CD4 and infection: In testing this hypothesis, we discovered that substitution of a single residue, 375-Ser, in primary or T/F HIV-1 Envs by Trp, Phe, Tyr, His, or Met resulted in SHIVs that exhibited enhanced binding to rhesus CD4, increased infection of primary rhesus CD4+ T cells in culture, and consistent infection and replication by SHIVs in RMs in vivo (35).