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.

Data availability

The scRNA-seq data generated in this study have been deposited in the NCBI Gene Expression Omnibus database under accession code GSE293173. The scRNA-seq data generated in this study are provided in the Supplementary Information/Source Data file. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE293173. Accession for Bulk RNA-seq SRA data: PRJNA1327945. https://trace.ncbi.nlm.nih.gov/Traces/study/?acc=PRJNA1327945%20&o=acc_s%3Aa Source data are provided with this paper.

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Acknowledgements

This work was supported by National Institutes of Health investigator- AI111943 (awarded to D.K.), AI123047 (to D.K.), OD031898 (to D.K.), AI170148 (to D.K.), R21AI170148 (to R.S.), K01OD031898 (to R.S.), institutional- grants OD010442, AI168439, AI161943, OD028732, OD032443 and CPRIT Core Facility Award (RP220662). We also acknowledge the role of institutional grants U42OD10442 (to D.K.), P30AI168439 (Texas D-CFAR, co-director D.K., and P30AI161943 (IN-TRAC; both R.S. and D.K. are members). SIVmac239 was graciously provided by Drs. Preston Marx and Nick Manness, Tulane National Primate Research Center. SIV viral load assays were performed by the NHP Core Virology Laboratory for AIDS Research and Development, Division of AIDS, NIAID. PMPA and FTC were provided by Gilead Sciences, and DTG was provided by Viiv Healthcare. Data was generated in the Genome Sequencing Facility, which is supported by UT Health San Antonio, NIH Shared Instrument grant S10OD030311 (S10 grant to NovaSeq 6000 System), S10OD028732 (to SNPRC).

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Author notes

Bindu Singh

Present address: Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, MP, India

Authors and Affiliations

Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, USA

Riti Sharan, Bindu Singh, Vinay Shivanna, Edward J. Dick Jr., Shannan Hall-Ursone, Xavier Alvarez, Smriti Mehra & Deepak Kaushal 1.

Greehey Children’s Cancer Research Institute, Long School of Medicine, UT Health, San Antonio, TX, USA

Yi Zou 1.

UTHealth Houston School of Public Health, Houston, TX, USA

Xi Luo, Guanlin Guo & Hulin Wu 1.

Bernard and Betty Roizman Professor and Chair, University of Chicago Department of Microbiology and Immunology, Chicago, IL, USA

Shabaana A. Khader 1.

Emory Vaccine Center and Emory National Primate Research Center, Emory University School of Medicine, Atlanta, GA, USA

Jyothi Rengarajan 1.

Greehey Children’s Cancer Research Institute, Department of Molecular Medicine, Long School of Medicine, UT Health, San Antonio, TX, USA

Zhao Lai

Authors

1. Riti Sharan
2. Yi Zou
3. Bindu Singh
4. Vinay Shivanna
5. Edward J. Dick Jr.
6. Shannan Hall-Ursone
7. Xi Luo
8. Guanlin Guo
9. Shabaana A. Khader
10. Xavier Alvarez
11. Jyothi Rengarajan
12. Zhao Lai
13. Smriti Mehra
14. Hulin Wu
15. Deepak Kaushal

Contributions

R.S., J.R., and D.K. designed the study. R.S. and B.S. performed sample collection and processing. V.S. and E.J. performed macaque necropsies and pathology studies. S.H.U. was the attending veterinarian for the study. X.A. performed the PET/CT and related analysis. R.S., Z.L., Y.Z., X.L., G.G., H.W., and D.K. performed the data analysis. Z.L. performed quality control of BAL cells, 10x scRNA-seq and NGS workflow. S.A.K., J.R., and S.M. helped R.S. and D.K. in writing the manuscript.

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Correspondence to Riti Sharan or Deepak Kaushal.

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Sharan, R., Zou, Y., Singh, B. et al. Concurrent TB and HIV therapies control TB reactivation during co-infection but not chronic immune activation. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67188-4

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Received: 16 August 2024

Accepted: 24 November 2025

Published: 12 December 2025

DOI: https://doi.org/10.1038/s41467-025-67188-4