TGF-β promotes the resolution of acute hepatitis B virus infection

Abstract

Abstract An estimated 296 million people live with a chronic hepatitis B virus (HBV) infection, resulting in approximately 800,000 annual deaths. Thus, despite the availability of an effective vaccine, HBV remains a global health concern. Most children and a fraction of adults infected with HBV develop a persistent liver infection that yields lifelong complications. It is believed that the immune tolerogenic environment of the liver and the dysfunction of T and B cells contribute to HBV persistence in these individuals. Here, an adeno-associated virus (AAV)-based mouse model of HBV infection was utilized to investigate the underlying mechanisms of immune dysfunction that impede viral clearance. HBV infection was initiated in mice by AAV-HBV transduction, and TGF-β was depleted to determine the role of this cytokine in HBV persistence. As TGF-β is often associated with negative regulation of the immune response, we hypothesized that its inhibition might improve HBV-specific T and B cell responses. However, the lack of TGF-β resulted in impaired HBV surface antigen (HBsAg) clearance and diminished anti-HBsAg antibody levels, revealing a positive role for TGF-β in the antibody response to HBV. This effect of TGF-β on the antibody response to HBsAg was unique to AAV-HBV transduction, as a similar increase in anti-HBsAg was not observed by TGF-β depletion following infection with recombinant vesicular stomatitis virus expressing HBsAg. We also observed differences in B cell activation marker expression during HBsAg clearance in mice transduced with AAV-HBV and depleted of TGF-β. Together, these findings highlight the impact of TGF-β on the B cell response to HBV and have begun to define a unique role for this cytokine in promoting HBV clearance. Supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R01AI148354. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.