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

> **NIH NIH R01** · TEXAS BIOMEDICAL RESEARCH INSTITUTE · 2020 · $898,189

## 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 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.

## Key facts

- **NIH application ID:** 9965812
- **Project number:** 5R01AI123047-05
- **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:** $898,189
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965812

## Citation

> US National Institutes of Health, RePORTER application 9965812, Impact of concurrent HIV and latent TB therapies on Mtb-specific immune function (5R01AI123047-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9965812. Licensed CC0.

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