Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1

Nature Genetics volume 39, pages 733–740 (2007)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Allele frequency of KIR3DL1 alleles and HLA-B Bw4 subtypes.
Figure 2: Effect of KIR3DL1*004 + HLA-B Bw4 on AIDS progression.
Figure 3: Effect of KIR3DL1 + HLA-B Bw4 genotypes on progression to CD4+ T-cell count < 200 cells/mm3.
Figure 4: Synergistic influence of specific HLA-B allotypes with KIR3DL1*h and KIR3DL1*l genotypes on progression to two AIDS outcomes.
Figure 5: KIR3DL1 + Bw4 continuum of protection.

Similar content being viewed by others

References

  1. Biron, C.A., Nguyen, K.B., Pien, G.C., Cousens, L.P. & Salazar-Mather, T.P. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu. Rev. Immunol. 17, 189–220 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Colucci, F., Di Santo, J.P. & Leibson, P.J. Natural killer cell activation in mice and men: different triggers for similar weapons? Nat. Immunol. 3, 807–813 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. 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).

    CAS  PubMed  Google Scholar 

  6. Carr, W.H., Pando, M.J. & Parham, P. KIR3DL1 polymorphisms that affect NK cell inhibition by HLA-Bw4 ligand. J. Immunol. 175, 5222–5229 (2005).

    Article  CAS  Google Scholar 

  7. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. 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).

    Article  CAS  Google Scholar 

  10. Yawata, M. 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).

    Article  CAS  Google Scholar 

  11. Pando, M.J., Gardiner, C.M., Gleimer, M., McQueen, K.L. & Parham, P. 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).

    Article  CAS  Google Scholar 

  12. Carrington, M. & O'Brien, S.J. The influence of HLA genotype on AIDS. Annu. Rev. Med. 54, 535–551 (2003).

    Article  CAS  Google Scholar 

  13. Goulder, P.J. & Watkins, D.I. HIV and SIV CTL escape: Implications for vaccine design. Nat. Rev. Immunol. 4, 630–640 (2004).

    Article  CAS  Google Scholar 

  14. 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).

    Article  CAS  Google Scholar 

  15. Rammensee, H., Bachmann, J., Emmerich, N.P., Bachor, O.A. & Stevanovic, S. SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 50, 213–219 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Fernandez, N.C. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Storey, J.D. & Tibshirani, R. Statistical significance for genomewide studies. Proc. Natl. Acad. Sci. USA 100, 9440–9445 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. 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).

    Article  CAS  Google Scholar 

  25. Lopez-Vazquez, A. 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).

    Article  CAS  Google Scholar 

  26. Jennes, W. 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).

    Article  CAS  Google Scholar 

  27. Dorfman, J.R. & Raulet, D.H. Acquisition of Ly49 receptor expression by developing natural killer cells. J. Exp. Med. 187, 609–618 (1998).

    Article  CAS  Google Scholar 

  28. Held, W., Dorfman, J.R., Wu, M.F. & Raulet, D.H. Major histocompatibility complex class I-dependent skewing of the natural killer cell Ly49 receptor repertoire. Eur. J. Immunol. 26, 2286–2292 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  30. Raulet, D.H. & Vance, R.E. Self-tolerance of natural killer cells. Nat. Rev. Immunol. 6, 520–531 (2006).

    Article  CAS  Google Scholar 

  31. Yokoyama, W.M. & Kim, S. How do natural killer cells find self to achieve tolerance? Immunity 24, 249–257 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  33. Carrington, M. 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).

    Article  CAS  Google Scholar 

  34. Klein, J., Satta, Y., O'hUigin, C. & Takahata, N. The molecular descent of the major histocompatibility complex. Annu. Rev. Immunol. 11, 269–295 (1993).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  36. Yawata, M., Yawata, N., Abi-Rached, L. & Parham, P. Variation within the human killer cell immunoglobulin-like receptor (KIR) gene family. Crit. Rev. Immunol. 22, 463–482 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  39. Phair, J. 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).

    Article  CAS  Google Scholar 

  40. Goedert, J.J. 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).

    Article  CAS  Google Scholar 

  41. Buchbinder, S.P., Katz, M.H., Hessol, N.A., O'Malley, P.M. & Holmberg, S.D. Long-term HIV-1 infection without immunologic progression. AIDS 8, 1123–1128 (1994).

    Article  CAS  Google Scholar 

  42. Vlahov, D. 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).

    Article  CAS  Google Scholar 

  43. Emu, B. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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

Authors and Affiliations

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

    Eriko Yamada & Daniel W McVicar

  3. Department of Epidemiology and Biostatistics, University of California, 995 Potrero Avenue, San Francisco, 94105, California, USA

    Jeffrey N Martin

  4. Partners AIDS Research Center and Infectious Disease Division, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Boston, 02129, Massachusetts, 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. Division of Cancer Epidemiology and Genetics, Viral Epidemiology Branch, National Cancer Institute, 6120 Executive Boulevard, EPS 7066, Rockville, 20852, Maryland, USA

    Elizabeth E Brown & James J Goedert

  7. Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, 903 South Fourth Street, Hamilton, 59840, Montana, USA

    W Lesley Shupert

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

    John Phair

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

    Susan Buchbinder

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

    Gregory D Kirk

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

    Mark Connors

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

    Stephen J O'Brien

  13. Department of Structural Biology, Stanford University School of Medicine, Fairchild D-159, 299 Campus Drive West, Stanford, 94305, California, USA

    Peter Parham

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

    Steven G Deeks

Authors
  1. Maureen P Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ying Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaojiang Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eriko Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jeffrey N Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Florencia Pereyra
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sara Colombo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elizabeth E Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. W Lesley Shupert
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. John Phair
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. James J Goedert
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Susan Buchbinder
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Gregory D Kirk
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Amalio Telenti
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Mark Connors
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Stephen J O'Brien
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Bruce D Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Peter Parham
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Steven G Deeks
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Daniel W McVicar
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Mary Carrington
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Mary Carrington.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Effect of KIR3DL1 alleles with HLA-Bw4 on progression to AIDS (PDF 9 kb)

Supplementary Table 2

Direct comparison of genotypes (PDF 59 kb)

Supplementary Table 3

Synergistic effect of HLA-B*57 and −B*27 with KIR3DL1*h and *l on AIDS progression (PDF 9 kb)

Supplementary Table 4

Effect of combinations of KIR3DL1 and HLA-B on MVL (excluding samples that overlap with the progression analysis) (PDF 63 kb)

Supplementary Table 5

Synergistic effects of KIR3DL1 and HLA-B on HIV disease progression and MVL (PDF 63 kb)

Supplementary Table 6

KIR3DL1 primers and probes (PDF 9 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Martin, M., Qi, Y., Gao, X. et al. Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. Nat Genet 39, 733–740 (2007). https://doi.org/10.1038/ng2035

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng2035

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing