title: Copy number variation of KIR genes influences HIV-1 control.
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.
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Pelak
authors.forename: Anna C
authors.initials: AC
authors.lastname: Need
authors.forename: Jacques
authors.initials: J
authors.lastname: Fellay
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Shianna
authors.forename: Sheng
authors.initials: S
authors.lastname: Feng
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Urban
authors.forename: Dongliang
authors.initials: D
authors.lastname: Ge
authors.forename: Andrea
authors.initials: A
authors.lastname: De Luca
authors.forename: Javier
authors.initials: J
authors.lastname: Martinez-Picado
authors.forename: Steven M
authors.initials: SM
authors.lastname: Wolinsky
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Martinson
authors.forename: Beth D
authors.initials: BD
authors.lastname: Jamieson
authors.forename: Jay H
authors.initials: JH
authors.lastname: Bream
authors.forename: Maureen P
authors.initials: MP
authors.lastname: Martin
authors.forename: Persephone
authors.initials: P
authors.lastname: Borrow
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McMichael
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.forename: Galit
authors.initials: G
authors.lastname: Alter
mesh_terms: D015331:Cohort Studies; D056915:DNA Copy Number Variations; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism / Q000502:physiology; D008213:Lymphocyte Activation; D018448:Models, Immunological; D054340:Receptors, KIR / Q000235:genetics* / Q000378:metabolism; D019562:Viral Load; D014779:Virus Replication
chemical_list: D054340:Receptors, KIR