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

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

[1]  Eric O Long,et al.  Regulation of immune responses through inhibitory receptors. , 1999, Annual review of immunology.

[2]  B. Walker,et al.  HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes , 1998, Nature.

[3]  P. Parham,et al.  The Bw4 public epitope of HLA-B molecules confers reactivity with natural killer cell clones that express NKB1, a putative HLA receptor , 1995, The Journal of experimental medicine.

[4]  D. Ho,et al.  Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome , 1994, Journal of virology.

[5]  H. Ploegh,et al.  Viral immune evasion strategies and the underlying cell biology. , 2001, Seminars in immunology.

[6]  J J Goedert,et al.  Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS. , 2001, The New England journal of medicine.

[7]  M. Carrington,et al.  Considering genetic profiles in functional studies of immune responsiveness to HIV-1. , 2001, Immunology letters.

[8]  E. Rosenberg,et al.  Control of HIV-1 viremia and protection from AIDS are associated with HLA-Bw4 homozygosity , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[9]  R. Biassoni,et al.  The human leukocyte antigen (HLA)-C-specific "activatory" or "inhibitory" natural killer cell receptors display highly homologous extracellular domains but differ in their transmembrane and intracytoplasmic portions , 1996, The Journal of experimental medicine.

[10]  Eric O Long,et al.  HLA class I recognition by killer cell Ig-like receptors. , 2000, Seminars in immunology.

[11]  P. Parham,et al.  Superantigen-dependent, cell-mediated cytotoxicity inhibited by MHC class I receptors on T lymphocytes. , 1995, Science.

[12]  G. Ferrara,et al.  NK3-specific natural killer cells are selectively inhibited by Bw4- positive HLA alleles with isoleucine 80 , 1994, The Journal of experimental medicine.

[13]  P. Sun,et al.  Structure of killer cell immunoglobulin‐like receptors and their recognition of the class I MHC molecules , 2001, Immunological reviews.

[14]  T. Dryja,et al.  Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. , 1994, Science.

[15]  P Parham,et al.  Conserved and variable residues within the Bw4 motif of HLA-B make separable contributions to recognition by the NKB1 killer cell-inhibitory receptor. , 1997, Journal of immunology.

[16]  S. Beck,et al.  Plasticity in the organization and sequences of human KIR/ILT gene families. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Michael J. Wilson,et al.  The genomic context of natural killer receptor extended gene families , 2001, Immunological reviews.

[18]  A. Fauci,et al.  Expression of HLA class I-specific inhibitory natural killer cell receptors in HIV-specific cytolytic T lymphocytes: impairment of specific cytolytic functions. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Eric O Long,et al.  A p70 killer cell inhibitory receptor specific for several HLA-B allotypes discriminates among peptides bound to HLA-B*2705 , 1996, The Journal of experimental medicine.

[20]  L. Lanier.  NK cell receptors. , 1998, Annual review of immunology.

[21]  E. Brooks,et al.  Generation of allospecific natural killer cells by stimulation across a polymorphism of HLA-C. , 1993, Science.

[22]  S. Rowland-Jones,et al.  Cellular immune responses to HIV , 2001, Nature.

[23]  William H. Carr,et al.  Different NK Cell Surface Phenotypes Defined by the DX9 Antibody Are Due to KIR3DL1 Gene Polymorphism1 , 2001, The Journal of Immunology.

[24]  Edward C. Holmes,et al.  Clustered Mutations in HIV-1 Gag Are Consistently Required for Escape from Hla-B27–Restricted Cytotoxic T Lymphocyte Responses , 2001, The Journal of experimental medicine.

[25]  Eric O Long,et al.  Binding of a soluble p70 killer cell inhibitory receptor to HLA‐B*5101: Requirement for all three p70 immunoglobulin domains , 1997, European journal of immunology.

[26]  M. Carrington,et al.  Peptide binding function and the paradox of HLA disease associations , 1996, Immunology and cell biology.

[27]  J. Goedert,et al.  Influence of combinations of human major histocompatibility complex genes on the course of HIV–1 infection , 1996, Nature Medicine.

[28]  Jun Wu,et al.  Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells , 1998, Nature.

[29]  M. Carrington,et al.  HLA and AIDS: a cautionary tale. , 2001, Trends in molecular medicine.