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.

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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


  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


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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

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