Host-directed therapy in TB/HIV


We have previously shown that while three-month isoniazid and rifapentine (3HP) treatment improved survival, it failed to achieve 100% sterilization of lung TB burden with 2 out of the 6 treated macaques showing culturable Mtb, failed to reduce immune activation and replenish the depleted effector memory response in the lungs of Mtb/SIV coinfected macaques. Administration of anti-tubercular therapy, concurrently with ART reduces reactivation significantly better than ART among individuals with LTBI. However, long-term sterilization of bacteria and immune reconstitution in the lungs has not been shown in these individuals.

We hypothesize that supplementing antiretroviral therapy and 3HP treatment with IL-21 in TB/HIV coinfection will result in a long-term reconstitution of TH17, Mtb-specific CD4+T effector memory (TEM) and functional CD8+ T cell response. Further, IL-21 therapy adjunctive to ART and 3HP, will augment cytotoxic function of NK cells, thus significantly reducing immune activation and LTBI reactivation in TB/HIV co-infection. The hypothesis is based on the seminal work done by our collaborators who have previously shown that administration of rhesus IL-21-IgFc fusion protein to acutely SIV-infected macaques resulted in preserved intestinal TH17 cells, increased CD8+ T cell function.

Highlighted Publications

  • Sharan, Riti, Shashank R Ganatra, Dhiraj K Singh, Journey Cole, Taylor W Foreman, Rajesh Thippeshappa, Charles A Peloquin, et al. (2022) 2022. “Isoniazid and Rifapentine Treatment Effectively Reduces Persistent M. Tuberculosis Infection in Macaque Lungs”. The Journal of Clinical Investigation 132 (18).

    A once-weekly oral dose of isoniazid and rifapentine for 3 months (3HP) is recommended by the CDC for treatment of latent tuberculosis infection (LTBI). The aim of this study is to assess 3HP-mediated clearance of M. tuberculosis bacteria in macaques with asymptomatic LTBI. Twelve Indian-origin rhesus macaques were infected with a low dose ( 10 CFU) of M. tuberculosis CDC1551 via aerosol. Six animals were treated with 3HP and 6 were left untreated. The animals were imaged via PET/CT at frequent intervals. Upon treatment completion, all animals except 1 were coinfected with SIV to assess reactivation of LTBI to active tuberculosis (ATB). Four of 6 treated macaques showed no evidence of persistent bacilli or extrapulmonary spread until the study end point. PET/CT demonstrated the presence of significantly more granulomas in untreated animals relative to the treated group. The untreated animals harbored persistent bacilli and demonstrated tuberculosis (TB) reactivation following SIV coinfection, while none of the treated animals reactivated to ATB. 3HP treatment effectively reduced persistent infection with M. tuberculosis and prevented reactivation of TB in latently infected macaques.