Mechanisms of disrupted intestinal epithelial homeostasis during HIV infection

Abstract

Human immunodeficiency virus type 1 (HIV) infection causes gastrointestinal (GI) pathology, termed “HIV enteropathy”, which is marked by local inflammation, villous blunting, and loss of epithelial barrier integrity. Intestinal damage is thought to play a significant role in driving HIV disease progression by promoting systemic inflammation. Despite the critical role that disrupted epithelial homeostasis plays in HIV disease progression, very little is known regarding the effects of HIV infection on intestinal stem cells (ISCs) and other intestinal epithelial cell (IEC) subsets. Using intestinal pinch biopsy samples, we performed comprehensive histological, flow cytometric, and transcriptional profiling of ISCs and IEC subsets from multiple GI sites of HIV-infected individuals and healthy controls. We describe a specific disruption in small intestinal epithelial homeostasis marked by transit-amplifying (TA) cell expansion and hyperproliferation, accompanied by increased villous apoptosis. This was associated with Tumor Necrosis Factor alpha (TNFα) and interferon (IFN) signaling in a population of ISCs and TA cells. Using an in vitro mouse intestinal epithelial organoid model, we demonstrate that TNFα promotes epithelial proliferation and increased stemness, while type I and type II IFNs cause cell death. These data support a model where pro-inflammatory cytokines induced by HIV infection drive accelerated epithelial turnover, resulting in the small intestinal enteropathy observed in HIV-infected individuals. Our findings characterize HIV enteropathy at a cellular and molecular level and identify specific signaling pathways involved in HIV-associated disruption of intestinal epithelial homeostasis.