Elevated HLA-A expression impairs HIV control through inhibition of NKG2A-expressing cells.
Veron RamsuranVivek NaranbhaiAmir HorowitzYing QiMaureen P MartinYuko YukiXiaojiang GaoVictoria E K Walker-SperlingGregory Q Del PreteDouglas K SchneiderJeffrey D LifsonJacques FellaySteven G DeeksJeffrey N MartinJames J GoedertSteven M WolinskyNelson L MichaelGregory D KirkSusan BuchbinderDavid W HaasThumbi Ndung'uPhilip J R GoulderPeter ParhamBruce D WalkerJonathan M CarlsonMary N CarringtonPublished in: Science (New York, N.Y.) (2018)
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.