Copy number variation of KIR genes influences HIV-1 control

Kimberly Pelak, Anna C. Need, Jacques Fellay, Kevin V. Shianna, Sheng Feng, Thomas J. Urban, Dongliang Ge, Andrea de Luca, Javier Martinez-Picado, Steven M. Wolinsky, Jeremy J. Martinson, Beth D. Jamieson, Jay H. Bream, Maureen P. Martin, Persephone Borrow, Norman L. Letvin, Andrew J. McMichael, Barton F. Haynes, Amalio Telenti, Mary CarringtonDavid B. Goldstein, Galit Alter*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

Abstract

A genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control as measured by plasma viral load at set point in individuals of European ancestry. This CNV encompasses the KIR3DL1-KIR3DS1 locus, encoding receptors that interact with specific HLA-Bw4 molecules to regulate the activation of lymphocyte subsets including natural killer (NK) cells. We quantified the number of copies of KIR3DS1 and KIR3DL1 in a large HIV-1 positive cohort, and showed that an increase in KIR3DS1 count associates with a lower viral set point if its putative ligand is present (p = 0.00028), as does an increase in KIR3DL1 count in the presence of KIR3DS1 and appropriate ligands for both receptors (p = 0.0015). We further provide functional data that demonstrate that NK cells from individuals with multiple copies of KIR3DL1, in the presence of KIR3DS1 and the appropriate ligands, inhibit HIV-1 replication more robustly, and associated with a significant expansion in the frequency of KIR3DS1+, but not KIR3DL1+, NK cells in their peripheral blood. Our results suggest that the relative amounts of these activating and inhibitory KIR play a role in regulating the peripheral expansion of highly antiviral KIR3DS1+ NK cells, which may determine differences in HIV-1 control following infection.

Original languageEnglish (US)
Article numbere1001208
JournalPLoS biology
Volume9
Issue number11
DOIs
StatePublished - Nov 2011

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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