All HIV and SIV strains can enter cells by binding to cell-surface CD4. Therapeutics designed to intervene in viral entry by blocking HIV attachment to CD4, may not work if entry mechanisms independent of CD4 occur frequently in vivo. A range of cell-surface molecules as well as CD4 can bind gp120, yet few act as receptors for HIV infection, indicating that passive attachment to the cell surface is not sufficient to confer virus entry. In vitro, HIV entry independent of CD4 has frequently been described, although this route to infection is usually inefficient. Variants of HIV-1 and HIV-2 that infect CD4-negative cell types more efficiently can be selected in vitro. However, there is currently no evidence that such variants evolve in vivo. Furthermore, present knowledge suggests that few CD4-negative cells types are productively infected in vivo. It is thus unlikely that CD4-independent infection significantly influences HIV induced pathogenesis in vivo.