New insights into HBV replication: new opportunities for improved therapies

HBV is one of the smallest animal viruses yet one of the most successful human pathogens, inflicting potentially life-threatening liver disease on more than 5% of the global population. While infection is preventable by prophylactic vaccination, few options for the treatment of established chronic hepatitis B are available and none are effective in more than a fraction of patients. Moreover, interferons may cause severe side effects and the, as of August 2008, five approved nucleos(t)ide analogs suffer from rapid emergence of viral resistance. Hence, improved and sustained therapeutic success will require new treatments based on alternative modes of action. The minimalistic genetic outfit of HBV offers few obvious targets, and virus-specific restrictions have hampered understanding, particular, of the early infection steps. However, recently established in vitro reconstitution systems for initation of reverse transcription and capsid assembly are ready to be exploited for mechanism-based screens for new inhibitors, Moreover, other as yet poorly understood aspects, including the function of the viral HBx protein and the metabolism of covalently-closed circular DNA as a persistance reservoir, rely on an intimate interplay between the virus and host that holds numerous opportunities for drug development, as discussed in this article.