Overview
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.