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.

Public Health Relevance

TB is the most common co-infection during HIV infection worldwide, and is associated with significant HIV-related morbidity and mortality. This research will identify mechanisms by which TB impacts HIV that may be modulated by adjunctive therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL051636-18
Application #
8289507
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Peavy, Hannah H
Project Start
1993-09-30
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
18
Fiscal Year
2012
Total Cost
$384,916
Indirect Cost
$113,158
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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