The objectives of this proposal are to examine the impact of active tuberculosis on expression of Human Immunodeficiency Virus (HIV) infection, and to examine the consequences of HIV-M. tuberculosis interaction on lung injury. Tuberculosis is a major infection in HIV seropositive populations worldwide, which adversely affects HIV disease and occurs earlier in the course of HIV disease as compared to AIDS- related opportunistic infections. Our studies in the HIV-uninfected population with active pulmonary tuberculosis indicate that blood monocytes are susceptible to a productive infection with HIV, which may relate to their in vivo (priming) for cytokine expression. Mycobacterial products induce monocyte cytokines, and augment HIV expression in monocytoid cell lines latently infected with HIV, and primary monocytes infected with HIV in vitro. The hypothesis of this proposal is that activation of mononuclear cells during tuberculosis and by M. tuberculosis and its products enhances production of HIV by latently-infected or newly-infected cells, and the resulting augmentation in HIV interferes with a proper granulomatous response against M. tuberculosis.
The specific aims of the proposal seek to elucidate the basis by which monocytes from tuberculous patients, and M. tuberculosis favor replication of HIV and how amplified viral and cytokine activity affects alveolar cell damage and formation of granulomas.
The Specific Aims of this proposal are:
Specific Aim 1 : To examine the molecular basis for the enhanced susceptibility of monocytes from HIV-seronegative patients with active tuberculosis to a productive infection with HIV.
Specific Aim 2 : To determine the effect of M. tuberculosis on expression of viral activity by blood monocytes and alveolar macrophages from healthy individuals subsequent to in vitro infection with HIV, and from HIV- infected individuals.
Specific Aim 3 : To examine the effects of enhanced viral expression and amplified cytokine activity resulting from the interaction of HIV and M. tuberculosis on damage to alveolar epithelial cells and noncellular matrix, and on formation of multinucleated giant cells (MGC).
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