Cancer and diseases associated with hepatitis B virus (HBV) infection kill over 800,000 people every year. Antiviral therapies are rarely able to cure patients of HBV infection. To try to answer why, researchers at the University of Wisconsin – Madison’s Institute of Molecular Virology are investigating where and how the virus persists in human cells.
In a new publication in the Journal of Virology, a team led by Assistant Professor Kinjal Majumder shows that HBV DNA nestles into busy areas of the cell nucleus. In these hotspots, the virus disrupts normal DNA replication, causing cellular stress and triggering DNA damage signals across the cell. Processes like these can set the stage for cancer-causing mutations, quietly undermining the integrity of human DNA long before symptoms of liver disease appear.
In their new study, the team found that HBV infection of cells increased a variety of cellular replication stress responses, particularly at sites containing the protein DDIT3. Other work has shown DDIT3 is produced by cells when something goes wrong with DNA replication or when a cell’s environment becomes toxic. Prof. Majumder’s team observed that DDIT3 appeared nearby to the viral DNA hiding in infected cells. What was surprising is that rather than helping the cells clear the viral infection, DDIT3 seemed to increase cell stress and DNA replication problems. When DDIT3 was suppressed experimentally, cells recovered their ability to replicate DNA normally, even though the viral DNA continued to remain hidden in the nucleus.
“Even though HBV DNA can persist in a liver cell for many years, it has the capacity to alter the replisome within a few days, which is remarkable for such a small virus. This finding is important because we are starting to discover that the virus alters the host environment where it establishes its nuclear reservoir. These are regions that can be targeted for eliminating the virus long-term.” said Majumder.
Chronic HBV infection affects approximately 1 out of every 25 people in the world and is a leading cause of hepatocellular carcinoma, the most common type of liver cancer. While current drugs can suppress the virus, they rarely eliminate it. By understanding the mechanics of how HBV hijacks and manipulates cells, studies like this one can provide a roadmap for developing treatments to block the signals that turn infected cells into cancerous cells.
The Institute for Molecular Virology (IMV) is a Center administered by the University of Wisconsin-Madison Office of the Vice Chancellor for Research focused on uncovering how viruses replicate, evolve, and cause disease, developing strategies for prevention and treatment of viral infections, and harnesses viruses as tools to understand biological processes. The IMV is composed of a core group of faculty from across the UW-Madison campus with tenure homes in the Departments of Oncology, Biochemistry, Medical Microbiology & Immunology, and Plant Pathology. Housed in the Robert M. Bock Laboratories, IMV anchors a much broader network of over 40 virology-focused researchers across UW-Madison who make up the Madison Virology Collective.