Structural and functional constraints limit options for cytotoxic T-lymphocyte escape in the immunodominant HLA-B27-restricted epitope in human immunodeficiency virus type 1 capsid.
Control of human immunodeficiency virus type 1 (HIV-1) by HLA-B27-positive subjects has been linked to an immunodominant CD8(+) cytotoxic T-lymphocyte (CTL) response targeting the conserved KK10 epitope (KRWIILGLNK(263-272)) in p24/Gag. Viral escape in KK10 typically occurs through development of an R(264)K substitution in conjunction with the upstream compensatory mutation S(173)A, and the difficulty of the virus to escape from the immune response against the KK10 epitope until late in infection has been associated with slower clinical progression. Rare alternative escape mutations at R(264) have been observed, but factors dictating the preferential selection of R(264)K remain unclear. Here we illustrate that while all observed R(264) mutations (K, G, Q, and T) reduced peptide binding to HLA-B27 and impaired viral replication, the replicative defects of the alternative mutants were actually less pronounced than those for R(264)K. Importantly, however, none of these mutants replicated as well as an R(264)K variant containing the compensatory mutation S(173)A. In assessing the combined effects of viral replication and CTL escape using an in vitro coculture assay, we further observed that the compensated R(264)K mutant also displayed the highest replication capacity in the presence of KK10-specific CTLs. Comparisons of codon usage for the respective variants indicated that generation of the R(264)K mutation may also be favored due to a G-to-A bias in nucleotide substitutions during HIV-1 replication. Together, these data suggest that the preference for R(264)K is due primarily to the ability of the S(173)A-compensated virus to replicate better than alternative variants in the presence of CTLs, suggesting that viral fitness is a key contributor for the selection of immune escape variants.
Schneidewind
Arne
A
Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Brockman
Mark A
MA
Sidney
John
J
Wang
Yaoyu E
YE
Chen
Huabiao
H
Suscovich
Todd J
TJ
Li
Bin
B
Adam
Rahma I
RI
Allgaier
Rachel L
RL
Mothé
Bianca R
BR
Kuntzen
Thomas
T
Oniangue-Ndza
Cesar
C
Trocha
Alicja
A
Yu
Xu G
XG
Brander
Christian
C
Sette
Alessandro
A
Walker
Bruce D
BD
Allen
Todd M
TM
D000595:Amino Acid Sequence; D001483:Base Sequence; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D015796:HLA-B27 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D009154:Mutation / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology
D036022:Capsid Proteins; D018984:Epitopes, T-Lymphocyte; D015796:HLA-B27 Antigen