Abstract

Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)+ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , , & Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu. Rev. Immunol. 17, 189–220 (1999).

  2. 2.

    NK cell recognition. Annu. Rev. Immunol. 23, 225–274 (2005).

  3. 3.

    , & Natural killer cell activation in mice and men: different triggers for similar weapons? Nat. Immunol. 3, 807–813 (2002).

  4. 4.

    & KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu. Rev. Immunol. 20, 217–251 (2002).

  5. 5.

    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).

  6. 6.

    , & KIR3DL1 polymorphisms that affect NK cell inhibition by HLA-Bw4 ligand. J. Immunol. 175, 5222–5229 (2005).

  7. 7.

    , , , & NK3-specific natural killer cells are selectively inhibited by Bw4- positive HLA alleles with isoleucine 80. J. Exp. Med. 180, 1235–1242 (1994).

  8. 8.

    et al. Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors. Immunity 7, 739–751 (1997).

  9. 9.

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

  10. 10.

    et al. Roles for HLA and KIR polymorphisms in natural killer cell repertoire selection and modulation of effector function. J. Exp. Med. 203, 633–645 (2006).

  11. 11.

    , , , & The protein made from a common allele of KIR3DL1 (3DL1*004) is poorly expressed at cell surfaces due to substitution at positions 86 in Ig domain 0 and 182 in Ig domain 1. J. Immunol. 171, 6640–6649 (2003).

  12. 12.

    & The influence of HLA genotype on AIDS. Annu. Rev. Med. 54, 535–551 (2003).

  13. 13.

    & HIV and SIV CTL escape: Implications for vaccine design. Nat. Rev. Immunol. 4, 630–640 (2004).

  14. 14.

    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).

  15. 15.

    , , , & SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 50, 213–219 (1999).

  16. 16.

    , & HLA and AIDS: a cautionary tale. Trends Mol. Med. 7, 379–381 (2001).

  17. 17.

    et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat. Genet. 31, 429–434 (2002).

  18. 18.

    et al. KIR/HLA pleiotropism: Protection against both HIV and opportunistic infections. PLoS Pathog. 2, e79 (2006).

  19. 19.

    et al. Human NK cell education by inhibitory receptors for MHC class I. Immunity 25, 331–342 (2006).

  20. 20.

    et al. A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules. Blood 105, 4416–4423 (2005).

  21. 21.

    et al. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436, 709–713 (2005).

  22. 22.

    & Statistical significance for genomewide studies. Proc. Natl. Acad. Sci. USA 100, 9440–9445 (2003).

  23. 23.

    et al. AIDS restriction HLA allotypes target distinct intervals of HIV-1 pathogenesis. Nat. Med. 11, 1290–1292 (2005).

  24. 24.

    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).

  25. 25.

    et al. Interaction between KIR3DL1 and HLA-B*57 supertype alleles influences the progression of HIV-1 infection in a Zambian population. Hum. Immunol. 66, 285–289 (2005).

  26. 26.

    et al. Cutting edge: resistance to HIV-1 infection among African female sex workers is associated with inhibitory KIR in the absence of their HLA ligands. J. Immunol. 177, 6588–6592 (2006).

  27. 27.

    & Acquisition of Ly49 receptor expression by developing natural killer cells. J. Exp. Med. 187, 609–618 (1998).

  28. 28.

    , , & Major histocompatibility complex class I-dependent skewing of the natural killer cell Ly49 receptor repertoire. Eur. J. Immunol. 26, 2286–2292 (1996).

  29. 29.

    Taking license with natural killer cell maturation and repertoire development. Immunol. Rev. 214, 155–160 (2006).

  30. 30.

    & Self-tolerance of natural killer cells. Nat. Rev. Immunol. 6, 520–531 (2006).

  31. 31.

    & How do natural killer cells find self to achieve tolerance? Immunity 24, 249–257 (2006).

  32. 32.

    et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 305, 872–874 (2004).

  33. 33.

    et al. Hierarchy of resistance to cervical neoplasia mediated by combinations of killer immunoglobulin-like receptor and human leukocyte antigen loci. J. Exp. Med. 201, 1069–1075 (2005).

  34. 34.

    , , & The molecular descent of the major histocompatibility complex. Annu. Rev. Immunol. 11, 269–295 (1993).

  35. 35.

    et al. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 432, 769–775 (2004).

  36. 36.

    , , & Variation within the human killer cell immunoglobulin-like receptor (KIR) gene family. Crit. Rev. Immunol. 22, 463–482 (2002).

  37. 37.

    & Natural selection drives recurrent formation of activating killer cell immunoglobulin-like receptor and Ly49 from inhibitory homologues. J. Exp. Med. 201, 1319–1332 (2005).

  38. 38.

    et al. Rapid evolution of NK cell receptor systems demonstrated by comparison of chimpanzees and humans. Immunity 12, 687–698 (2000).

  39. 39.

    et al. Acquired immune deficiency syndrome occurring within 5 years of infection with human immunodeficiency virus type-1: the Multicenter AIDS Cohort Study. J. Acquir. Immune Defic. Syndr. 5, 490–496 (1992).

  40. 40.

    et al. A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with hemophilia. N. Engl. J. Med. 321, 1141–1148 (1989).

  41. 41.

    , , , & Long-term HIV-1 infection without immunologic progression. AIDS 8, 1123–1128 (1994).

  42. 42.

    et al. Prognostic indicators for AIDS and infectious disease death in HIV-infected injection drug users: plasma viral load and CD4+ cell count. J. Am. Med. Assoc. 279, 35–40 (1998).

  43. 43.

    et al. Phenotypic, functional, and kinetic parameters associated with apparent T-cell control of human immunodeficiency virus replication in individuals with and without antiretroviral treatment. J. Virol. 79, 14169–14178 (2005).

  44. 44.

    et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat. Immunol. 3, 1061–1068 (2002).

  45. 45.

    Council of State and Territorial Epidemiologists; AIDS Program, Center for Infectious Diseases. Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR Morb. Mortal. Wkly. Rep. 36(suppl. 1), 1S–15S (1987).

Download references

Acknowledgements

This project has been funded in whole or in part with federal funds from the US National Cancer Institute, National Institutes of Health (NIH), under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The ALIVE study was supported by US National Institute on Drug Abuse RO1-DA04334. The SCOPE cohort was supported by the NIH (P30 AI027763) and the University of California at San Francisco AIDS Research Institute. The Swiss HIV Cohort study was funded by the Swiss National Science Foundation.

Author information

Affiliations

  1. Laboratory of Genomic Diversity, Science Applications International Corporation–Frederick, Inc., National Cancer Institute, P.O. Box B, Building 560, Frederick, Maryland 21702, USA.

    • Maureen P Martin
    • , Ying Qi
    • , Xiaojiang Gao
    •  & Mary Carrington
  2. Laboratory of Experimental Immunology, National Cancer Institute, P.O. Box B, Building 560, Frederick, Maryland 21702, USA.

    • Eriko Yamada
    •  & Daniel W McVicar
  3. Department of Epidemiology and Biostatistics, University of California, 995 Potrero Avenue, San Francisco, California 94105, USA.

    • Jeffrey N Martin
  4. Partners AIDS Research Center and Infectious Disease Division, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Boston, Massachusetts 02129, USA.

    • Florencia Pereyra
    •  & Bruce D Walker
  5. Institute of Microbiology, University of Lausanne, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland.

    • Sara Colombo
    •  & Amalio Telenti
  6. Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, EPS 7066, Rockville, Maryland 20852, USA.

    • Elizabeth E Brown
    •  & James J Goedert
  7. Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, 903 South Fourth Street, Hamilton, Montana 59840, USA.

    • W Lesley Shupert
  8. Department of Medicine, Northwestern University Medical School, 676 North St. Clair, No. 200, Chicago, Illinois 60611, USA.

    • John Phair
  9. San Francisco Department of Public Health, HIV Research Section, 25 Van Ness Avenue, Suite 710, San Francisco, California 94102, USA.

    • Susan Buchbinder
  10. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, Maryland 21205, USA.

    • Gregory D Kirk
  11. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, 10 Center Drive, MSC 1876, Bethesda, Maryland 20892, USA.

    • Mark Connors
  12. Laboratory of Genomic Diversity, National Cancer Institute, P.O. Box B, Building 560, Frederick, Maryland 21702, USA.

    • Stephen J O'Brien
  13. Department of Structural Biology, Stanford University School of Medicine, Fairchild D-159, 299 Campus Drive West, Stanford, California 94305, USA.

    • Peter Parham
  14. San Francisco General Hospital, 995 Potrero Avenue, California 94110, USA.

    • Steven G Deeks

Authors

  1. Search for Maureen P Martin in:

  2. Search for Ying Qi in:

  3. Search for Xiaojiang Gao in:

  4. Search for Eriko Yamada in:

  5. Search for Jeffrey N Martin in:

  6. Search for Florencia Pereyra in:

  7. Search for Sara Colombo in:

  8. Search for Elizabeth E Brown in:

  9. Search for W Lesley Shupert in:

  10. Search for John Phair in:

  11. Search for James J Goedert in:

  12. Search for Susan Buchbinder in:

  13. Search for Gregory D Kirk in:

  14. Search for Amalio Telenti in:

  15. Search for Mark Connors in:

  16. Search for Stephen J O'Brien in:

  17. Search for Bruce D Walker in:

  18. Search for Peter Parham in:

  19. Search for Steven G Deeks in:

  20. Search for Daniel W McVicar in:

  21. Search for Mary Carrington in:

Contributions

M.C. designed and supervised the project, and prepared the manuscript; M.P.M. performed KIR genotyping and prepared the manuscript; Y.Q. conducted the data analyses; X.G. performed HLA genotyping; E.Y. contributed to KIR genotyping experiments; P.P., S.G.D, D.W.M. provided intellectual input; S.J.O. provided access to samples and clinical data; E.E.B. participated in data analysis; and J.N.M., F.P., S.C., W.L.S., J.P., J.J.G., S.B., G.D.K., A.T., M.C., B.D.W., and S.G.D. provided clinical samples and data. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Mary Carrington.

Supplementary information

PDF files

  1. 1.

    Supplementary Table 1

    Effect of KIR3DL1 alleles with HLA-Bw4 on progression to AIDS

  2. 2.

    Supplementary Table 2

    Direct comparison of genotypes

  3. 3.

    Supplementary Table 3

    Synergistic effect of HLA-B*57 and −B*27 with KIR3DL1*h and *l on AIDS progression

  4. 4.

    Supplementary Table 4

    Effect of combinations of KIR3DL1 and HLA-B on MVL (excluding samples that overlap with the progression analysis)

  5. 5.

    Supplementary Table 5

    Synergistic effects of KIR3DL1 and HLA-B on HIV disease progression and MVL

  6. 6.

    Supplementary Table 6

    KIR3DL1 primers and probes

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng2035

Further reading