Journal Article

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

Martin, Maureen P., Detels, Roger, Gao, Xiaojiang, O'Brien, Stephen J., Lee, Jeong-Hee, Nelson, George W., Trowsdale, John, Carrington, Mary, Wilson, Michael, Goedert, James J., Buchbinder, Susan, Hoots, Keith, Vlahov, David

2002

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Acquired immune deficiency syndrome / Acquired Immunodeficiency Syndrome - epidemiology / Acquired Immunodeficiency Syndrome - genetics / Agriculture / AIDS / AIDS (Disease) / Alleles / Animal Genetics and Genomics / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Black or African American / Black People - genetics / Cancer Research / CD4-Positive T-Lymphocytes / Cytotoxicity / Disease Progression / Epidemiology / Epistasis, Genetic / Epitopes / Fundamental and applied biological sciences. Psychology / Gene Function / Genes / Genetic aspects / Genetic Predisposition to Disease / Health aspects / Histocompatibility antigens / HIV / HIV-1 / HLA histocompatibility antigens / HLA-B Antigens - genetics / HLA-B Antigens - immunology / Human Genetics / Human immunodeficiency virus / Human immunodeficiency virus 1 / Humans / Immune response / Immunoglobulins / Interactions. Associations / Intermolecular phenomena / Killer cells / Killer Cells, Natural - immunology / Killer Cells, Natural - virology / letter / Leukocytes / Ligands / Molecular biophysics / Physiological aspects / Prevention / Public health / Receptors, Immunologic - genetics / Receptors, KIR / Receptors, KIR3DS1 / Regression Analysis / Risk factors / Survival Rate / Synergistic effect / United States - epidemiology / White People - genetics