Impact of HLA class I functional divergence on HIV control

Science. 2024 Jan 19;383(6680):319-325. doi: 10.1126/science.adk0777. Epub 2024 Jan 18.

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.

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Disease Progression
  • Female
  • HIV Infections* / genetics
  • HIV Infections* / pathology
  • HLA-B Antigens* / genetics
  • Heterozygote*
  • Humans
  • Male
  • Middle Aged
  • Peptides / genetics
  • Peptides / immunology
  • Young Adult

Substances

  • HLA-B Antigens
  • Peptides

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