How hepatitis E virus invades hepatocytes: the mystery of viral entry

Hepatitis E virus (HEV) is the leading cause of acute viral hepatitis globally. HEV infections can progress to chronic disease in immunocompromised individuals and may also cause extrahepatic complications. By contrast to other hepatitis viruses, HEV exhibits a broad tissue tropism, and certain genotypes have the ability to infect multiple species. The initial steps of surface attachment and host cell entry are critical steps in the viral infection cycle and serve as key determinants to establish an infection. This review summarizes the current understanding of HEV entry, focusing on molecular entry factors, such as viral receptors, and discusses differences between quasi-enveloped and non-enveloped HEV. We further cover recent developments of assay systems to study HEV entry and highlight experimental strategies to identify novel host components required for HEV entry. Advancing our understanding in these areas could help to guide the development of targeted antiviral strategies to block the early stages of HEV infection.