HIV-1 Vpu Mediates HLA-C Downregulation

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. [Display omitted] •Most primary HIV-1 clones downregulate HLA-C, in contrast to lab-adapted strains•Vpu is responsible for HLA-C downregulation in viruses of multiple HIV-1 subtypes•Primary HIV-1 clones frequently vary in their magnitude of HLA-C reduction•HIV-2 shows a Vpu-independent mechanism of HLA-C downregulation HIV-1 Nef downregulates HLA-A and -B but not HLA-C molecules on infected cells, presumably allowing viral subversion of CTL responses while preserving NK cell inhibition. Apps et al. determine that Vpu in primary HIV clones downregulates HLA-C, collectively resulting in decreased expression of all classical HLA class I molecules by HIV.