Elevated HLA-A expression impairs HIV control through inhibition of Natural Killer cells

Abstract

The highly polymorphic human leukocyte antigen (HLA) locus encodes cell surface proteins that are critical for immunity. HLA-A expression levels vary in an allele-dependent manner, diversifying allele-specific effects beyond peptide binding preference. Analysis of 9,763 HIV infected subjects from 21 cohorts shows that higher HLA-A levels confer poorer control of HIV. Elevated HLA-A expression provides enhanced levels of an HLA-A derived signal peptide that specifically binds and determines expression levels of HLA-E, the ligand for the inhibitory NKG2A Natural Killer (NK) cell receptor. HLA-B haplotypes that favor NKG2A-mediated NK cell licensing/education exacerbate the deleterious effect of high HLA-A on HIV control, consistent with NKG2A-mediated inhibition impairing NK cell clearance of HIV-infected targets. Therapeutic blockade of HLA-E:NKG2A interaction may yield benefit in HIV disease.