# Impact of concurrent HIV and latent TB therapies on Mtb-specific immune function-Diversity Supplement

> **NIH NIH R01** · TEXAS BIOMEDICAL RESEARCH INSTITUTE · 2020 · $148,967

## Abstract

Abstract
 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 coinfection 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.

## Key facts

- **NIH application ID:** 10116897
- **Project number:** 3R01AI123047-05S1
- **Recipient organization:** TEXAS BIOMEDICAL RESEARCH INSTITUTE
- **Principal Investigator:** Deepak Kaushal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $148,967
- **Award type:** 3
- **Project period:** 2017-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116897

## Citation

> US National Institutes of Health, RePORTER application 10116897, Impact of concurrent HIV and latent TB therapies on Mtb-specific immune function-Diversity Supplement (3R01AI123047-05S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10116897. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*