CD4 Th1 and TCM as Modulators of Neuroinflammation

Project Summary Anti-retroviral therapy (ART) has transformed the management of HIV, turning a once-fatal illness into a chronic condition. However, the success of ART has also led to the emergence of chronic inflammatory diseases, particularly neurodegenerative disorders, as a significant challenge. HIV-positive individuals are at a significantly higher risk of developing HIV-associated neurocognitive disorders (HAND), with nearly half of those on ART experiencing HAND symptoms due to persistent neuroinflammation. Infiltrating immune cells, alongside brain- resident counterparts, are key drivers of neuroinflammation, yet targeting the central nervous system (CNS) T cell infiltration remains largely unexplored. Our R21 proposal aims to bridge this gap by targeting specific CD4 T cell subsets to uncover their roles and interaction in the CNS and to develop innovative strategies to mitigate neuroinflammation. We will investigate the role of T helper 1 (Th1) cells and T central memory (TCM) cells in driving acute neuroinflammatory processes within the brain parenchyma and border tissues. We will use a highly relevant rhesus macaque model of HIV, where SIV infection is followed by ART initiated on day 7 to simulate clinical conditions. In Aim 1, we will assess the impact of a novel monoclonal antibody designed to block CD4 Th1 influx into the CNS and determine if this intervention decreases viral loads and inflammatory profiles in regions such as the prefrontal cortex, hippocampus, and other CNS areas. Aim 2 will explore whether additionally blocking CNS entry of CD4 TCM cells further reduces viral loads and neuroinflammation. Through high-dimensional flow cytometry and comprehensive virological analyses of distinct brain regions and border tissues, this study will provide insights into how CD4 Th1 and TCM cells contribute to neuroinflammation and CNS viral seeding. By targeting these specific CD4 T cell subsets, we aim to uncover detailed mechanisms and explore potential interventions to mitigate neuroinflammatory and neurodegenerative effects in HIV-infected individuals.