Tuberculosis (TB) is the most common co-infection during HIV-1 worldwide, and is associated with significant HIV-related morbidity and mortality. In dually infected subjects, HIV load and heterogeneity are increased both locally and systemically. Mycobacterium tuberculosis (MTB) infection supports HIV replication and dissemination through dysregulations of host cytokines, chemokines and their receptors. Host molecules such as TNFalpha and MCP-1 and TGF-beta sites of MTB infection induce HIV-1 replication in mononuclear cells in part through activation of nuclear factor kappaB. The regulatory component of host P-TEF-beta (Cyclin T1), which is critical to HIV tat activity is inducible in macrophages by bacterial LPS, and therefore its activation during co-infections such as TB. Furthermore, MTB activates alveolar macrophages from HIV-infected subjects with latent HIV-1 infection to viral expression. In addition, the expression of CCR5 is upregulated on macrophages at sites of MTB infection. Furthermore, the concentrations of the HIV- 1 inhibitory chemokines are limited during TB and at sites of MTB infection. The Hypothesis of this proposal is that MTB induces HIV transcription in macrophages by upregulation of P-TEF-[3, and that host molecules produced by macrophages at sites of MTB infection (TNF-alpha, MCP-1, and TGF-beta) are conducive to transcriptional activation of HIV, and antiretroviral therapies are able to contain viral expression from macrophages during HIV/TB.
The Specific Aims are: 1) To determine the basis of transcriptional activation of HIV by MTB in mononuclear phagocytes; to examine the role of activation of P-TEF-I], and transcription factors in augmentation of HIV by MTB in alveolar macrophages and monocytes; 2) To determine mechanisms of transcriptional activation of HIV operative at sites of active MTB infection in HIV/TB patients with pleural TB, and to assess the role of excess cytokines and chemokines in viral production, and the role of new rounds of HIV infection in enhanced HIV activity in situ; 3) To determine whether HIV viral set point, viral heterogeneity, frequency of latently and productively infected CD4 cells and release of virions by macrophages are effectively controlled by antiretroviral therapy during HIV/TB.
In Aim 1, molecular assays will be applied to assessment of transcriptional activation of HIV in human alveolar macrophages obtained from healthy subjects. Mononuclear cells from HIV/TB patients with pleural TB will be used as a model of interaction of these two 9athogens at sites of active TB (Aim 2). For purposes of Aim 3, HIV/TB patients with pulmonary TB enrolled in a placebo-controlled trial of ARV will be assessed longitudinally.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL051636-13S1
Application #
7282171
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Peavy, Hannah H
Project Start
1993-09-30
Project End
2009-07-31
Budget Start
2006-09-10
Budget End
2007-07-31
Support Year
13
Fiscal Year
2006
Total Cost
$9,820
Indirect Cost
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
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; 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, 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, 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

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