE?Nekk O_FR.RUD ----H----------------------M-----------R--AI-----Q--E--G-N--...---R----Q-----A-V--F---K--E--E-- O_CM.MVP51 ----H----------------Q----------R----------I--------TS-S-RYNDDS---N----Q---H-N-V--I------A--D---K-V-A O_CM.ANT70 ----------x----------------L------S-----------------R--I-NE-...---T-------R--S----T--E---K------Q---- O_CM.2901 ----H----------------Q-----M---------------I--------E--G-NL-...---S----Q----VA-V--L---K--E--E---K--RA O_FR.VAU ----H---P-----------------F-------------NR-I--------K--G-DNES..---E----Q-----N-V--F--EK--E--E---K---E

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