Sirtuin2 blockade inhibits replication of human immunodeficiency virus-1 and Mycobacteriumtuberculosis in macrophages and humanized mice

Vipul K Singh; Abhishek Mishra; Khanghy Truong; Jose Alejandro Bohorquez; Suman Sharma; Arshad Khan; Franz Bracher; Kangling Zhang; Janice J Endsley; Mark Endsley; Andrew P Rice; Jason T Kimata; Guohua Yi; Chinnaswamy Jagannath

doi:10.1016/j.ymthe.2026.03.019

Sirtuin2 blockade inhibits replication of human immunodeficiency virus-1 and Mycobacteriumtuberculosis in macrophages and humanized mice

Mol Ther. 2026 Mar 25:S1525-0016(26)00204-2. doi: 10.1016/j.ymthe.2026.03.019. Online ahead of print.

Authors

Affiliations

¹ Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Weill Cornell Medicine, Houston, TX, USA.
² Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX, USA.
³ Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX, USA.
⁴ Department of Pharmacy, Ludwig-Maximilians University, Munich, Germany.
⁵ Department of Pharmacology and Microbiology and Immunology, UTMB Galveston, Galveston, TX, USA.
⁶ Microbiology and Immunology, UTMB Galveston, Galveston, TX, USA.
⁷ Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX, USA. Electronic address: jkimata@bcm.edu.
⁸ Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX, USA. Electronic address: guohua.yi@uttyler.edu.
⁹ Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Weill Cornell Medicine, Houston, TX, USA. Electronic address: cjagannath@houstonmethodist.org.

PMID: 41883165
DOI: 10.1016/j.ymthe.2026.03.019

Abstract

Co-infections with Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus-1 (HIV-1) present a critical health challenge and require treatment for patient survival. We found that human M1 macrophages inhibit Mtb growth, while M2 macrophages, characterized by elevated Sirt2 expression, permit Mtb growth. Further, we found that HIV-1 augmented Sirt2 gene expression in MФs. Therefore, we explored the therapeutic potential of sirtuin-modulating drugs using human MФs. Sirtinol, a Sirt2 inhibitor, significantly reduced HIV-1 growth in M0, M1, and M2-MФs by >1log10 over 7 days. Conversely, individual doses of resveratrol and SRT1460, which activate Sirt1, did not affect HIV-1. However, their combination showed a strong synergistic inhibition of HIV-1. The combination of sirtinol with resveratrol was neither synergistic nor antagonistic. Sirtinol upregulated iNOS and ATG5 mRNA in HIV-1-infected MФs in a phenotype-dependent manner. In a humanized mouse model (Hu-NSG-SGM3) co-infected with Mtb H37Rv and the HIV-1 BAL strain, treatment with sirtinol alone, or in combination with combination antiretroviral therapy (cART), showed promising results; sirtinol alone reduced Mtb growth, while its combination with cART effectively inhibited HIV-1 replication in the organs. We propose that Sirt2 blockade and Sirt1-activation represent a novel dual therapeutic strategy for treating HIV-1 and Mtb co-infections.

Keywords: C57BL/6; CD4 T cells; HIV-1; NF-kB; co-infection; epigenetics; humanized mouse; macrophages; resveratrol; sirtinol; sirtuin1; sirtuin2; sirtuins; tuberculosis.