HLA class I-driven evolution of human immunodeficiency virus type 1 subtype c proteome: immune escape and viral load
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.
Journal of Virology 82(13): 6434-6446
2008
ISSN/ISBN: 1098-5514 PMID: 18434400 DOI: 10.1128/jvi.02455-07Document Number: 202314
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 < or = 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 C) confer susceptibility to the CTL response and are likely to be important in the development of vaccines targeted to decrease the viral load.