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HXB2 Location	Pol(90-98) Protease(34-42) DNA(2352..2378)	Pol Epitope Map
Author Location	Protease(34-42 HXB2)
Epitope	EEMNLPGRW	Epitope Alignment
		Show epitope variants
Epitope Name	EW9
Subtype	B
Species (MHC/HLA)	human(B18, B40, B44)
Immunogen	HIV-1 infection
Country	Germany
Experimental methods	CD8 T-cell Elispot - IFNγ
Keywords	escape, variant cross-reactivity, mutation acquisition, HLA associated polymorphism, drug resistance

Notes

• To assess HIV-1-specific CTL influence on development and patterns of drug resistance in protease (PR) 94 HLA-typed patients were analyzed. 10 new CTL epitopes were defined statistically and experimentally, and 26 correlations (positive and negative) between HLA class-I alleles and PR mutations - some leading to escape mutations - were detected, demonstrating that CTL epitopes can be predicted based on HLA-amino acid substitution associations.
• Some patient CTL escape mutations were detectable by other CTLs of the same patient. Correlations between resistance mutations, polymorphisms and specific PR inhibitors were not detected.
• HLA-B had the strongest impact on PR sequence change, though HLAs-A and -C also had some impact.
• The authors suggest that CTL escape is active in developing drug-resistance related polymorphisms as well as major and minor mutations in HIV-1 infected persons.
• HIV-1 subtype breakdown in this cohort was follows - 83/94 patients infected with subtype B virus, 3 with subtype C, 4 CRF01_AE, 1 CRF03_AB, 1 CRF15_01B and 2 subtype Ds.
• This highly immunogenic index epitope, EEMNLPGRW, EW9, developed variants EEiNLPGRW, EW9 M/I, EEMdLPGRW, EW9 N/D, EdMNLPGRW, EW9 E/D, EdiNLPGRW, EW9 D/I, EEMNLPGkW, EW9 R/K, EEMNLsGRW, EW9 P/S. E35D and P39S mutants were located in the previously reported HLA-B44 restricted epitope EEMSLPGRW (EW9). The correlation between the minor drug mutation E35D and HLA-B44 was strong, while that of -B44 with P39S was weak. E35D mutations induced a strong decrease in CTL recognition, but few patient samples did mount specific responses against it giving a negative correlation between this mutation and HLA-B44. A novel association between the E35D mutant and HLA-B18 was also found.
• Cross-reactivity of CTL recognition of EW9 and variants occurred for most patients. This showed that cells from several patients mount oligoclonal CTL responses, indicating immune system reactions to escape by recruitment of CTLs with new TCR specificities. On the other hand, most patients showed mutually exclusive recognition of variant epitopes containing either E35D or E35E; HLA-B44 subtypes and other factors tested could not explain this phenomenon.
• EW9 epitope and variant peptides include the S37N substitution when compared to HXB2 strain sequences.
• HLA-restrictions to this epitope were HLA-18, -40, -44.

References

Mueller2007 Sandra M. Mueller, Birgit Schaetz, Kathrin Eismann, Silke Bergmann, Michael Bauerle, Matthias Schmitt-Haendle, Hauke Walter, Barbara Schmidt, Klaus Korn, Heinrich Sticht, Bernd Spriewald, Ellen G. Harrer, and Thomas Harrer. Dual Selection Pressure by Drugs and HLA Class I-Restricted Immune Responses on Human Immunodeficiency Virus Type 1 Protease. J. Virol., 81(6):2887-2898, Mar 2007. PubMed ID: 17202219. Show all entries for this paper.