Concurrent TB and HIV Therapies Control TB Reactivation During Co-infection but Not Chronic Immune Activation

Authors

• Riti Sharan
• Yi Zou
• Bindu Singh
• Vinay Shivanna
• Edward J Dick
• Shannan Hall-Ursone
• Xi Luo
• Guanlin Guo
• Shabaana A Khader
• Xavier Alvarez
• Jyothi Rengarajan
• Zhao Lai
• Smriti Mehra
• Hulin Wu
• Deepak Kaushal

Language

English

Publication Date

12-12-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-67188-4

PMID

41387448

PMCID

PMC12804781

PubMedCentral® Posted Date

12-12-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Most HIV-negative individuals exposed to Mycobacterium tuberculosis (Mtb) control infection as latent TB infection (LTBI), but HIV co-infection greatly increases progression to tuberculosis (TB), the leading cause of death in people living with HIV (PLHIV). Although combination antiretroviral therapy (cART) reduces LTBI reactivation, immune control of Mtb is not fully restored, as shown by persistent TB incidence in PLHIV on cART. In macaques, skewed pulmonary effector memory CD4⁺ T-cell (TEM) responses and new TB lesions persist despite cART. We hypothesize that concurrent anti-TB therapy with cART would improve bacterial control and immune restoration compared to cART alone. Using rhesus macaques (RM) with LTBI and Simian Immunodeficiency Virus (SIV) co-infection, we tested three months of weekly isoniazid and rifapentine (3HP) plus daily cART. Concurrent cART+3HP improves clinical and microbiological outcomes but fails to fully restore lung CD4⁺ T-cell immunity. Treated RMs retain caseous granulomas with high FDG uptake and incomplete CD4⁺ T-cell reconstitution, marked by persistent activation, exhaustion, and inflammation. CD4⁺ TEM cells remain depleted. Concurrent therapy induces Type I IFN signatures and enhances Mtb-specific TH1/TH17—but reduces TNFα—responses. These findings reveal persistent pulmonary immune defects underlying TB risk in HIV co-infection and identify potential targets for host-directed adjunctive therapies.

Keywords

Animals, Macaca mulatta, Coinfection, Simian Acquired Immunodeficiency Syndrome, Mycobacterium tuberculosis, Latent Tuberculosis, HIV Infections, CD4-Positive T-Lymphocytes, Antitubercular Agents, Isoniazid, Simian Immunodeficiency Virus, Rifampin, Male, Lung, Female, Humans, Tuberculosis, HIV infections, Rhesus macaque

Published Open-Access

yes

Recommended Citation

Sharan, Riti; Zou, Yi; Singh, Bindu; et al., "Concurrent TB and HIV Therapies Control TB Reactivation During Co-infection but Not Chronic Immune Activation" (2025). Faculty, Staff and Student Publications. 1474.
https://digitalcommons.library.tmc.edu/uthsph_docs/1474