Impact of Tuberculosis on HIV Disease

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DESCRIPTION (provided by applicant): Tuberculosis (TB) is the most common co-infection during Human Immunodeficiency Virus-1 (HIV) infection worldwide, and is associated with significant HIV-related morbidity and mortality. Unlike other HIV associated opportunistic infections (OI), TB occurs throughout the course of HIV infection, and its impact on viral activity is not reversible by anti-TB treatment alone. Studies by HL-51636 have examined the basis of HIV expansion systemically and at local sites of dual HIV/TB infection. At these sites MTB induces HIV replication in both macrophages and T-cells, and this HIV compartment contributes to systemic HIV load and heterogeneity. Cytokines/chemokine and the cellular composition at sites of dual HIV/MTB infection are important factors in the impact of TB on HIV disease. The milieu at pleural sites of HIV/TB infection is characterized by excessive TGF-2, IL-6, M-CSF-1, and MCP-1 activity in addition to a TH1 profile, and a massive expansion of memory and regulatory T-cells (T-reg). PFMC T-reg have survival advantage over non T-reg, suppress effector T-cell immune responses to HIV, and are particularly poised to productive HIV infection. Further, upon MTB stimulation macrophages both transmit HIV infection to, trans-activate HIV production in CD4 T-cells, and support T-reg expansion. Recent studies have identified three compounds that potentially target the excessive cytokine/chemokine profile of HIV/TB, and therefore may be useful as short-term adjuncts to anti-TB treatment. These include; 1. Derivatives of erythromycin, some of which may be useful in MDR TB, 2. an inhibitor of CDK9 (of P-TEFb), Indirubicin Monoxime, and 3. the anti-neoplastic agent Imatinib, which counter-acts the pro-survival factor M-CSF, and may be conducive to apoptosis of HIV-infected macrophages. We hypothesize that the cellular composition and cytokine/chemokine milieu at sites of HIV/TB co- infection is conducive to increased HIV replication and spread to CD4 T-cells by macrophages and T-reg. These mononuclear cell subsets undermine anti-HIV T-cell immune responses and contribute to HIV reservoirs. Modulation of the interface of HIV and host molecules by novel adjunctive anti-HIV therapies may allow control of the co-pathogenesis of HIV and MTB infection at sites of dual infection. The Specific Aims are: 1. To determine the mechanism(s) of enhanced HIV infection of MTB-specific CD4+ T cells by macrophages and DC in PFMC from HIV/TB dually infected patients, and to examine the role of macrophages and DC in expansion of T-reg. 2. To determine the role of T-reg expanded at pleural sites of HIV/TB infection on immune responses to HIV, and their contribution to viral dynamics including productive infection and latency during HIV/TB. 3. To determine whether specific adjunctive therapies such as EM-703, IM, or Imatinib that have been shown to have anti-HIV activity in macrophages and/or inhibit T-reg are useful in HIV/TB patients with pleural TB.