Compact, glycan-restricted envelope (Env) glycoproteins are selected during heterosexual transmission of subtype C HIV-1. Donor and recipient glycoproteins (Envs) from six transmission pairs were evaluated for entry into HeLa cells expressing different levels of CD4 and CCR5. Donor and recipient Envs demonstrated efficient entry into cells expressing high levels of CD4 and CCR5, and entry declined as CCR5 levels decreased. Infectivity for all Envs was severely impaired in cells expressing low levels of CD4, even at the highest CCR5 levels. In 5/6 pairs, there was no significant difference in efficiency of receptor utilization between the donor and recipient Envs in these HeLa-derived cell lines. Thus, HIV-1 transmission does not appear to select for viruses that can preferentially utilize low levels of entry receptors.