We used human immunodeficiency virus (HIV) transgenic (Tg) mice incorporating the entire viral genome to study the effect of Mycobacterium tuberculosis infection on the induction of integrated HIV gene expression. When aerogenically infected with M. tuberculosis, these mice displayed a progressive increase in pulmonary gag and env mRNA levels and of p24 antigen production by cultured splenocytes. In situ hybridization of lungs revealed increased viral transcription associated with areas of inflammation and acid-fast bacilli. By neutralizing tumor necrosis factor (TNF) in vivo after M. tuberculosis exposure, we found that, although initially TNF independent, the increased HIV expression triggered by M. tuberculosis was highly dependent on this cytokine by 4 weeks after infection. Furthermore, treatment with antimycobacterial drugs markedly reduced HIV transgene expression. These studies establish an animal model for investigating the influence of M. tuberculosis on latent HIV expression and for testing therapeutic regimens for reducing the disease burden in patients with acquired immunodeficiency syndrome-associated tuberculosis.