Natural HIV-1 Nef Polymorphisms Impair SERINC5 Downregulation Activity

Abstract

Summary: HIV-1 Nef enhances virion infectivity by counteracting host restriction factor SERINC5; however, the impact of natural Nef polymorphisms on this function is largely unknown. We characterize SERINC5 downregulation activity of 91 primary HIV-1 subtype B nef alleles, including isolates from 45 elite controllers and 46 chronic progressors. Controller-derived Nef clones display lower ability to downregulate SERINC5 (median 80% activity) compared with progressor-derived clones (median 96% activity) (p = 0.0005). We identify 18 Nef polymorphisms associated with differential function, including two CTL escape mutations that contribute to lower SERINC5 downregulation: K94E, driven by HLA-B∗08, and H116N, driven by the protective allele HLA-B∗57. HIV-1 strains encoding Nef K94E and/or H116N display lower infectivity and replication capacity in the presence of SERINC5. Our results demonstrate that natural polymorphisms in HIV-1 Nef can impair its ability to internalize SERINC5, indicating that variation in this recently described function may contribute to differences in viral pathogenesis. : HIV-1 Nef counteracts the cellular restriction factor SERINC5, but the importance of this for pathogenesis is unclear. Jin et al. show that Nef clones isolated from HIV controllers display lower ability to antagonize SERINC5, in part because of viral mutations that are selected to evade host T cells. Keywords: HIV-1 Nef, elite controllers, serine incorporator, host restriction, viral infectivity, viral pathogenesis