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. Co-infection with HIV increases the risk of progressing to active TB disease (ATB) by over 20 fold but the underlying immune mechanisms remain unclear. Antiretroviral therapy (ART) decreases the incidence of ATB in HIV-infected individuals and remains the cornerstone of HIV care. However, the incidence of TB in HIV-coinfected individuals remains 4- to 7-fold higher after ART than in HIV-uninfected people in TB-endemic settings, regardless of the duration of ART or attainment of high CD4 counts. Thus, immune control of Mtb infection is not fully restored by ART. Recent clinical trials have shown that regimens that concurrently administer Isoniazid Preventive Treatment (IPT) and ART are significantly better than ART alone in reducing TB incidence among individuals with LTBI. However, uptake of concurrent ART and IPT regimens remains poor and the immune mechanisms underlying the benefits of concurrent ART and IPT have not been defined. We propose to identify the components of TB immunity in the blood and lung compartments that remain impaired after ART, versus those that are restored by concurrent ART and IPT, in the rhesus macaque nonhuman primate (NHP) aerosol model of LTBI and Simian Immunodeficiency Virus (SIV) co-infection. We hypothesize that co-infection with SIV increases Mtb burden within alveolar macrophages in the lung and progressively impairs the functional capacities of tissue-resident Mtb-specific CD4 and CD8 T cells in the lung; ART only partially restores these functions. We further hypothesize that IPT-mediated reduction in Mtb burden, in conjunction with ART, enhances protective Mtb-specific T cell immunity compared to ART alone. We will model these concurrent regimens in a highly faithful model of Mtb/HIV co-infection in rhesus macaques to study the kinetics of lung-specific CD4 and CD8 T cell responses by longitudinal sampling of blood, bronchoalveolar lavage (BAL) and lung biopsy tissue.
In Aim 1 we will investigate the role of tissue-resident CD4 T cells in reconstituting Mtb-specific immunity after concurrent ART/IPT regimens versus ART alone.
In Aim 2 we will test the hypothesis that SIV-induced progressive impairment of Mtb-specific CD8 functions in lung compartments are better restored by concurrent ART/IPT regimens than by ART alone. By identifying mechanisms underlying restoration of Mtb-specific immune function after concurrent ART and IPT, our studies have the potential to provide new insights into immune pathways that can be targeted for host-directed adjunctive therapies for TB/HIV co-infection and incorporated into designing better vaccines for TB.

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 latently infected (LTBI) but 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, and how their loss results 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. We will mechanistically assess the impact of ART as well as concurrent isoniazid preventive therapy directed at viable Mtb bacilli, on antigen-specific immune responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI123047-04
Application #
9744549
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Frank, Daniel J
Project Start
2017-08-15
Project End
2021-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
4
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
Gautam, Uma S; Foreman, Taylor W; Bucsan, Allison N et al. (2018) In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 115:E62-E71