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

  1. Author:
    Martin, M. P.
    Gao, X. J.
    Lee, J. H.
    Nelson, G. W.
    Detels, R.
    Goedert, J. J.
    Buchbinder, S.
    Hoots, K.
    Vlahov, D.
    Trowsdale, J.
    Wilson, M.
    O'Brien, S. J.
    Carrington, M.

  2. Author Address

    NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21702 USA NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21702 USA NCI, Lab Genom Divers, Frederick, MD 21702 USA Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90095 USA NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA San Francisco City Clin Cohort, San Francisco, CA 94102 USA Univ Texas, Hlth Sci Ctr, Gulf States Hemophilia Ctr, Houston, TX 77030 USA Johns Hopkins Med Inst, Sch Hyg & Publ Hlth, Baltimore, MD 21205 USA Univ Cambridge, Dept Pathol, Div Immunol, Cambridge CB2 1QP, England Carrington M NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21702 USA
    1. Year: 2002
  2. Journal: Nature Genetics
    1. 31
    2. 4
    3. Pages: 429-434
  4. Type of Article: Article
  1. Abstract:

    Natural killer (NK) cells provide defense in the early stages of the innate immune response against viral infections by producing cytokines and causing cytotoxicity(1). 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 cells(2). 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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