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Elevated HLA-A expression impairs HIV control through inhibition of NKG2A-expressing cells

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Science  05 Jan 2018:
Vol. 359, Issue 6371, pp. 86-90
DOI: 10.1126/science.aam8825

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Inhibiting natural killer cells in AIDS

The human leukocyte antigen (HLA) gene complex varies enormously among individuals and helps explain individual variation in immunity to infectious diseases. Ramsuran et al. examined data from almost 10,000 HIV infections. Expression of the HLA-A and -B alleles was associated with higher viral load, reduced CD4+ T cell counts, and accelerated progression to AIDS. Higher levels of HLA-A expression increased expression of HLA-E, which blocks a specific receptor (NKG2A) on the immune cells that normally eliminate virus-infected cells. Thus, targeting NKG2A might provide a therapeutic avenue for HIV treatment.

Science, this issue p. 86

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 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.

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