Tuberculosis (TB) is the leading cause of death in Human Immunodeficiency Virus (HIV)-infected individuals globally. The majority of HIV-negative individuals infected with Mycobacterium tuberculosis (Mtb) are asymptomatic, and are considered to have latent TB infection (LTBI), providing compelling evidence for host immune control of infection. However, a subset of individuals with LTBI progress to clinically active TB disease when co-infected with HIV. This results from the reactivation of LTBI, potentially due to a loss of control of Mtb within pulmonary granulomatous lesions. Antigen-specific T cells are crucial for controlling Mtb infection in humans and in experimental animal models and lowering of CD4 T cell counts after HIV infection greatly increases the risk of developing TB. However, the mechanisms by which Mtb-specific T cell responses maintain LTBI, confer protective immunity or result in HIV-induced reactivation of LTBI, remain unclear. To develop an effective TB vaccine for populations with high HIV prevalence and to effectively treat Mtb/HIV co- infection, we urgently need to understand how HIV perturbs the latent control of Mtb infection in a chronic state by the primate immune system. We hypothesize that co-infection with HIV depletes and/or impairs in the functional capacities of Mtb-specific CD4 and CD8 T cells to drive reactivation of LTBI and that antiretroviral therapy (ART) only partially restores these functions. We propose to test this hypothesis using mechanistic experiments in the highly human-like nonhuman primate model of inhalation TB. Towards this goal we will i) Define the nature of Mtb-specific CD4 and CD8 T cell responses associated with immune control of Mtb infection in the lungs, BAL and peripheral blood of Indian rhesus macaques with LTBI; ii) Test the hypothesis that co-infection with SIVmac239 progressively impairs Mtb-specific CD4 and CD8 T cell functions, leading to reactivation of LTBI; and iii) Examine the effect of antiretroviral therapy on reconstitution of Mt-specific CD4 and CD8 T cell responses in Mtb/SIV co-infected NHPs.

Public Health Relevance

Tuberculosis (TB) is the leading cause of death in Human Immunodeficiency Virus (HIV)-infected individuals globally. The majority of HIV-negative individuals infected with Mycobacterium tuberculosis (Mtb) are asymptomatic, considered to be latently infected (LTBI). Large numbers of individuals with LTBI progress to clinically active TB when co-infected with HIV. Antigen-specific T cells are crucial for controlling Mtb infection in humans and lowering of CD4 T cell counts after HIV infection greatly increases the risk of developing TB. However, the mechanisms by which Mtb-specific T cell responses maintain LTBI in the lung, confer protective immunity or result in HIV-induced reactivation of LTBI remain unclear. We hypothesize that co-infection with HIV depletes and/or impairs in the functional capacities of Mtb-specific CD4 and CD8 T cells to drive reactivation of LTBI and that antiretroviral therapy (ART) only partially restores these functions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI111943-05
Application #
9852853
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Frank, Daniel J
Project Start
2015-07-01
Project End
2020-12-31
Budget Start
2019-04-01
Budget End
2020-12-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Texas Biomedical Research Institute
Department
Type
DUNS #
007936834
City
San Antonio
State
TX
Country
United States
Zip Code
78227
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