Investigating the Establishment of Intestinal Epithelial Dysfunction during Viremic HIV Infection and Recovery upon Antiretroviral Therapy
- Author(s): Chitre, Avantika Sanjeev
- Advisor(s): Hermiston, Michelle
- et al.
Untreated HIV infection is characterized by intestinal epithelial barrier dysfunction and chronic inflammation, features that are thought to be related and that are reversed to variable degrees by suppressive antiretroviral therapy (ART). While mucosal inflammation during HIV disease and treatment has been thoroughly studied, targeted study of epithelial pathways and how they are affected during these clinical phases has not yet been done. In this thesis, we sought to identify intestinal epithelial cell (IEC)-specific components that were altered during HIV infection in an effort to understand what drives epithelial dysfunction and whether these pathways remain altered during ART. We identified NFkB-inhibitor and anti-inflammatory gene A20 as being upregulated during ART, associating with the expression of barrier-related genes and suggesting a relationship to recovery in these subjects. Using murine organoid models, we demonstrated that viremia-associated IFNa suppressed A20 expression in IECs and that A20 downregulation rendered IECs more susceptible to epithelial damage and cell death in the presence of proinflammatory cytokines, potentially explaining the development of epithelial dysfunction in viremic individuals. In addition to the induction of anti-inflammatory pathways during ART, we also observed an upregulation of repair pathways, specifically showing elevated levels of Trefoil Factor 3 (TFF3). Taken together, our work indicates a concerted effort on the part of the epithelium, engaging pathways to both restrict inflammation and repair existing damage, to promote recovery and re-establish intestinal homeostasis.