Mentored Scientist Award

Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) continue to experience chronic immune activation and remain at increased risk for non-AIDS-related comorbidities. The gastrointestinal (GI) tract is a central site of HIV pathogenesis, serving as an early target of viral replication and CD4+ T-cell depletion and persisting as a major viral reservoir during long-term ART. Ongoing immune activation in the gut is associated with epithelial dysfunction and barrier disruption, yet the underlying mechanisms remain poorly understood, partly due to the lack of physiologically relevant in vitro models. The intestinal epithelium depends on tightly regulated, stem cell-driven regeneration to maintain tissue integrity. While transient regeneration supports repair, chronic inflammation can disrupt this balance, leading to aberrant regeneration, epithelial dysfunction, and increased risk of neoplastic transformation. Consistent with this, PLWH show a higher prevalence of intestinal adenomas, suggesting that chronic inflammation may drive maladaptive repair programs.

To investigate the impact of HIV-associated chronic immune activation on epithelial homeostasis, we will develop a human intestinal organoid model with an integrated immune compartment to study interactions between HIV infection, immune activation, and epithelial regeneration. In Aim 1, we will establish an HIV immuno-organoid platform by co-culturing donor-matched intestinal organoids with HIV-infected CD4+ T cells and macrophages derived from peripheral blood mononuclear cells. This system will recapitulate key immune-epithelial interactions and provide a tractable platform for mechanistic studies. In Aim 2, we will investigate how HIV-associated inflammatory signals, particularly IFN- and TNF-, affect epithelial regeneration. Using intestinal organoid cultures, we will model chronic inflammatory exposure and assess its impact on proliferation, differentiation, and functional transformation, including growth factor independence as a hallmark of dysregulated regeneration. Together, these studies establish novel models to investigate the impact of chronic HIV-associated inflammation on intestinal epithelial, improving our understanding non-AIDS related comorbidity development in the gut.