Copy number variation of KIR genes influences HIV-1 control

TY - JOUR

T1 - Copy number variation of KIR genes influences HIV-1 control

AU - Pelak, Kimberly

AU - Need, Anna C

AU - Fellay, Jacques

AU - Shianna, Kevin V

AU - Feng, Sheng

AU - Urban, Thomas

AU - Ge, Dongliang

AU - De Luca, Andrea

AU - Martinez-Picado, Javier

AU - Wolinsky, Steven M

AU - Martinson, Jeremy J

AU - Jamieson, Beth D

AU - Bream, Jay H

AU - Martin, Maureen P

AU - Borrow, Persephone

AU - Letvin, Norman L

AU - McMichael, Andrew J

AU - Haynes, Barton F

AU - Telenti, Amalio

AU - Carrington, Mary

AU - Goldstein, David B

AU - Alter, Galit

AU - NIAID Center for HIV/AIDS Vaccine Immunology

AU - Obel, Niels

PY - 2011/11

Y1 - 2011/11

N2 - 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.

AB - 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.

U2 - http://dx.doi.org/10.1371/journal.pbio.1001208

DO - http://dx.doi.org/10.1371/journal.pbio.1001208

M3 - Journal article

SN - 1544-9173

VL - 9

SP - e1001208

JO - PLoS Biology

JF - PLoS Biology

IS - 11

ER -