HLA class I-driven evolution of human immunodeficiency virus type 1 subtype c proteome: immune escape and viral load.
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.
Rousseau
Christine M
CM
Department of Microbiology, University of Washington, 1959 NE Pacific Street, Box 358070, Seattle, WA 98195-8070, USA. cmr@u.washington.edu
Daniels
Marcus G
MG
Carlson
Jonathan M
JM
Kadie
Carl
C
Crawford
Hayley
H
Prendergast
Andrew
A
Matthews
Philippa
P
Payne
Rebecca
R
Rolland
Morgane
M
Raugi
Dana N
DN
Maust
Brandon S
BS
Learn
Gerald H
GH
Nickle
David C
DC
Coovadia
Hoosen
H
Ndung'u
Thumbi
T
Frahm
Nicole
N
Brander
Christian
C
Walker
Bruce D
BD
Goulder
Philip J R
PJ
Bhattacharya
Tanmoy
T
Heckerman
David E
DE
Korber
Bette T
BT
Mullins
James I
JI
D000595:Amino Acid Sequence; D001483:Base Sequence; D018984:Epitopes, T-Lymphocyte / Q000235:genetics; D019143:Evolution, Molecular; D005805:Genes, MHC Class I / Q000235:genetics*; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D008969:Molecular Sequence Data; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D013019:South Africa; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014766:Viremia / Q000097:blood
D018984:Epitopes, T-Lymphocyte