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Inhibition of infectivity, cytopathicity, and binding by soluble CD4 was determined for several human immunodeficiency virus (HIV)-l and HIV-2 strains. Although infectivity and binding of both groups were blocked equally well by OKT4A, HIV-2 viruses were more refractory to inhibition by soluble CD4. Rates of envelope shedding, as determined by thermal stability, did not differ between HIV-1 and HIV-2; however, Scatchard plot analysis of radio- labeled virus binding revealed that fewer HIV-2 virions were bound to CD4 + cells under saturating conditions. The HIV-2 viruses also possessed consistently greater infectivity, whereas greater concentrations of gpl20 were found in supernatants of HIV-1-infected cells and in HIV-2 virus pellets, suggesting that more envelope glycoprotein remains associated with HIV-2 virions. This factor may contribute to the observed in-vitro resistance of HIV-2 viruses to soluble CD4.