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 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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Figure 1: Effect of HLA-B Bw4-80Ile and KIR3DS1 on AIDS progression.


  1. 1

    Lanier, L.L. NK cell receptors. Annu. Rev. Immunol. 16, 359–393 (1998).

  2. 2

    Long, E.O. & Rajagopalan, S. HLA class I recognition by killer cell Ig-like receptors. Semin. Immunol. 12, 101–108 (2000).

  3. 3

    Lorenzo, M.E., Ploegh, H.L. & Tirabassi, R.S. Viral immune evasion strategies and the underlying cell biology. Semin. Immunol. 13, 1–9 (2001).

  4. 4

    Collins, K.L., Chen, B.K., Kalams, S.A., Walker, B.D. & Baltimore, D. HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 391, 397–401 (1998).

  5. 5

    Trowsdale, J. et al. The genomic context of natural killer receptor extended gene families. Immunol. Rev. 181, 20–38 (2001).

  6. 6

    Wilson, M.J. et al. Plasticity in the organization and sequences of human KIR/ILT gene families. Proc. Natl Acad. Sci. USA 97, 4778–4783 (2000).

  7. 7

    Rojo, S., Wagtmann, N. & Long, E.O. Binding of a soluble p70 killer cell inhibitory receptor to HLA-B*5101: requirement for all three p70 immunoglobulin domains. Eur. J. Immunol. 27, 568–571 (1997).

  8. 8

    Gardiner, C.M. et al. Different NK cell surface phenotypes defined by the DX9 antibody are due to KIR3DL1 gene polymorphism. J. Immunol. 166, 2992–3001 (2001).

  9. 9

    Long, E.O. Regulation of immune responses through inhibitory receptors. Annu. Rev. Immunol. 17, 875–904 (1999).

  10. 10

    Lanier, L.L., Corliss, B.C., Wu, J., Leong, C. & Phillips, J.H. Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature 391, 703–707 (1998).

  11. 11

    Biassoni, R. 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. J. Exp. Med. 183, 645–650 (1996).

  12. 12

    Muller, C.A. et al. Genetic and serological heterogeneity of the supertypic HLA-B locus specificities Bw4 and Bw6. Immunogenetics 30, 200–207 (1989).

  13. 13

    Gumperz, J.E., Litwin, V., Phillips, J.H., Lanier, L.L. & Parham, P. The Bw4 public epitope of HLA-B molecules confers reactivity with natural killer cell clones that express NKB1, a putative HLA receptor. J. Exp. Med. 181, 1133–1144 (1995).

  14. 14

    Cella, M., Longo, A., Ferrara, G.B., Strominger, J.L. & Colonna, M. NK3-specific natural killer cells are selectively inhibited by Bw4- positive HLA alleles with isoleucine 80. J. Exp. Med. 180, 1235–1242 (1994).

  15. 15

    Gumperz, J.E. 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. J. Immunol. 158, 5237–5241 (1997).

  16. 16

    McMichael, A.J. & Rowland-Jones, S.L. Cellular immune responses to HIV. Nature 410, 980–987 (2001).

  17. 17

    Carrington, M., Nelson, G. & O'Brien, S.J. Considering genetic profiles in functional studies of immune responsiveness to HIV-1. Immunol. Lett. 79, 131–140 (2001).

  18. 18

    Kaslow, R.A. et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nature Med. 2, 405–411 (1996).

  19. 19

    Gao, X. et al. Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS. N. Engl. J. Med. 344, 1668–1675 (2001).

  20. 20

    Flores-Villanueva, P.O. et al. Control of HIV-1 viremia and protection from AIDS are associated with HLA-Bw4 homozygosity. Proc. Natl Acad. Sci. USA 98, 5140–5145 (2001).

  21. 21

    O'Brien, S.J., Gao, X. & Carrington, M. HLA and AIDS: a cautionary tale. Trends Mol. Med. 7, 379–381 (2001).

  22. 22

    Colonna, M., Brooks, E.G., Falco, M., Ferrara, G.B. & Strominger, J.L. Generation of allospecific natural killer cells by stimulation across a polymorphism of HLA-C. Science 260, 1121–1124 (1993).

  23. 23

    Boyington, J.C., Brooks, A.G. & Sun, P.D. Structure of killer cell immunoglobulin-like receptors and their recognition of the class I MHC molecules. Immunol. Rev. 181, 66–78 (2001).

  24. 24

    Phillips, J.H., Gumperz, J.E., Parham, P. & Lanier, L.L. Superantigen-dependent, cell-mediated cytotoxicity inhibited by MHC class I receptors on T lymphocytes. Science 268, 403–405 (1995).

  25. 25

    De Maria, A. et al. Expression of HLA class I-specific inhibitory natural killer cell receptors in HIV-specific cytolytic T lymphocytes: impairment of specific cytolytic functions. Proc. Natl Acad. Sci. USA 94, 10285–10288 (1997).

  26. 26

    Koup, R.A. et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J. Virol. 68, 4650–4655 (1994).

  27. 27

    Kelleher, A.D. et al. Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses. J. Exp. Med. 193, 375–386 (2001).

  28. 28

    Hughes, A.L., Yeager, M. & Carrington, M. Peptide binding function and the paradox of HLA disease associations. Immunol. Cell. Biol. 74, 444–448 (1996).

  29. 29

    Peruzzi, M., Wagtmann, N. & Long, E.O. A p70 killer cell inhibitory receptor specific for several HLA-B allotypes discriminates among peptides bound to HLA-B*2705. J. Exp. Med. 184, 1585–1590 (1996).

  30. 30

    Kajiwara, K., Berson, E.L. & Dryja, T.P. Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. Science 264, 1604–1608 (1994).

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We thank P. Parham for comments. This work was supported by funds from the US National Cancer Institute and National Institutes of Health. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government.

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Correspondence to Mary Carrington.

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