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

Retrovirology. 2015 Feb 20;12:20. doi: 10.1186/s12977-015-0149-5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • CD8-Positive T-Lymphocytes / immunology*
  • Epitopes, T-Lymphocyte / genetics
  • Epitopes, T-Lymphocyte / immunology*
  • HIV Antigens / genetics
  • HIV Antigens / immunology*
  • HIV Infections / immunology*
  • HIV Infections / virology
  • HIV-1 / genetics
  • HIV-1 / immunology*
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Immune Evasion*

Substances

  • Epitopes, T-Lymphocyte
  • HIV Antigens
  • Histocompatibility Antigens Class I