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.
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.
|Hirsch, Christina S; Rojas, Roxana; Wu, Mianda et al. (2016) Mycobacterium tuberculosis Induces Expansion of Foxp3 Positive CD4 T-cells with a Regulatory Profile in Tuberculin Non-sensitized Healthy Subjects: Implications for Effective Immunization against TB. J Clin Cell Immunol 7:|
|Meng, Qinglai; Canaday, David H; McDonald, David J et al. (2016) Productive HIV-1 infection is enriched in CD4(-)CD8(-) double negative (DN) T cells at pleural sites of dual infection with HIV and Mycobacterium tuberculosis. Arch Virol 161:181-7|
|Hirsch, Christina S; Baseke, Joy; Kafuluma, John Lusiba et al. (2016) Expansion and productive HIV-1 infection of Foxp3 positive CD4 T cells at pleural sites of HIV/TB co-infection. J Clin Exp Immunol 1:|
|Toossi, Zahra; Meng, Qinglai; Aung, Htin et al. (2015) Short Communication: Expression of APOBEC3G and Interferon Gamma in Pleural Fluid Mononuclear Cells from HIV/TB Dual Infected Subjects. AIDS Res Hum Retroviruses 31:692-5|
|Toossi, Zahra; Wu, Mianda; Liu, Shigou et al. (2014) Role of protease inhibitor 9 in survival and replication of Mycobacterium tuberculosis in mononuclear phagocytes from HIV-1-infected patients. AIDS 28:679-87|
|Toossi, Zahra; Wu, Mianda; Rojas, Roxana et al. (2012) Induction of serine protease inhibitor 9 by Mycobacterium tuberculosis inhibits apoptosis and promotes survival of infected macrophages. J Infect Dis 205:144-51|
|Wu, M; Aung, H; Hirsch, C S et al. (2012) Inhibition of Mycobacterium tuberculosis-induced signalling by transforming growth factor-? in human mononuclear phagocytes. Scand J Immunol 75:301-4|
|Toossi, Zahra; Wu, Mianda; Hirsch, Christina S et al. (2012) Activation of P-TEFb at sites of dual HIV/TB infection, and inhibition of MTB-induced HIV transcriptional activation by the inhibitor of CDK9, Indirubin-3'-monoxime. AIDS Res Hum Retroviruses 28:182-7|
|Toossi, Z; Hirsch, C S; Wu, M et al. (2011) Distinct cytokine and regulatory T cell profile at pleural sites of dual HIV/tuberculosis infection compared to that in the systemic circulation. Clin Exp Immunol 163:333-8|
|El Fenniri, L; Toossi, Z; Aung, H et al. (2011) Polyfunctional Mycobacterium tuberculosis-specific effector memory CD4+ T cells at sites of pleural TB. Tuberculosis (Edinb) 91:224-30|
Showing the most recent 10 out of 33 publications