title: A molecular switch in immunodominant HIV-1-specific CD8 T-cell epitopes shapes differential HLA-restricted escape.
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.
authors: Henrik N
authors: HN
authors: Kløverpris
authors: David K
authors: DK
authors: Cole
authors: Anna
authors: A
authors: Fuller
authors: Jonathan
authors: J
authors: Carlson
authors: Konrad
authors: K
authors: Beck
authors: Andrea J
authors: AJ
authors: Schauenburg
authors: Pierre J
authors: PJ
authors: Rizkallah
authors: Søren
authors: S
authors: Buus
authors: Andrew K
authors: AK
authors: Sewell
authors: Philip
authors: P
authors: Goulder
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D015488:HIV Antigens / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D057131:Immune Evasion
chemical_list: D018984:Epitopes, T-Lymphocyte; D015488:HIV Antigens; D015395:Histocompatibility Antigens Class I