Simian and human immunodeficiency virus Nef proteins use different surfaces to downregulate class I major histocompatibility complex antigen expression

Simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 (HIV-1) Nef proteins are related regulatory proteins that share several fu nctions, including the ability to downregulate class I major histocompatibi lity complex (MHC) and CD4 expression on the cell surface and to alter T-ce ll-receptor-initiated signal transduction in T cells. We compared the mecha nisms used by SN mac239 Nef and HIV-I Nef to downregulate class I MHC and f ound that the ability of SN Nef to downregulate class I MHC requires a uniq ue C-terminal region of the SIV mac239 Nef molecule which is not found in H IV-1 Nef, Interestingly, mutation of the PxxP motif in SIV Nef, unlike in H IV-1 Nef, does not affect class I MHC downregulation. We also found that do wnregulation of class I MHC by SIV Nef requires a conserved tyrosine in the cytoplasmic domain of the class I MHC heavy chain and involves accelerated endocytosis of class I complexes, as previously found with HIV-1 Nef. Thus , while SN and HIV-1 Nef proteins use a similar mechanism to downregulate c lass I MHC expression, they have evolved different surfaces for molecular i nteractions with cell factors that regulate class I MHC traffic. Mutations in the C-terminal domain of SIV mac239 Nef selectively disrupt class I MHC downregulation, having no detectable effect on other functions of Nef, such as the downregulation of CD4 and CD3 surface expression, the stimulation o f SIV virion infectivity, and the induction of SIV replication from T cells infected in the absence of stimulation. The resulting mutants will be usef ul reagents for studying the importance of class I MHC downregulation for S IV replication and AIDS pathogenesis in infected rhesus macaques.