Slow Receptor Binding of the Noncytopathic HIV-2_UC1 Envs Is Balanced by Long-Lived Activation State and Efficient Fusion Activity

Many HIV strains downregulate the levels of CD4 receptor on the surface of infected cells to prevent superinfection. In contrast, the rare HIV-2_UC1 strain is noncytopathic and has no effect on CD4 expression in infected cells but still replicates as efficiently as more cytopathic strains in peripheral blood mononuclear cells (PBMCs). Here, we show that HIV-2_UC1 Env interactions with the CD4 receptor exhibit slow association kinetics, whereas the dissociation kinetics is within the range of cytopathic strains. Despite the resulting 10- to 100-fold decrease in binding affinity, HIV-2_UC1 Envs exhibit long-lived activation state and efficient fusion activity. These observations suggest that HIV-2_UC1 Envs evolved to balance low affinity with an improved and readily triggerable molecular machinery to mediate entry. Resistance to cold exposure, similar to many primary HIV-1 isolates, and to sCD4 neutralization suggests that HIV-2_UC1 Envs preferentially sample a closed Env conformation. Our data provide insights into the mechanism of HIV entry.