title: 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.
abstract: 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.
authors.affiliation: Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Arne
authors.initials: A
authors.lastname: Schneidewind
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Yaoyu E
authors.initials: YE
authors.lastname: Wang
authors.forename: Huabiao
authors.initials: H
authors.lastname: Chen
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Suscovich
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Rahma I
authors.initials: RI
authors.lastname: Adam
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Allgaier
authors.forename: Bianca R
authors.initials: BR
authors.lastname: Mothé
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuntzen
authors.forename: Cesar
authors.initials: C
authors.lastname: Oniangue-Ndza
authors.forename: Alicja
authors.initials: A
authors.lastname: Trocha
authors.forename: Xu G
authors.initials: XG
authors.lastname: Yu
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
mesh_terms: 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
chemical_list: D036022:Capsid Proteins; D018984:Epitopes, T-Lymphocyte; D015796:HLA-B27 Antigen