Killer cell immunoglobulin-like receptor 3DL1 variation modifies HLA-B*57 protection against HIV-1

J Clin Invest. 2018 May 1;128(5):1903-1912. doi: 10.1172/JCI98463. Epub 2018 Apr 3.

Abstract

HLA-B*57 control of HIV involves enhanced CD8+ T cell responses against infected cells, but extensive heterogeneity exists in the level of HIV control among B*57+ individuals. Using whole-genome sequencing of untreated B*57+ HIV-1-infected controllers and noncontrollers, we identified a single variant (rs643347A/G) encoding an isoleucine-to-valine substitution at position 47 (I47V) of the inhibitory killer cell immunoglobulin-like receptor KIR3DL1 as the only significant modifier of B*57 protection. The association was replicated in an independent cohort and across multiple outcomes. The modifying effect of I47V was confined to B*57:01 and was not observed for the closely related B*57:03. Positions 2, 47, and 54 tracked one another nearly perfectly, and 2 KIR3DL1 allotypes differing only at these 3 positions showed significant differences in binding B*57:01 tetramers, whereas the protective allotype showed lower binding. Thus, variation in an immune NK cell receptor that binds B*57:01 modifies its protection. These data highlight the exquisite specificity of KIR-HLA interactions in human health and disease.

Keywords: AIDS/HIV; Innate immunity; MHC class 1; NK cells.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cohort Studies
  • Female
  • Genetic Variation*
  • HIV Infections* / genetics
  • HIV Infections* / immunology
  • HIV-1 / immunology*
  • HLA-B Antigens* / genetics
  • HLA-B Antigens* / immunology
  • Humans
  • Male
  • Middle Aged
  • Receptors, KIR3DL1* / genetics
  • Receptors, KIR3DL1* / immunology

Substances

  • HLA-B Antigens
  • HLA-B*57:01 antigen
  • KIR3DL1 protein, human
  • Receptors, KIR3DL1

Grant support