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Letter
Nature Genetics  31, 429 - 434 (2002)
Published online: 22 July 2002; | doi:10.1038/ng934

Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS

Maureen P. Martin1, 10, Xiaojiang Gao1, 10, Jeong-Hee Lee2, 9, George W. Nelson1, Roger Detels3, James J. Goedert4, Susan Buchbinder5, Keith Hoots6, David Vlahov7, John Trowsdale8, Michael Wilson8, 9, Stephen J. O'Brien2 & Mary Carrington1

1  Basic Research Program, SAIC Frederick, Frederick, Maryland 21702-1201, USA.

2  Laboratory of Genomic Diversity, National Cancer Institute (NCI), Frederick, Maryland 21702-1201, USA.

3  Department of Epidemiology, School of Public Health, University of California, Los Angeles, California 90095, USA.

4  Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, Executive Plaza North, Bethesda, Maryland 20892, USA.

5  San Francisco City Clinic Cohort, San Francisco, California 94102, USA.

6  Gulf States Hemophilia Center, University of Texas Health Science Center, Houston, Texas 77030, USA.

7  The Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 21205, USA.

8  University of Cambridge, Immunology Division, Department of Pathology, Tennis Court Road, Cambridge CB2 1QP, UK.

9  Present addresses: Department of Pathology, College of Medicine, GyeonSang National University, Chinju, South Korea (J.-H.L.); GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK (M.W).

10  These authors contributed equally to this work.

Correspondence should be addressed to Mary Carrington carringt@ncifcrf.gov
Natural killer (NK) cells provide defense in the early stages of the innate immune response against viral infections by producing cytokines and causing cytotoxicity1. The killer immunoglobulin-like receptors (KIRs) on NK cells regulate the inhibition and activation of NK-cell responses through recognition of human leukocyte antigen (HLA) class I molecules on target cells2 KIR and HLA loci are both highly polymorphic, and some HLA class I products bind and trigger cell-surface receptors specified by KIR genes. Here we report that the activating KIR allele KIR3DS1, in combination with HLA-B alleles that encode molecules with isoleucine at position 80 (HLA-B Bw4-80Ile), is associated with delayed progression to AIDS in individuals infected with human immunodeficiency virus type 1 (HIV-1). In the absence of KIR3DS1, the HLA-B Bw4-80Ile allele was not associated with any of the AIDS outcomes measured. By contrast, in the absence of HLA-B Bw4-80Ile alleles, KIR3DS1 was significantly associated with more rapid progression to AIDS. These observations are strongly suggestive of a model involving an epistatic interaction between the two loci. The strongest synergistic effect of these loci was on progression to depletion of CD4+ T cells, which suggests that a protective response of NK cells involving KIR3DS1 and its HLA class I ligands begins soon after HIV-1 infection.


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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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