THE NEF GENE-PRODUCTS OF BOTH SIMIAN AND HUMAN IMMUNODEFICIENCY VIRUSES ENHANCE VIRUS INFECTIVITY AND ARE FUNCTIONALLY INTERCHANGEABLE

Adult rhesus macaques infected with nef-defective simian immunodeficie ncy virus (SIV) exhibit extremely low levels of steady-state virus rep lication, do not succumb to immunodeficiency disease, and are protecte d from experimental challenge with pathogenic isolates of SIV. Similar ly, rare humans found to be infected with nef-defective human immunode ficiency virus type 1 (HIV-1) variants display exceptionally low viral burdens and do not show evidence of disease progression after many ye ars of infection, HIV-1 Nef induces the rapid endocytosis and lysosoma l degradation of cell surface CD4 and enhances virus infectivity in pr imary human T cells and macrophages, Although expression of SIV Nef al so leads to down-modulation of cell surface CD4 levels, no evidence fo r SIV Nef-induced enhancement of virus infectivity was observed in ear lier studies, Thus, it remains unclear whether fundamental differences exist between the activities of HIV-1 and SIV Nef, To establish more clearly whether the SIV and HIV-1 nef gene products are functionally a nalogous, we compared the replication kinetics and infectivity of vari ants of SIVmac239 that either do (SIVnef+) or do not (SIV Delta nef) e ncode intact nef gene products, SIVnef+ replicates more rapidly than n ef-defective viruses in both human and rhesus peripheral blood mononuc lear cells (PBMCs), As previously described for HIV-1 Nef, SIV Nef als o enhances virus infectivity within each cycle of virus replication, A s a strategy for evaluating the in vivo contribution of HIV-1 nef alle les and long terminal repeat regulatory sequences to the pathogenesis of immunodeficiency disease, we constructed SN-HN chimeras in which th e nef coding and U3 regulatory regions of SIVmac239 were replaced by t he corresponding regions from HIV-1/R73 (SIVR7nef+), SIVR7nef+ display s enhanced infectivity and accelerated replication kinetics in primary human and rhesus PBMC infections compared to its nef-defective counte rpart, Converse chimeras, containing SIV Nef in an HIV-1 background (R 7SIVnef+) also exhibit greater infectivity than matched nef-defective viruses (R7SIV Delta nef), These data indicate that SIV Nef, like that of HIV-1, does enhance virus replication in primary cells in tissue c ulture and that HIV-1 and SIV Nef are functionally interchangeable in the context of both HIV-1 and SIV.