Friday, November 22, 2024
11/22/2024
Abstract The global control of TB is compounded by co-infection with HIV. Those infected with HIV are at high risk of reactivating latent TB infection (LTBI). Decades of research has not yielded a successful vaccine for the TB/HIV syndemic. While therapeutics control Mycobacterium tuberculosis (Mtb) and HIV burden, they have a potential disadvantage of selecting for resistance and not rescuing from the immune dysfunction. Targeting the host immune response via a host-directed immunotherapy (HDT) provides an opportunity to augment immunity during the short-window of acute HIV-1 co-infection of Mtb. Treatment of LTBI in people living with HIV (PLHIV) reduces the risk of active TB by only 35% and is dependent on the CD4 counts at the time of initiation. Though combinatorial antiretroviral therapy (cART) concurrently given with anti-TB therapy improves the clinical and microbiological parameters, it leads to insufficient reconstitution of protective TH1, TH17 and CD4+ TEM levels in the lungs and fails to rescue from virus-driven immune activation. Additionally, the long-term sterilization of bacteria and immune reconstitution in the lungs has not been shown in the individuals treated concurrently with cART and 3HP. HIV infection depletes IL-21 producing CD4+ T cells and cART only partially restores IL-21 in humans. We hypothesize that supplementing cART and once-weekly, three-month isoniazid and rifapentine (3HP) treatment with IL-21-IgFc fusion protein in Mtb/SIV co-infection will result in a long-term reconstitution of TH1 response and functional CD4+T effector memory (TEM) response in the lung. Further, IL-21-IgFc fusion protein adjunctive to cART and 3HP, will augment cytotoxic function of NK cells, thus significantly reducing the likeliness of LTBI reactivation in Mtb/SIV co-infection. Hence, we aim to explore a HDT that utilizes IL-21-IgFc fusion protein supplementation of cART+3HP to mitigate virus-driven immune dysregulation and thus reduce incidence of LTBI reactivation. By concurrently treating Mtb/SIV co-infected macaques with cART+3HP+IL-21-IgFc fusion protein, our goal is to significantly reduce LTBI reactivation by providing long-term immune reconstitution concurrent to bacterial control by i) induction of an adequate TH1 response via STAT1, ii) generation of CD4+ TEM cells, iii) maintenance of TH17 responses via STAT3 and iv) promotion of cytotoxic function of NK cells. The significance of our novel, translational approach is underscored by our strong preliminary data, and a reproducible, human-like model system. The data from the proposed study will be critical to the development of an immune-based intervention along with cART and anti-TB therapy to control dysregulated immune responses generated during early events of HIV co-infection of LTBI and provide long-term immune reconstitution. This will lead to the future clinical testing of such host-directed therapeutic approaches to control TB/HIV co-infection related mortality and morbidities.
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