Friday, May 9, 2025
5/9/2025
Single cell trancriptomics to identify LTBI reactivation markers in TB/HIV co-infection - Project Summary The global control of tuberculosis (TB) is compounded by co-infection with Human Immunodeficiency Virus (HIV). Those infected with HIV are at high risk of reactivating latent TB infection (LTBI). Viral-induced chronic immune activation rather than mere depletion of CD4+ T cells correlates with LTBI reactivation due to SIV co-infection. Further, combinatorial antiretroviral therapy (cART) fails to restore T-effector functions and thus prevent LTBI reactivation in a nonhuman primate model of TB/SIV co-infection. Investigating the impact of cART on chronic immune activation in a relevant co-infected preclinical model at the single cell level will lead to the identification of key biomarkers predicting LTBI reactivation. We will synergize the research proposed here with a funded K01-award aims to collect cohesive data from archived control samples (uninfected, LTBI, SIV infected, Mtb/SIV co-infected but cART naïve; archived samples) and Mtb/SIV co-infected short-term, long-term cART treated (K-award) rhesus macaques. Based on our findings from the co-infection study, we hypothesize that while initiating cART at peak viremia in Mtb/SIV co- infection causes a significant decline in immune activation and macrophage turnover, it fails to rescue the skewed CD4+T effector memory responses leading to LTBI reactivation. Thus, in Aim 1, we will identify the specific lineage markers in the interplay between macrophages and CD4+ T cells that remain impaired despite cART in Mtb/SIV co-infected rhesus macaques. In Aim 2, we will investigate the earliest events of SIV-driven chronic immune activation and compare our findings to cART treated cohorts. For this, i) we will compare the activation status of plasmacytoid dendritic cells (pDCs) and NK cells in Mtb/SIV co-infection, ii) we will study the impact of cART on plasmacytoid dendritic cell (pDC)-driven Type-I Interferon (IFN) production and its impact on downstream effector responses compared to untreated controls. Overall, we will be able to determine if i) macrophage turnover interferes with CD4+ T cell restoration and function, ii) if cART effectively controls the earliest events of virus-driven immune activation by improving NK cell function and iii) the impact of cART on Type-I IFN response in driving the immune activation in Mtb/SIV co- infection. Studying the impact of cART on immune activation in Mtb/SIV co-infection is critical to identifying biomarkers for therapeutics and vaccine design to prevent LTBI reactivation.
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