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Copy number variation of KIR genes influences HIV-1 control

Pelak, K and Need, AC and Fellay, J and Shianna, KV and Feng, S and Urban, TJ and Ge, D and de Luca, A and Martinez-Picado, J and Wolinsky, SM and Martinson, JJ and Jamieson, BD and Bream, JH and Martin, MP and Borrow, P and Letvin, NL and McMichael, AJ and Haynes, BF and Telenti, A and Carrington, M and Goldstein, DB and Alter, G (2011) Copy number variation of KIR genes influences HIV-1 control. PLoS Biology, 9 (11). ISSN 1544-9173

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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. © 2011 Pelak et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Pelak, K
Need, AC
Fellay, J
Shianna, KV
Feng, S
Urban, TJ
Ge, D
de Luca, A
Martinez-Picado, J
Wolinsky, SM
Martinson, JJjmartins@pitt.eduJMARTINS
Jamieson, BD
Bream, JH
Martin, MP
Borrow, P
Letvin, NL
McMichael, AJ
Haynes, BF
Telenti, A
Carrington, M
Goldstein, DB
Alter, G
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
InvestigatorHaynes, BartonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorGoldstein, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorTelenti, AmalioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorLedergerber, BrunoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorFrancioli, PUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Investigatord'Arminio Monforte, AUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorDe Luca, AUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorCastagna, AUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorMallal, SUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorMartinez-Picado, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorDalmau, JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorEasterbrook, PUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorObel, NUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorCossarizza, AUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorGatell, J MUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorMargolick, JosephUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorPhair, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorDetels, RogerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorRinaldo, CharlesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
InvestigatorJacobson, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
EditorEmerman, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 November 2011
Date Type: Publication
Journal or Publication Title: PLoS Biology
Volume: 9
Number: 11
DOI or Unique Handle: 10.1371/journal.pbio.1001208
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Refereed: Yes
ISSN: 1544-9173
MeSH Headings: Cohort Studies; DNA Copy Number Variations; HIV-1--immunology; HIV-1--physiology; Humans; Killer Cells, Natural--metabolism; Killer Cells, Natural--physiology; Lymphocyte Activation; Models, Immunological; Receptors, KIR--genetics; Receptors, KIR--metabolism; Viral Load; Virus Replication
Other ID: NLM PMC3226550
PubMed Central ID: PMC3226550
PubMed ID: 22140359
Date Deposited: 07 Sep 2012 19:44
Last Modified: 02 Feb 2019 15:55
URI: http://d-scholarship.pitt.edu/id/eprint/14000

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