Two proviral HIV transgenic mouse models, one bearing wild-type HIV proviral DNA and the other a modified provirus in which the viral LTRs contained the core enhancer of the Moloney murine leukemia virus (MLV), were compared. The MLV/HIV chimeric LTR, in which the MLV enhancer replaced the NF-kappa B-binding motifs, was transcriptionally active in human and murine cells in vitro and virus containing the chimeric LTR was replication competent in human cell cultures. Transgenic mice derived from microinjections of chimeric MLV/HIV proviral DNA transcribed HIV genes at a greater frequency and at higher levels than wild-type HIV proviral transgenic mice. MLV/HIV mice were also more apt to develop disease; wasting, periocular infections, and a degenerative myopathy characterized the most predominant phenotype. The tissue specificities of the wild-type and chimeric LTRs in transgenic mice were remarkably similar, but a significant difference was apparent in lymphoid cells. Basal level and LPS-inducible HIV gene expression occurred in peritoneal and bone marrow-derived macrophages from wild-type HIV transgenic mice. In contrast, HIV gene expression in macrophages from MLV/HIV mice was undetectable, even following LPS induction. However, cultured splenocytes from MLV/HIV mice supported HIV proviral gene transcription better than splenocytes from HIV mice, particularly after induction with LPS or anti-IgD antibody but not with concanavalin A. These data suggest that in transgenic mice, the HIV and MLV/HIV LTRs display a differential tropism for macrophages and B cells, respectively. HIV and MLV/HIV transgenic mice represent alternative models amenable to in vivo studies of HIV gene regulation in lymphoid cells, the induction of HIV-related disease and the evaluation of anti-HIV therapies.