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A molecular switch in immunodominant HIV-1-specific CD8 T-cell epitopes shapes differential HLA-restricted escape

Kløverpris, Henrik N., Cole, David, Fuller, Anna, Carlson, Jonathan, Beck, Konrad, Schauenburg, Andrea J. A., Rizkallah, Pierre, Buus, Søren, Sewell, Andrew K. and Goulder, Philip 2015. A molecular switch in immunodominant HIV-1-specific CD8 T-cell epitopes shapes differential HLA-restricted escape. Retrovirology 12 (1) , 20. 10.1186/s12977-015-0149-5

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Abstract

Background 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. The molecular mechanisms by which HLAI micropolymorphisms can induce differential HIV-1 escape patterns within identical peptide epitopes remain unknown. Results Here, 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. Conclusions These 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Dentistry
Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > R Medicine (General)
Uncontrolled Keywords: HIV-1; CD8+ T-Cells; Viral escape; pHLA structure
Publisher: BioMed Central
ISSN: 1742-4690
Funders: BBSRC
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 29 January 2015
Last Modified: 12 Mar 2019 11:23
URI: http://orca.cf.ac.uk/id/eprint/74262

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