Coinfection with human immunodeficiency virus type 1 (HIV-1) and opportunistic mycobacteria, especially Mycobacterium tuberculosis, is a cause of high morbidity and mortality worldwide. Both mycobacteria and HIV-1 may infect macrophages, and thus, coinfection may generate conditions that reciprocally influence the intracellular replication of the pathogens. Elucidation of the interaction between HIV-1 and mycobacteria in their common target cell is important for understanding pathogenesis in coinfected individuals. In this study, we investigated the effects of in vitro HIV-1 infection on the growth of M. tuberculosis, M. avium, and M. paratuberculosis in human peripheral blood monocyte-derived macrophages. Interestingly, HIV-1 infection induced a greater bacterial burden in coinfected cell cultures for all of the mycobacterial species tested and specifically induced accelerated growth of M. tuberculosis with a reduced mean generation time. The interaction of HIV-1 and M. tuberculosis was especially detrimental to the host cell, causing a significant synergistic reduction in macrophage viability. Also, in M. tuberculosis/HIV-1-coinfected cultures, increased levels of interleukin-1 (IL-1), IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor were observed and viral replication was enhanced. Overall, the present data suggest that HIV-1 infection of macrophages may impair their ability to contain mycobacterial growth. Furthermore, coinfection with HIV-1 and M. tuberculosis seems to give rise to synergistic effects at the cellular level that mutually enhance the replication of both pathogens. This may, in part, contribute to the increased morbidity and mortality seen in coinfected individuals.Human immunodeficiency virus type 1 (HIV-1) has caused a global pandemic, and approximately 33.4 million people were living with HIV infection by the end of 2008 (34). HIV ϩ individuals have an increased susceptibility to a wide range of opportunistic bacterial infections (reviewed in references 2 and 25). However, infections with certain opportunistic organisms like Mycobacterium tuberculosis are of particular concern, as people in resource-poor countries are often struck disproportionately hard, with increased morbidity and mortality due to the relatively high prevalence of HIV-1 and mycobacterial coinfections and limited access to appropriate treatment.In the clinical context of HIV-1 infection, M. tuberculosis and M. avium complex (MAC) infections are the most frequent. These mycobacteria display various propensities to cause disease. Notably, M. tuberculosis is the leading cause of death in HIV ϩ patients and a major public health concern, while MAC infections are typically seen in the later stages of HIV infection, when the adaptive immunity of the host is compromised. By current classical genetic criteria, the MAC consists of mainly two species, M. intracellulare and M. avium, and M. avium is further subdivided into three subsets, M. avium subsp. avium (here referred to as M. avium) M. avium subsp. paratuber...