Elevated HLA-A expression impairs HIV control through inhibition of NKG2A-expressing cells.
Ramsuran V., Naranbhai V., Horowitz A., Qi Y., Martin MP., Yuki Y., Gao X., Walker-Sperling V., Del Prete GQ., Schneider DK., Lifson JD., Fellay J., Deeks SG., Martin JN., Goedert JJ., Wolinsky SM., Michael NL., Kirk GD., Buchbinder S., Haas D., Ndung'u T., Goulder P., Parham P., Walker BD., Carlson JM., Carrington M.
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 9763 HIV-infected individuals 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 (i.e., 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.