The role of Innate Lymphoid Cells in the Gut to understand HIV pathology (360G-Wellcome-202485_Z_16_Z)

HIV pathology precipitates irreversible loss of mucosal barrier integrity. Innate Lymphoid Cells (ILCs) are crucial for rapid tissue repair and homeostasis and stimulate epithelial cell proliferation at gut mucosal barrier sites. I have shown that HIV-1 infection depletes ILCs in the circulation, and that this depletion correlates with disease stage and is not restored by antiretroviral treatment (ART) in chronic infection. Critically, ART initiated during early acute infection prior to peak viremia preserved ILC depletion1. This is a strong rationale for a role of ILCs in HIV pathology that involves gut barrier breakdown. However, the impact on ILC function at mucosal gut barrier sites remains unclear and is the specific focus of this proposal through studies of unique gut samples not available in Europe and US. Goals: 1: To define the role of ILCs in gut barrier integrity during different stages of HIV infection and study the impact of ART treatment. 2: To study the impact on gut epithelial cells after HIV infection and investigate those mechanisms using the "mini-gut model". 3: To use ILC and epithelial cell interaction as a first step to develop a novel treatment strategy focused on restoring gut dysbiosis to prevent immune activation and AIDS.