Inhibition of HBV gene expression and replication by stably expressed interferon-α1 via adeno-associated viral vectors

Abstract

Background: Interferon-α2 (IFNα2) is routinely used for anti-hepatitis B virus (HBV) treatment. However, the therapeutic efficiency is unsatisfactory, particularly in East Asia. Such inefficiency might be a result of the short half-life, relatively low local concentration and strong side-effects of interferons. Frequent and repeated injection is also a big burden for patients. In the present study, a single dose of vector-delivered IFNα1 was tested for its anti-HBV effects. Methods: Adeno-associated viral vector (AAV-IFNα1) was generated to deliver the IFNα1 gene into hepatocytes. IFNα1, hepatitis B surface (HBsAg) and e (HBeAg) antigens were measured by enzyme-linked immunosorbent assay and/or western blotting. The level of viral DNA was measured by quantitative real-time polymerase chain reaction. Results: AAV-IFNα1 effectively transduced HBV-producing cells (HepAD38) and mouse hepatocytes, where IFNα1 was expressed in a stable manner. Both intracellular and extracellular HBsAg and HBeAg were significantly reduced in vitro. In the HBV-producing mice, the concentration of IFNα1 in the liver was eight-fold higher than that in plasma. Compared with control groups, HBeAg/HBsAg antigen levels were reduced by more than ten-fold from day 1-5, and dropped to an undetectable level on day 9 in the AAV-IFNα1 group. Concurrently, the level of viral DNA decreased over 30-fold for several weeks. Conclusions: A single dose administration of AAV-IFNα1 viral vector displayed prolonged transgene expression and superior antiviral effects both in vitro and in vivo. Therefore, the use of AAV-IFNα1 might be a potential alternative strategy for anti-HBV therapy. Copyright © 2008 John Wiley & Sons, Ltd.