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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
agricultural and biological sciences
HLA class I-driven evolution of human immunodeficiency virus type 1 subtype C proteome: Immune escape and viral load
Journal of Virology, Volume 82, No. 13, Year 2008
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Description
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 (χ2; P = 3.59 × 10-5) and HLA-C (χ2; P = 4.71 × 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. Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Authors & Co-Authors
Rousseau, Christine M.
United States, Seattle
University of Washington
Daniels, Marcus G.
United States, Los Alamos
Los Alamos National Laboratory
Carlson, Jonathan M.
United States, Seattle
University of Washington
United States, Redmond
Microsoft Research
Kadie, Carl M.
United States, Redmond
Microsoft Research
Crawford, Hayley
United Kingdom, Oxford
Nuffield Department of Medicine
Prendergast, Andrew J.
United Kingdom, Oxford
Nuffield Department of Medicine
Matthews, Philippa C.
United Kingdom, Oxford
Nuffield Department of Medicine
Payne, Rebecca P.
United Kingdom, Oxford
Nuffield Department of Medicine
Rolland, Morgane M.
United States, Seattle
University of Washington
Raugi, Dana Noelle
United States, Seattle
University of Washington
Maust, Brandon S.
United States, Seattle
University of Washington
Learn, Gerald H.
United States, Seattle
University of Washington
Nickle, David C.
United States, Seattle
University of Washington
Coovadia, Hoosen Mahomed
South Africa, Durban
The Nelson R. Mandela Medical School
Ndung'u, Thumbi P.
South Africa, Durban
The Nelson R. Mandela Medical School
Frahm, Nicole
United States, Boston
Massachusetts General Hospital
Brander, Christian
United States, Boston
Massachusetts General Hospital
Walker, Bruce D.
United States, Boston
Massachusetts General Hospital
United States, Chevy Chase
Howard Hughes Medical Institute
Goulder, Philip Jeremy Renshaw
United Kingdom, Oxford
Nuffield Department of Medicine
South Africa, Durban
The Nelson R. Mandela Medical School
United States, Boston
Massachusetts General Hospital
Bhattacharya, Tanmoy
United States, Los Alamos
Los Alamos National Laboratory
United States, Santa fe
Santa fe Institute
Heckerman, David E.
United States, Seattle
University of Washington
United States, Redmond
Microsoft Research
Korber, Bette T.
United States, Los Alamos
Los Alamos National Laboratory
United States, Santa fe
Santa fe Institute
Mullins, James I.
United States, Seattle
University of Washington
Statistics
Citations: 23
Authors: 23
Affiliations: 8
Identifiers
Doi:
10.1128/JVI.02455-07
ISSN:
0022538X
Research Areas
Infectious Diseases
Study Design
Cohort Study