Abstract
BackgroundPresentation of identical HIV-1 peptides by closely related Human Leukocyte Antigen class I (HLAI) molecules can select distinct patterns of escape mutation that have a significant impact on viral fitness and disease progression. The molecular mechanisms by which HLAI micropolymorphisms can induce differential HIV-1 escape patterns within identical peptide epitopes remain unknown.ResultsHere, we undertook genetic and structural analyses of two immunodominant HIV-1 peptides, Gag180–188 (TPQDLNTML, TL9-p24) and Nef71–79 (RPQVPLRPM, RM9-Nef) that are among the most highly targeted epitopes in the global HIV-1 epidemic. We show that single polymorphisms between different alleles of the HLA-B7 superfamily can induce a conformational switch in peptide conformation that is associated with differential HLAI-specific escape mutation and immune control. A dominant R71K mutation in the Nef71-79 occurred in those with HLA-B*07:02 but not B*42:01/02 or B*81:01. No structural difference in the HLA-epitope complexes was detected to explain this observation.ConclusionsThese data suggest that identical peptides presented through very similar HLAI landscapes are recognized as distinct epitopes and provide a novel structural mechanism for previously observed differential HIV-1 escape and disease progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0149-5) contains supplementary material, which is available to authorized users.
Highlights
Presentation of identical HIV-1 peptides by closely related Human Leukocyte Antigen class I (HLAI) molecules can select distinct patterns of escape mutation that have a significant impact on viral fitness and disease progression
HLAI micropolymorphisms result in distinct targeting frequencies and selection pressure through two HIV-1 epitopes We studied four members of the human leukocyte antigen (HLA)-B7 superfamily, HLA-B*07:02, HLA-B*42:01, HLA-B*42:02 and HLAB*81:01
To better understand the mechanisms underlying the observed differential HIV-1 selection pressure imposed on HIV-1 by distinct HLAI molecules within the B7 superfamily, we focused on two epitopes, TL9-p24 and RM9-Nef, that dominate the HIV-1-specific CD8 T-cell response in the Southern African HIV-1 epidemic [14,17]
Summary
Presentation of identical HIV-1 peptides by closely related Human Leukocyte Antigen class I (HLAI) molecules can select distinct patterns of escape mutation that have a significant impact on viral fitness and disease progression. Minor differences between the HLAI molecules expressed (‘HLAI micropolymorphisms’), even of a single amino acid, can have a profound impact on both T-cell immunity and disease outcome during a range of infections, including HIV-1 [3,4,5,6,7,8] This disparity has been partly explained by the selection of escape mutations that have different consequences for viral fitness [8,9,10]. The mutation principally responsible for this protective effect is the above-mentioned HLA-B*81:01-driven T186S variant that fails to yield replicating virus stocks in studies of C clade virus [13] This is in line with the lower viral loads and higher CD4 counts observed in HLA-B*81:01 positive subjects in studies of exclusively C-clade infection [9,14,16]. In a study of cohorts in Zambia, Rwanda and Kenya involving several clades of virus, including clade A which carries a different consensus residue at Gag186, stable CD4 counts but not lower viraemia was observed in association with HLA-B*81:01 [15]
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