Impact of HLA class I functional divergence on HIV control

Mathias Viard, Colm O’hUigin, Yuko Yuki, Arman A. Bashirova, David R. Collins, Jonathan M. Urbach, Steven Wolinsky, Susan Buchbinder, Gregory D. Kirk, James J. Goedert, Nelson L. Michael, David W. Haas, Steven G. Deeks, Bruce D. Walker, Xu Yu, Mary Carrington*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)319-325
Number of pages7
Issue number6680
StatePublished - 1 Jan 2024
Externally publishedYes


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