Copy number variation of KIR genes influences HIV-1 control |
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Authors: | Pelak Kimberly Need Anna C Fellay Jacques Shianna Kevin V Feng Sheng Urban Thomas J Ge Dongliang De Luca Andrea Martinez-Picado Javier Wolinsky Steven M Martinson Jeremy J Jamieson Beth D Bream Jay H Martin Maureen P Borrow Persephone Letvin Norman L McMichael Andrew J Haynes Barton F Telenti Amalio Carrington Mary Goldstein David B Alter Galit;NIAID Center for HIV/AIDS Vaccine Immunology |
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Institution: | Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA. |
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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. |
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