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PLoS Biology
Copy Number Variation of KIR Genes Influences HIV-1 Control
<p>Kimberly Pelak<sup>1#</sup>, Anna C. Need<sup>1#</sup>, Jacques Fellay<sup>1,2#</sup>, Kevin V. Shianna<sup>1</sup>, Sheng Feng<sup>3</sup>, Thomas J. Urban<sup>1</sup>, Dongliang Ge<sup>1</sup>, Andrea De Luca<sup>4,5,</sup> Javier Martinez-Picado<sup>6,7</sup>, Steven M. Wolinsky<sup>8</sup>, Jeremy J. Martinson<sup>9</sup>, Beth D. Jamieson<sup>10</sup>, Jay H. Bream<sup>11</sup>, Maureen P. Martin<sup>12</sup>, Persephone Borrow<sup>13</sup>, Norman L. Letvin<sup>14</sup>, Andrew J. McMichael<sup>15</sup>, Barton F. Haynes<sup>16</sup>, Amalio Telenti<sup>17</sup>, Mary Carrington<sup>10,18</sup>, David B. Goldstein<sup>1</sup>, Galit Alter<sup>18*</sup>, on behalf of NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI)</p>
November 29, 2011

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.