Elevated HLA-A expression impairs HIV control through inhibition of NKG2A-expressing cells.
- Veron Ramsuran ,
- Vivek Naranbhai ,
- Amir Horowitz ,
- Ying Qi ,
- Maureen P. Martin ,
- Yuko Yuki ,
- Xiaojiang Gao ,
- Victoria Walker-Sperling ,
- Gregory Q. Del Prete ,
- Douglas K. Schneider ,
- Jeffrey D. Lifson ,
- Jacques Fellay ,
- Steven G. Deeks ,
- Jeffrey N. Martin ,
- James J. Goedert ,
- Steven M. Wolinsky ,
- Nelson L. Michael ,
- Gregory D. Kirk ,
- Susan Buchbinder ,
- David Haas ,
- Thumbi Ndung’u ,
- Philip Goulder ,
- Peter Parham ,
- Bruce D. Walker ,
- Jonathan M. Carlson ,
- Mary Carrington
Science | , Vol 359: pp. 86-90
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.