期刊
JOURNAL OF VIROLOGY
卷 82, 期 13, 页码 6434-6446出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.02455-07
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资金
- MRC [G0500384] Funding Source: UKRI
- Medical Research Council [G0500384] Funding Source: researchfish
- Medical Research Council [G0500384] Funding Source: Medline
- NIAID NIH HHS [P30 AI027757, R37 AI047734, R01 AI047734, AI27757, P01 AI061734, AI27005, R01 AI067077, AI067077, AI047734, AI11514, AI058894, AI061734, N01-AI-15422, R01 AI058894] Funding Source: Medline
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.
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