Background: Pneumonia is a major complication of HIV pathogenesis but it develops only after prolonged infection. We used the macaque model to explore a hypothesis that the disease is a two stage process, the first stage being establishment of the viral infection in the lung, and the second, amplification of virus replication by host factors induced by chemical agents or opportunistic pathogens (OP) or in the lung. Methods: Bleomycin, (a chemical known to induce diffuse alveolar damage, pulmonary fibrosis, with accumulation of macrophages, and a rich Th2 cytokine environment), was inoculated intra-tracheally into five of eight SHIV_89.6 P-infected macaques, and in one uninfected macaque. Three additional SHIV infected macaques without bleomycin treatment served as untreated virus controls. Results: Although none of the animals became clinically ill, bleomycin induced classical host responses in the lungs of all the treated, virus-infected macaques. There was enhanced production of the chemokine, MCP-1 that had previously been shown to cause enhanced replication of the virus. Four of the five treated animals developed more productive SHIV infection in the lungs compared to the infected untreated animals. Enhanced virus replication was found primarily in infiltrating macrophages. Conclusion: Enhanced replication of the virus in the lungs was associated with host factors induced by the drug and supported the hypothesis for a two-stage process of pulmonary pathogenesis.