UC San Diego

HIV protease inhibitors (HPIs) are a major treatment option within highly active antiretroviral therapy (HAART) for HIV patients. Diarrhea is a common side effect found in 16-62% of patients using HPIs. Little is known about the mechanism that mediates the HPI-induced diarrhea. It has been suggested that intestinal barrier disruption is the cause of HPI-induced diarrhea. Recent studies have shown that HPIs disrupt intestinal barrier function via cell death in intestinal epithelial cells (IECs). Using an in-vitro human IEC line, HCA7, we show that the HPI, Ritonavir, induces apoptosis of IECs via an autophagic/ apoptotic pathway. Importantly, we also identify an alternative pathway for intestinal barrier disruption through a Ritonavir-induced downregulation of tight junction proteins. These findings implicate two independent pathways for HPI-induced intestinal barrier disruption. Future study may provide therapeutic solutions that exploit these pathways to reduce diarrhea in HAART patients and increase patient compliance to treatment