Concurrent TB and HIV therapies control TB reactivation during co-infection but not chronic immune activation

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. The basis for inefficient Mtb control in PLWH despite treatment is unclear. Here, the authors show that combined TB/HIV therapy in Mtb/SIV co-infected macaques reduces bacterial and viral burden and improved lung pathology, but failed to fully restore immune balance, revealing persistent inflammation.