# Sirtuin -Dependent Regulation of Tuberculosis and HIV Interactions in Macrophages

> **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2024 · $1,297,775

## Abstract

ABSTRACT
Tuberculosis continues to kill about 1 million people including children each year with 8 million new cases.
Regrettably, coinfection with HIV-1 has aggravated the problem because HIV-1 depletes CD4 T cells, which are
the main defense mechanism against tuberculosis. For the reason, BCG, which is a live attenuated vaccine
against tuberculosis, cannot be given to people living with HIV. We recently discovered that Sirtuin type of
protein and histone deacetylates play a major role in regulating the growth of both M. tuberculosis and HIV-1 in
human macrophages and drug targeting Sirtuins could control both pathogens in cell culture models and in
humanized mice. Therefore, we propose to investigate Sirtuin-dependent intervention to understand how TB and
HIV-1 infections induce these enzymes and how we can develop novel immunochemotherapy for confections.
Specifically:
Aim-1: We will analyze the impact of early Mtb and HIV infection on Sirtuin gene and protein induction in
macrophages and identify their epigenetic targets. We will examine the hypothesis that Mtb-induced Sirtuin-2
can augment HIV-1 replication, whereas HIV-1 induced Sirtuin-2, in turn enhances Mtb growth in MФs thereby
aggravating coinfections. We will then develop an immunochemotherapy (ICT) using a combination of Sirtuin
drugs, TB and HIV targeting drugs to kill and eradicate both HIV-1 and M. tuberculosis in macrophages. Aim-2:
We will investigate the effect of Sirtuin drugs on early and late stages of TB-HIV-1 coinfection using humanized
mice and determine whether ICT can eradicate confections. Aim-3: Tuberculosis granulomas can restrict growth
of M. tuberculosis pathogen, although prior infection with HIV-1 can deplete CD4 T cells and affect granuloma
formation. We will use a TB-HIV coinfection model of humanized mice to determine if Sirtuin-drug therapy can
activate macrophages of granulomas and increase host-defense against tuberculosis. Our overall goal is to
develop innovative immune defense-based intervention methods to eradicate TB-HIV coinfections.

## Key facts

- **NIH application ID:** 10947239
- **Project number:** 1R01AI184551-01
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Janice J Endsley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,297,775
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10947239

## Citation

> US National Institutes of Health, RePORTER application 10947239, Sirtuin -Dependent Regulation of Tuberculosis and HIV Interactions in Macrophages (1R01AI184551-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10947239. Licensed CC0.

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