Update on the molecular and cellular biology of hepatitis E virus and therapeutic opportunities

Hepatitis E virus (HEV) is an emerging zoonotic pathogen and the leading cause of acute viral hepatitis worldwide. Nevertheless, HEV remains largely underestimated and poorly controlled. HEV infects a broad range of host species, transmits through diverse routes and can cause chronic infections in immunocompromised individuals and severe hepatitis in pregnant women. Currently, there is no HEV-specific antiviral treatment available and the only licensed vaccine is restricted to a few countries. Taken together, this highlights its significance as a global health treat and underscores the urgent need for new preventive and therapeutic strategies. This review provides a comprehensive overview of HEV molecular and cellular biology with a focus on antiviral opportunities. First, we summarize the epidemiology and clinical spectrum of HEV infection, as well as the current prevention, vaccination and treatment strategies. Next, we review the molecular mechanisms underlying HEV entry, replication, and assembly/egress, detailing host and viral factors that represent promising antiviral targets. We present the available in vitro and in vivo experimental models that are essential for studying the HEV life cycle and evaluating therapeutic candidates. Particular attention is given to recent discoveries in HEV entry pathways, the organization and functions of the ORF1 replicase complex, and host-virus interactions. Importantly, we provide an up-to-date overview of host-targeting antivirals (HTAs) and direct-acting antivirals (DAAs) against HEV that have been identified so far. This review emphasizes how fundamental virology informs drug discovery and paves the way toward the development of effective antivirals against this underestimated pathogen of increasing global concern.