Elevated <i>HLA-A</i> expression impairs HIV control through inhibition of NKG2A-expressing cells

Abstract

The highly polymorphic human leukocyte antigen (<i>HLA</i>) locus encodes cell surface proteins that are critical for immunity. <i>HLA-A</i> expression levels vary in an allele-dependent manner, diversifying allele-specific effects beyond peptide-binding preference. Analysis of 9763 HIV-infected individuals from 21 cohorts shows that higher <i>HLA-A</i> levels confer poorer control of HIV. Elevated <i>HLA-A</i> 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. <i>HLA-B</i> haplotypes that favor NKG2A-mediated NK cell licensing (i.e., education) exacerbate the deleterious effect of high <i>HLA-A</i> 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.