Here, we investigate three critical features of Nef’s role during HIV-1 infection: 1) the ability of the virus to mutate nef sequences to gain enhanced replicative fitness, 2) the role of CD4 downregulation in viral replication and pathogenesis and 3) the importance of Nef’s interactions with host SH3 domain proteins in replication and pathogenesis. The gene discussed is CD4; the disease is HIV-1 infection.