Immunometabolism of myeloid suppressor cell responses to M. tuberculosis in PWH

About This Grant

ABSTRACT People living with Human Immunodeficiency virus (HIV) are up to 20 times more likely to develop active tuberculosis (TB) than people without HIV (PWoH). While anti-retroviral therapy (ART) has increased their health and lifespan, people with HIV (PWH) on ART are still at 4-5 fold greater risk for developing TB following infection with Mycobacterium tuberculosis (Mtb) compared to people without HIV (PWoH). However, why viral suppression and CD4 reconstitution following ART do not fully abrogate the risk of TB remains unclear. Residual inflammation present in PWH on ART has been linked to increased risk of co-infections and comorbidities. In addition, several lines of evidence show that PWH on ART have alterations in cellular metabolism, mainly within myeloid compartments, suggesting compromised abilities to mount effective immune responses to pathogens. A population of immunosuppressive cells termed myeloid-derived suppressor cells (MDSCs) has been implicated in dysfunctional immunity to HIV and Mtb infection. MDSCs were first described in cancer as negatively regulating tumor environments and suppressing NK and T cell functions. Higher frequencies of monocytic MDSCs (M- MDSC) were reported in PWH compared to PWoH, and M-MDSCs have been shown to expand after interruption of ART. Interestingly, M-MDSCs are also induced following Mtb infection but their role in anti-TB imunity in PWH on ART are not understood. We hypothesize that M-MDSCs suppress T cell functions and promote dysregulated immunometabolic responses to Mtb in PWH on ART. We propose to leverage bio-banked cryopreserved PBMC samples available through the Emory Center for AIDS research (CFAR) and our own archived samples, including from people with active and latent TB, with and without HIV. In Aim 1 we will employ multi-omic and immunologic approaches to derive an integrated MDSC biosignature associated with their suppressive functions and evaluate MDSC signature and frequencies in ART-naïve PWH, PWH on ART and PWoH. In Aim 2 we will test the hypothesis that expansion of M-MDSCs in PWH on ART contributes to ineffective immunity against Mtb-infection and promotes immunometabolic dysregulation. Our studies will bridge major knowledge gaps and provide a framework for targeting MDSCs to improve ART and advance HIV cure.