Mechanisms restricting hepatitis B virus cross-species transmission

ABSTRACT Chronic hepatitis B virus (HBV) infection affects more than 250 million people worldwide and markedly increases the risk of terminal liver diseases, including liver cirrhosis and hepatocellular carcinoma. Despite its global impact, HBV exhibits a remarkably narrow host range, with natural infection largely restricted to humans and chimpanzees. This stringent tropism has posed a major barrier to the development of experimentally tractable in vivo models and has limited our ability to study viral persistence, pathogenesis, and immune control. Over the past decades, substantial progress has been made in identifying the host and viral factors that govern HBV species specificity. Efforts to overcome these constraints have led to the development of genetically engineered systems, the use of surrogate hepadnaviruses that naturally infect other species, and the establishment of humanized liver models that enable infection in vivo within a human hepatocyte context. While these approaches have provided important insights, no currently available model fully recapitulates chronic HBV infection in an immunocompetent host. Defining and overcoming the barriers that underlie HBV’s restricted host range remains a central challenge in the field. Addressing this limitation will be essential for establishing physiologically relevant model systems and, ultimately, for enabling the development of curative strategies for chronic hepatitis B.