Rousseau, C. M.,Daniels, M .G.,Carlson, J. M.,Kadie, C.,Crawford, H.,Prendergast, A.,Matthews, P.,Payne, R.,Rolland, M.,Raugi, D. N.,Maust, B. S.,Learn, G. H.,Nickle, D. C.,Coovadia, H.,Ndung'u, T.,Frahm, N.,Brander, C.,Walker, B. D.,Goulder, P. J. R.,Bhattacharya, T.,Heckerman, D. E.,Korber, B. T.,Mullins, J. I.

Human immunodeficiency virus type 1 (HIV-1) mutations that confer escape from cytotoxic T-lymphocyte (CTL) recognition can sometimes result in lower viral fitness. These mutations can then revert upon transmission to a new host in the absence of CTL-mediated immune selection pressure restricted by the HLA alleles of the prior host. To identify these potentially critical recognition points on the virus, we assessed HLA-driven viral evolution using three phylogenetic correction methods across full HIV-1 subtype C proteomes from a cohort of 261 South Africans and identified amino acids conferring either susceptibility or resistance to CTLs. A total of 558 CTL-susceptible and -resistant HLA-amino acid associations were identified and organized into 310 immunological sets (groups of individual associations related to a single HLA/epitope combination). Mutations away from seven susceptible residues, including four in Gag, were associated with lower plasma viral-RNA loads (q < 0.2 [where q is the expected false-discovery rate]) in individuals with the corresponding HLA alleles. The ratio of susceptible to resistant residues among those without the corresponding HLA alleles varied in the order Vpr > Gag > Rev > Pol > Nef > Vif > Tat > Env > Vpu (Fisher's exact test; P <= 0.0009 for each comparison), suggesting the same ranking of fitness costs by genes associated with CTL escape. Significantly more HLA-B (chi(2); p = 3.59 x 10(-5)) and HLA-C (chi(2); p = 4.71 x 10(-6)) alleles were associated with amino acid changes than HLA-A, highlighting their importance in driving viral evolution. In conclusion, specific HIV-1 residues (enriched in Vpr, Gag, and Rev) and HLA alleles (particularly B and Q confer susceptibility to the CTL response and are likely to be important in the development of vaccines targeted to decrease the viral load.