Abstract

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).

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL051636-01
Application #
3370355
Study Section
Special Emphasis Panel (ZHL1-CSR-N (S2))
Project Start
1993-09-30
Project End
2001-03-31
Budget Start
1993-09-30
Budget End
1994-08-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106

  Publications

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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