Clinical and seroepidemiological studies in West Africa indicate that human immunodeficiency virus type 2 (HIV-2) is widespread and associated with immunodeficiency states of variable degree. In this study, an isolate of HIV-2 from a patient in Senegal was molecularly cloned and characterized. This isolate (HIV-2ST) was shown by hybridization and restriction enzyme analysis to be more related to the prototype HIV-2ROD than to other human or primate retroviruses. Cultures of HIV-2ST showed genotypic polymorphism, and clones of the virus had transmembrane envelope glycoproteins of 30 and 42 kilodaltons. Unlike other immunodeficiency viruses, HIV-2ST did not cause cell death or induce cell fusion in peripheral blood lymphocytes or in any of four CD4+ cell lines tested. Although HIV-2ST entered cells by a CD4-dependent mechanism and replicated actively, cell-free transmission of the virus was retarded at the level of cell entry. These findings suggest that immunodeficiency viruses prevalent in West African populations are members of the HIV-2 virus group and that certain strains of this virus have attenuated virulence.