Journal of virology 2017 10 18() pii 10.1128/JVI.01409-17
Patient-derived HIV-1 subtype B Nef clones downregulate HLA-A more efficiently than HLA-B. However, it remains unknown whether this property is common to Nef proteins across primate lentiviruses, and how antiviral immune responses may be affected. We examined 263 Nef clones from diverse primate lentiviruses including different pandemic HIV-1 group M subtypes for their ability to downregulate MHC-A and MHC-B from the cell surface. Though lentiviral Nef proteins differed markedly in their absolute MHC-A and MHC-B downregulation abilities, all lentiviral Nef lineages downregulated MHC-A on average 11-32% more efficiently than MHC-B. Nef genotype/phenotype analyses in a cohort of HIV-1 subtype C-infected patients (N=168), together with site-directed mutagenesis, revealed Nef position 9 as a subtype-specific determinant of differential HLA-A vs. HLA-B downregulation activity. Nef clones harboring non-consensus variants at codon 9 downregulated HLA-B (though not HLA-A) significantly better than those harboring consensus at this site, resulting in reduced recognition of infected target cells by HIV-1-specific CD8(+) effector cells in vitro Among persons expressing protective HLA class I alleles, carriage of Nef codon 9 variants was also associated with reduced ex vivo HIV-specific T-cell responses. Our results demonstrate that Nef’s inferior ability to downregulate MHC-B compared to MHC-A is conserved across primate lentiviruses, and suggest that this property influences antiviral cellular immune responses.IMPORTANCE Primate lentiviruses encode the Nef protein that plays an essential role in establishing persistent infection in their respective host species. Nef interacts with the cytoplasmic region of MHC-A and MHC-B molecules and downregulates them from the infected cell surface to escape recognition by host cellular immunity. Using a panel of Nef alleles isolated from diverse primate lentiviruses including pandemic HIV-1 group M subtypes, we demonstrate that Nef proteins across all lentiviral lineages downregulate MHC-A approximately 20% more effectively than MHC-B. We further identify a naturally polymorphic site at Nef position 9 that contributes to MHC-B downregulation function in HIV-1 subtype C, and show that carriage of Nef variants with enhanced MHC-B downregulation ability is associated with reduced breadth and magnitude of MHC-B-restricted cellular immune responses in HIV-infected individuals. Our study underscores an evolutionally conserved interaction between lentiviruses and primate immune systems that may contribute to pathogenesis.