Defining the molecular mechanism of gut inflammation and barrier dysfunction in people with HIV (PWH)

Washington University, Saint Louis MO

Investigators

Abstract

ABSTRACT Substantial diarrhea is noted in about 50% of human immunodeficiency virus (HIV)-infected subjects with or without antiretroviral therapy (ART) in the U.S., of which the pathogenesis remains unclear. One of the challenges in studying HIV-associated diarrhea is that these patients often have comorbidities, such as malnutrition and co- infection with other gut pathogens, and hence it is difficult to dissect out the contributions of each cellular and microbial pathogenic components and their mechanisms. While a mouse model would provide a clean platform to study HIV-associated diarrhea, HIV does not infect murine immune cells, thus limiting the development of in vivo models. We recently established a novel humanized mouse model that supports robust reconstitution of human innate and adaptive immune systems in both lymphoid and non-lymphoid tissues, which provides an opportunity to investigate the pathogenesis of HIV enteropathy in vivo. The scientific premise of the findings is that the humanized mouse model faithfully recapitulates the molecular dynamics of HIV infection in immune cells. We also discovered that CARD8 inflammasome is activated in by the HIV protease. CARD8 inflammasome has been implicated in modulating the severity of inflammatory bowel disease (IBD) and inflammasome-mediated pyroptosis is known to trigger gut inflammation. In the gut, while HIV only infects immune cells (CD4+ T cells and macrophages), these cells also interact with intestinal epithelial cells (IEC), and could contribute to the homeostasis of gut barrier integrity. The knowledge gaps for advancing our understanding of HIV enteropathy are the clinical relevance of HIV infection and/or ART per se on gut barrier function, and if CARD8 inflammasome also adversely impacts IEC homeostasis. Our overarching hypothesis is that HIV-infected immune cells impede gut epithelial integrity through pyroptosis induction. We aim to understand the molecular mechanism governing gut inflammation and barrier leakiness during HIV infection and whether such damage persists despite suppressive ART, which impairs wound healing during subsequent injuries. We propose to define the interplay between IEC and HIV-infected immune cells in vitro, to define the how HIV infection dysregulates gut barrier function under injury using humanized mouse models, and to define the molecular crosstalk between IEC and immune cells in gut samples from HIV patients. Collectively, we will establish that HIV infection could negatively impact gut barrier integrity. We will additionally establish that HIV-activated inflammasome mediates the disruption of get epithelial barrier by recruitment of additional proinflammatory cytokines and chemokines that target the IEC. Other deliverables will also include the potential of targeting pyroptosis for HIV enteropathy.