New clues to hepatitis B species restriction could help build a novel model for studying infection The development of effective treatments for hepatitis B virus (HBV) has long been hindered by the lack of a suitable small animal model to study the full viral lifecycle, host immune response, and disease progression. For decades, researchers assumed the barrier to creating a workable mouse model stemmed from HBV’s unique partially double-stranded DNA genome, which was thought to prevent the virus from establishing a genetic foothold in mouse cells. Though, recent research from Rockefeller University has overturned this long-standing assumption, revealing that the true obstacle lies not in the virus’s genetic makeup but in a failure during the viral entry process. According to findings published in the Proceedings of the National Academy of Sciences (PNAS), scientists in the lab of Charles M. Rice discovered that human HBV fails to infect mouse liver cells not because it cannot replicate its DNA once inside, but because it is unable to deliver its genetic material to the host cell nucleus. This blockage occurs during the entry phase, suggesting that the virus cannot properly engage with the necessary receptors or complete the steps required to uncoat and release its genome into the mouse cell’s nucleus. The infection cycle is halted before replication can begin. This new understanding shifts the focus from overcoming intracellular replication barriers to fixing the virus’s ability to enter mouse cells. By identifying the specific step in the entry process that fails, researchers now have a clearer path toward engineering mice that express the human receptors or co-factors needed for HBV to successfully gain access to the nucleus. Such a model would allow scientists to study the entire course of HBV infection — from initial entry to chronic persistence, immune response, and the development of complications like cirrhosis and liver cancer — in a controlled laboratory setting. More than 250 million people worldwide live with chronic hepatitis B, a virus that often remains asymptomatic for decades before progressing to severe liver disease. Current therapies can suppress viral replication but rarely eliminate the virus entirely, largely because of the persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. Without a reliable animal model that mimics human infection, testing new strategies to target this persistent reservoir has been extremely challenging. The Rockefeller team’s perform, supported in part by the Stavros Niarchos Foundation (SNF) Institute for Global Infectious Disease Research, provides a foundation for developing a fully HBV-susceptible mouse model. If successful, such a model could transform HBV research by enabling preclinical testing of novel therapeutics, including those designed to eradicate cccDNA or stimulate curative immune responses. It would as well allow for a deeper understanding of how the virus establishes lifelong infection and why it evades immune clearance in some individuals. By correcting a decades-old misconception about the species barrier to HBV infection, this research opens a promising avenue toward overcoming one of the major obstacles in hepatitis B cure development. The ability to study HBV in a small animal model that accurately reflects human biology could accelerate the discovery and evaluation of interventions capable of achieving a true functional or complete cure.
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