Pelak, KimberlyNeed, Anna C.Fellay, JacquesShianna, Kevin V.Feng, ShengUrban, Thomas J.Ge, DongliangDe Luca, AndreaMartinez-Picado, JavierWolinsky, Steven M.Martinson, Jeremy J.Jamieson, Beth D.Bream, Jay H.Martin, Maureen P.Borrow, PersephoneLetvin, Norman L.McMichael, Andrew J.Haynes, Barton F.Telenti, AmalioCarrington, MaryGoldstein, David B.Alter, Galit2012-06-252012-06-252012-06-25201110.1371/journal.pbio.1001208https://infoscience.epfl.ch/handle/20.500.14299/82304WOS:000298152600019A 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.Natural-Killer-CellsMhc Class-ILy49 Receptor RepertoireVirus Type-1 InfectionHla Class-INk CellsInhibitory ReceptorsDisease ProgressionCutting EdgeKir3Ds1text::journal::journal article::research article