Disrupting surfaces of Nef required for downregulation of CD4 and for enhancement of virion infectivity attenuates simian immunodeficiency virus replication in vivo

The multifunctional simian and human immunodeficiency virus (SIV and HIV) N ef proteins are important for virulence. We studied the importance of selec ted Nef functions using an SIV Nef with mutations in two regions that are r equired for CD4 downregulation. This Nef mutant is defective for downregula ting CD4 and, in addition, for enhancing SN infectivity and induction of SI V replication from infected quiescent peripheral blood mononuclear cells, b ut not for other known functions, including downregulation of class I major histocompatibility complex (MHC) cell surface expression. Replication of S IV containing this Nef variant in rhesus monkeys was attenuated early durin g infection. Subsequent increases in viral load coincided with selection of reversions and second-site compensatory changes in Nef. Our results indica te that the surfaces of Nef that mediate CD4 downregulation and the enhance ment of virion infectivity are critical for SIV replication in vivo. Furthe rmore, these findings indicate that class I MHC downregulation by Nef is no t sufficient for SIV virulence early in infection.