Infection with Mycobacterium tuberculosis (Mtb) increases AIDS-related deaths in people living with HIV-1. Approximately, 99% of deaths due to HIV-Mtb coinfection take place in developing countries such as India. Furthermore, evolution of genetically and functionally distinct clinical strains of HIV and Mtb strains further fuel the HIV-B epidemic. Despite this, there remains limited understanding of mechanisms of HIV mediated exacerbation of TB infection. In the co-infected individual, both Mtb and HIV potentiate one another, promoting immunologic dysfunction, metabolic disorder and premature death. Various lines of evidence implicate HIV accessory proteins (Tat, Nef, Vpu) in orchestrating major alterations in the host cellular homeostasis processes such as redox balance, membrane potential, and central metabolism resulting in immune dysfunction, virus replication and progression to AIDS. Furthermore, clade-specific genetic diversity within HIV proteins distinctly manipulates host redox response and immune deregulation. Similarly, redox signaling also plays an important role in modulating survival and virulence of Mtb in vivo. It has been demonstrated that the major cellular antioxidant glutathione (GSH) either directly or indirectly modulates innate and adaptive immune mechanisms to control Mtb infection. Interestingly, HIV infected individuals demonstrate either depletion or oxidation of serum GSH levels. HIV-mediated changes in host redox physiology likely influences the pathogenesis of Mtb and has not been addressed in the HIV-TB field. In addition, the effect of distinct genotypic and phenotypic variations within various strains of HIV and Mtb on host redox homeostasis remains uncharacterized. We believe that a significant bottleneck exists in investigating redox-based signaling events during HIV-TB coinfection, primarily because of lack of non-invasive tools to dynamically measure HIV-induced redox stress at the cellular and sub- cellular levels and the absence of appropriate animal models. To address this, we propose to utilize a novel genetically encoded green fluorescent protein based redox bioprobe, Grx1-roGFP2 that allows us to determine specific, quantitative, and dynamic and compartment specific redox changes associated with HIV-TB coinfection. Furthermore, we plan to creatively use HIV-1 transgenic mice to study how HIV-induced redox changes modulate survival and persistence of Mtb in vivo. One of the major strengths of the proposal is the use of Indian clinical isolates of HIV and Mtb to dissect redox signaling events associated with HIV-TB coinfections. We believe that our study will provide significant insight into redox processes underlying HIV-TB dual infection which will lead to identification of novel drug targets and organelle-specific antioxidant therapy and ultimately to better therapeutic interventions for individuals afflicted with these co-morbidities.

Public Health Relevance

Oxidative stress is central to the pathogenesis of both HIV and Mtb. However, due to the lack of a sensitive tool to measure redox environment of HIV-TB coinfected cells and the absence of animal models, both the source and significance of redox stress remain elusive. Development of non-invasive real-time redox technology (Grx1-roGFP2) and use of HIV1 transgenic mice proposed in this application will allow us to dissect the role of redox stress in HIV-TB pathogenesis and will open up fresh avenues of research, such as organelle specific antioxidant therapy to treat HIV and TB comorbidity.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI106386-02
Application #
8720692
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Srinivasan, Sudha
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322