Mice infected with LP-BM5 murine leukemia viruses (MuLV) develop a syndrome with many features in common with AIDS including lymphadenopathy and profound immunodeficiency associated with enhanced susceptibility to infection and terminal B cell lymphomas. To evaluate cellular defects that may predispose infected mice to these sequelae, we studied the regulation of IFN gene expression. Spleen cells from mice infected with LP-BM5 MuLV expressed high levels of IFN-gamma mRNA by 1 wk post-inoculation and throughout the course of disease. By comparison, transcripts of IFN-alpha/beta genes were not detected in spleen cells at any time after infection. In uninfected mice, expression of IFN-alpha/beta genes is induced rapidly after infection with New-castle disease virus, but mice inoculated with LP-BM5 MuLV were unable to induce these genes by 4 wk after retroviral infection. Inhibition of IFN-alpha/beta induction due to LP-BM5 MuLV infection also occurred in nude mice, indicating this effect was not mediated by activated T cells. Furthermore, low levels of IFN-gamma transcripts were detected in spleens of nude infected mice, suggesting that cells other than T cells can express this gene. These results suggest that the normal contributions of IFN to control of microbial spread, immune surveillance, and lymphoid interactions are disrupted by infection with LP-BM5 MuLV.