Cell Host Microbe. 2016 May 11; 19(5):686-95.

PubMed ID: 27173934

HIV-1 vpu mediates HLA-C downregulation

Apps R, Del Prete GQ, Chatterjee P, Lara A, Brumme ZL, Brockman MA, Neil S, Pickering S, Schneider DK, Piechocka-Trocha A, Walker BD, Thomas R, Shaw GM, Hahn BH, Keele BF, Lifson JD, Carrington M

Many pathogens evade cytotoxic T lymphocytes (CTLs) by downregulating HLA molecules on infected cells, but the loss of HLA can trigger NK cell-mediated lysis. HIV-1 is thought to subvert CTLs while preserving NK cell inhibition by Nef-mediated downregulation of HLA-A and -B but not HLA-C molecules. We find that HLA-C is downregulated by most primary HIV-1 clones, including transmitted founder viruses, in contrast to the laboratory-adapted NL4-3 virus. HLA-C reduction is mediated by viral Vpu and reduces the ability of HLA-C restricted CTLs to suppress viral replication in CD4+ cells in vitro. HLA-A/B are unaffected by Vpu, and primary HIV-1 clones vary in their ability to downregulate HLA-C, possibly in response to whether CTLs or NK cells dominate immune pressure through HLA-C. HIV-2 also suppresses HLA-C expression through distinct mechanisms, underscoring the immune pressure HLA-C exerts on HIV. This viral immune evasion casts new light on the roles of CTLs and NK cells in immune responses against HIV.