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HLA-C cell surface expression and control of HIV/AIDS correlate with a variant upstream of HLA-C

Nature Genetics volume 41, pages 1290–1294 (2009)Cite this article

Abstract

A variant 35 kb upstream of the HLA-C gene (-35C/T) was previously shown to associate with HLA-C mRNA expression level and steady-state plasma HIV RNA levels. We genotyped this variant in 1,698 patients of European ancestry with HIV. Individuals with known seroconversion dates were used for disease progression analysis and those with longitudinal viral load data were used for viral load analysis. We further tested cell surface expression of HLA-C in normal donors using an HLA-C-specific antibody. We show that the -35C allele is a proxy for high HLA-C cell surface expression, and that individuals with high-expressing HLA-C alleles progress more slowly to AIDS and control viremia significantly better than individuals with low HLA-C expressing alleles. These data strongly implicate high HLA-C expression levels in more effective control of HIV-1, potentially through better antigen presentation to cytotoxic T lymphocytes or recognition and killing of infected cells by natural killer cells.

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Figure 1: Level of mRNA expression varies among HLA-C alleles and correlates with the -35 SNP.
Figure 2: Variation in the level of surface HLA-C protein correlates with -35 genotype.
Figure 3: Highly expressed HLA-C allotypes control HIV to a greater extent than HLA C allotypes with lower expression.
Figure 4: The phylogram shows neighbor-joining relationships among full-length HLA-C alleles estimated using Kimura's 2-parameter substitution model.

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Acknowledgements

This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contracts HHSN261200800001E, N02-CP-55504, R01-DA04334 and R01-DA12568. 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. This research was partially funded by a grant from the Bill & Melinda Gates Foundation as part of the Collaboration for AIDS Vaccine Discovery. We would also like to acknowledge the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation, and the SCOPE study was funded by the UL1 RR024131 (Clinical and Translational Sciences Award) and P30 AI27763 (Center for AIDS Research) grants. R.A. is funded by the Cambridge Center for Trophoblast Research. We also thank R. Fernando and the Anthony Nolan Research Institute for the Luminex analysis.

Author information

Authors and Affiliations

  1. Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, USA

    Rasmi Thomas, Ying Qi, Xiaojiang Gao, Colm O'hUigin, Maureen P Martin & Mary Carrington

  2. Department of Pathology, Cambridge University, Cambridge, UK

    Richard Apps, Victoria Male & Ashley Moffett

  3. Cancer and Inflammation Program, Laboratory of Experimental Immunology, NCI-Frederick, Frederick, Maryland, USA

    Geraldine O'Connor & Daniel W McVicar

  4. Center for Population Genomics & Pharmacogenetics, Duke University, Durham, North Carolina, USA

    Dongliang Ge, Jacques Fellay & David Goldstein

  5. Epidemiology and Biostatistics, University of California, San Francisco, California, USA

    Jeffrey N Martin

  6. Department of Molecular Microbiology & Immunology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA

    Joseph Margolick

  7. Division of Cancer Epidemiology and Genetics, Infections and Immunoepidemiology Branch, National Cancer Institute, Rockville, Maryland, USA

    James J Goedert

  8. San Francisco Department of Public Health, HIV Research Section, San Francisco, California, USA

    Susan Buchbinder

  9. Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA

    Gregory D Kirk

  10. Institute of Microbiology, University of Lausanne, Lausanne, Switzerland

    Amalio Telenti

  11. San Francisco General Hospital, San Francisco, California, USA

    Steven G Deeks

  12. Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA

    Bruce D Walker & Mary Carrington

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Contributions

Author contributions are listed in alphabetical order. Project conception and supervision: M.C.; study rationale: A.M., D.G., D.V.M., J.F., M.C.; data analysis: D.G., Y.Q.; data interpretation and manuscript preparation: M.C., R.A, R.T.; genotyping/sequencing: M.P.M.; R.T.; X.G.; HLA-C expression characterization: G.O.C., R.A., R.T., V.M.; phylogenetic analysis: C.O.H.; clinical samples and data: A.T., B.D.W., G.D.K., J.J.G., J.M., J.N.M., S.B., S.G.D.; manuscript editing: all authors.

Corresponding author

Correspondence to Mary Carrington.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1, 2, 3, 4 and 6 and Supplementary Figures 1 and 2 (PDF 359 kb)

Supplementary Table 5

Viral load analysis of 47 SNPs in the HLA-C region. (XLS 68 kb)

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Thomas, R., Apps, R., Qi, Y. et al. HLA-C cell surface expression and control of HIV/AIDS correlate with a variant upstream of HLA-C. Nat Genet 41, 1290–1294 (2009). https://doi.org/10.1038/ng.486

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