Thursday, April 3, 2025
4/3/2025
Effect of ILC3 loss on epithelial barrier function during ART Treated HIV infection - Project Summary: Our project aims to investigate the mechanisms behind the loss of Type 3 innate lymphoid cells (ILC3) in antiretroviral therapy (ART) treated People Living with HIV (PLWH) and the subsequent impact on intestinal epithelial barrier integrity. Chronic immune activation is a hallmark of HIV infection that persists in PLWH on ART and is linked to non-infectious comorbidities. Microbial translocation (MT) due to decreased mucosal barrier integrity is in part responsible for driving HIV-associated inflammation. Therefore, it is critical to understand mechanisms underlying barrier integrity in ART treated PLWH. ILC3s are essential for the maintenance of the gut epithelial barrier and are depleted during early HIV infection and are not restored with ART. Decreased frequency of these cells during HIV infection likely contributes to decreased epithelial barrier integrity leading to increased MT. Since ILC3s are not susceptible to direct HIV infection and a viable model to study their loss has yet to be developed, the mechanism behind their loss remains poorly understood. To address this gap in knowledge, we will use human intestinal explants as a model system to study early HIV infection. These explant tissues contain ILC3s, epithelial cells, and other immune cells that are susceptible to HIV infection. Our preliminary data show that these explant tissues remain viable for up to 7 days, can harbor HIV infection and ILC3s are depleted following HIV infection, providing this as a viable model to study HIV-associated ILC3 depletion. Furthermore, we and others have shown that ILC3s respond to specific bacteria found in the gut microbiome. This is emphasized as PLWH have a distinct enteric microbiome that is not reverted with ART. To fully model the intestinal environment during HIV infection, and the subsequent impact on ILC3 function, we will introduce an HIV-associated microbiome to the intestinal explant tissues. Ultimately, using these explants with HIV infection and HIV-associated microbiomes will shed light on the underlying mechanisms behind the loss of ILC3s and the effect on intestinal epithelial barrier integrity. This understanding could lead to the development of new therapeutic approaches to improve barrier integrity and reduce HIV-associated inflammation and comorbidities in PLWH.
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