Covariability of Selected Amino Acid Positions for HIV-1 Subtypes C and B

We studied covariability of selected amino acid positions in globally dominant HIV-1 subtype C viruses. The analyzed sequences spanned the V3 loop, Gag p17, Gag p24, and five CTL epitoperich regions in Gag, Nef, and Tat. The corresponding regions in HIV-1 subtype B were also evaluated. The analyses identified a great number of covarying pairs and triples of sites in the HIV-1B V3 loop (173 site pairs, 242 site triples). Several of these interactions were found in the earlier studies (e.g., the V3 loop covariability analyses by Korber et al. (Proc Natl Acad Sci USA 1993;90:7176-7180) and Bickel et al. (AIDS Res Hum Retroviruses 1996;12:1401-1411)) and have known biological significance. However, generally these key covarying sites did not covary in the HIV-1C V3 loop (total 17 covarying site pairs), suggesting that the V3 loop may have subtype-differences in functional or structural operating characteristics. Covariability of positions 309 and 312 was observed in the immunodominant region HIV-1C Gag 291-320 but no covariability was found in the corresponding region of HIV-1B, and vice versa for Nef 122-141; these findings may reflect subtype-specific covariability within immunologically relevant regions. Gag p17 exhibited greater covariability and less diversity for HIV-1B than HIV-1C, raising the hypothesis that Gag p17 is highly immunodominant in HIV-1B and is especially important for HIV-1B vaccines. Information on covariability should be better exploited in assessments of HIV-1 diversity and how to surmount it with vaccine design.