Mouse, rat, rabbit, cat, and mink cell lines expressing human CD4 restrict entry of HIV-1 strains at the cell surface. We now report that CD4(+) cat and rabbit cell lines are permissive to cell fusion induced by several HIV-2 and SIV strains. CD4(+) rat and mouse cells are only sensitive to HIV-2 and SIV fusion in the presence of active amphotericin B. HIV-2 and SIV replicate in CD4(+) cat and CD4(+) mink cells, but not in the CD4(+) rabbit, rat, or mouse cells. These latter cell lines poorly express a transfected DNA molecular clone of HIV-2 DNA. CD4(+) rat cells are sensitive to entry by HIV-2 (HTLV-I) pseudotypes and also to HIV-2 if amphotericin a is present. Early reverse transcription then occurs without subsequent viral gene expression, but the fusion-sensitive CD4(+) rabbit cells are not permissive for HIV-2 reverse transcription. Our observations demonstrate (i) that the cat and mink cell lines express everything required except human CD4 for entry and replication by several HIV-2 and SIV strains and (ii) that distinct postpenetration blocks to viral replication are evident in rabbit end rodent cell lines, (C) 1994 Academic Press, inc