Impact of HLA class I functional divergence on HIV control

Author:

Viard Mathias1ORCID,O’hUigin Colm1ORCID,Yuki Yuko1ORCID,Bashirova Arman A.1ORCID,Collins David R.2ORCID,Urbach Jonathan M.2ORCID,Wolinsky Steven3ORCID,Buchbinder Susan45ORCID,Kirk Gregory D.6,Goedert James J.7ORCID,Michael Nelson L.8ORCID,Haas David W.9ORCID,Deeks Steven G.10ORCID,Walker Bruce D.211ORCID,Yu Xu2ORCID,Carrington Mary12ORCID

Affiliation:

1. Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute Bethesda, MD, USA.

2. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.

3. Division of Infectious Diseases, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

4. Bridge HIV, San Francisco Department of Public Health, San Francisco, CA, USA.

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

6. Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.

7. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

8. US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.

9. Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.

10. Department of Medicine, University of California, San Francisco, CA, USA.

11. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.

Abstract

Heterozygosity of Human leukocyte antigen ( HLA ) class I genes is linked to beneficial outcomes after HIV infection, presumably through greater breadth of HIV epitope presentation and cytotoxic T cell response. Distinct allotype pairs, however, differ in the extent to which they bind shared sets of peptides. We developed a functional divergence metric that measures pairwise complementarity of allotype-associated peptide binding profiles. Greater functional divergence for pairs of HLA-A and/or HLA-B allotypes was associated with slower AIDS progression and independently with enhanced viral load control. The metric predicts immune breadth at the peptide level rather than gene level and redefines HLA heterozygosity as a continuum differentially affecting disease outcome. Functional divergence may affect response to additional infections, vaccination, immunotherapy, and other diseases where HLA heterozygote advantage occurs.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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