Copy number variation of KIR genes influences HIV-1 control

Andrea De Luca, K Pelak, Ac Need, J Fellay, Kv Shianna, S Feng, Tj Urban, D Ge, J Martinez Picado, Sm Wolinsky, Jj Martinson, Bd Jamieson, Jh Bream, Mp Martin, P Borrow, Nl Letvin, Aj Mcmichael, Bf Haynes, A Telenti, M CarringtonDb Goldstein, G. Alter

Risultato della ricerca: Contributo in rivistaArticolo in rivista

112 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)e1001208-e1001208
Numero di pagine1
RivistaPLoS Biology
Volume9
DOI
Stato di pubblicazionePubblicato - 2011

Keywords

  • Cohort Studies
  • DNA Copy Number Variations
  • HIV-1
  • Humans
  • Killer Cells, Natural
  • Lymphocyte Activation
  • Models, Immunological
  • Receptors, KIR
  • Viral Load
  • Virus Replication

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