Hepatitis E virus persists in the presence of a type III interferon response

Abstract

The RIG-I-like RNA helicase (RLR)-mediated interferon (IFN) response plays a pivotal role in the hepatic antiviral immunity. The hepatitis A virus (HAV) and the hepatitis C virus (HCV) counter this response by encoding a viral protease that cleaves the mitochondria antiviral signaling protein (MAVS), a common signaling adaptor for RLRs. However, a third hepatotropic RNA virus, the hepatitis E virus (HEV), does not appear to encode a functional protease yet persists in infected cells. We investigated HEV-induced IFN responses in human hepatoma cells and primary human hepatocytes. HEV infection resulted in persistent virus replication despite poor spread. This was companied by a type III IFN response that upregulated multiple IFN-stimulated genes (ISGs), but type I IFNs were barely detected. Blocking type III IFN production or signaling resulted in reduced ISG expression and enhanced HEV replication. Unlike HAV and HCV, HEV did not cleave MAVS; MAVS protein size, mitochondrial localization, and function remained unaltered in HEV-replicating cells. Depletion of MAVS or MDA5, and to a less extent RIG-I, also diminished IFN production and increased HEV replication. Furthermore, persistent activation of the JAK/STAT signaling rendered infected cells refractory to exogenous IFN treatment, and depletion of MAVS or the receptor for type III IFNs restored the IFN responsiveness. Collectively, these results indicate that unlike other hepatotropic RNA viruses, HEV does not target MAVS and its persistence is associated with continuous production of type III IFNs. HEV infection is a common cause for acute viral hepatitis worldwide. Approximately 20 millions of people are infected annually. In immunocompetent hosts the infection is self-limited and mostly asymptomatic, but the virus frequently persists when immunity is compromised leading to increased risk for cirrhosis. Currently there are no FDA-approved diagnostics or treatments for HEV. Understanding how HEV induces and manipulates host innate immune responses will help elucidate the mechanism(s) of HEV persistence and identify potential targets for therapy. Our results show that unlike other hepatotropic RNA viruses, HEV did not cleave MAVS and stimulated a sustained type III IFN response in persistently infected cells. Furthermore, the JAK/STAT pathway was persistently activated in HEV-replicating cells and responded poorly to exogenously added IFNs. This study uncovers a unique interplay between HEV and the host IFN pathway and provides insight into the mechanism of HEV persistence in patients.