New Insights into Hepatitis B and Hepatitis Delta Virus Entry

Stephan Urban

Disclosures

Future Virology. 2008;3(3):253-264. 

In This Article

Abstract and Introduction

Abstract

Notwithstanding the medical importance of the HBV infection, our understanding of how this pathogen enters hepatocytes is incomplete. This reflects a long-lasting dependence of in vitro infection studies solely on primary human hepatocytes, which are difficult to obtain and maintain in a susceptible state. The establishment of a polarizable HBV-susceptible human hepatoma cell line (HepaRG) and the utilization of Tupaia belangeri hepatocytes (PTHs) resolved this issue. Since then, important insight into viral and cellular determinants participating in HBV binding and infection have been achieved. We now know that the large viral surface protein (L) plays a pivotal role in HBV entry. It mediates diverse functions, commencing binding of virions to heparan sulfate proteoglycans at the hepatocytes surface as a prerequisite for entry. Subsequently, (a) highly specific event(s) involving the myristoylated N-terminal preS1 subdomain of L, as well as the cytosolic and antigenic loops of the S-domain, initiates a series of less well understood steps, resulting in a pH independent, reduction-sensitive fusion of the viral membrane with a cellular membrane. One of these steps is highly sensitive to synthetic N-acylated preS1 lipopeptides and can be blocked in vitro and in vivo at picomolar concentrations. This opens novel therapeutic options addressing virus entry. Future approaches aiming at the elucidation of HBV hepatotropism, the identification of (a) specific receptor(s), the clarification of the endocytic entry pathway and imaging of fluorescently-labeled virions will allow us to decipher more precisely the HBV entry pathway in the near future. Furthermore, clinical efficacy studies with HBV-preS-derived lipopeptides will tell us whether entry inhibition is a passable way to defend acute and chronic HBV and hepatitis delta virus infections.

Introduction

HBV is a small, enveloped DNA virus that replicates its genome via reverse transcription of a RNA intermediate. HBV causes temporary and chronic liver diseases and is characterized by a remarkable hepatotropism and a pronounced species specificity, which is related to one of the early infection events.[1] Today, approximately 2 billion people carry serological markers related to HBV. Some 360 million of them are chronic HBV carriers, replicating the virus at different levels. They are consequently prone to develop liver fibrosis, cirrhoses and hepatocellular carcinoma (HCC).[2] With the availability of a vaccine in 1986, HBV vaccination programs have been launched in several countries. Recent studies demonstrate that these programs result in long-term reduction of the HBV-related HCC incidence.[3,4] Even so, the number of chronically infected people will increase in the future due to the rising world population and the limited accessibility of the vaccine in developing nations.

The currently approved antiviral drugs used to treat chronic hepatitis B are IFN-α or its pegylated form PEG-IFN-α and the nucleo(s)tide analogs lamivudine, adeforvir and, since recently, entecavir and telbivudine. Although efficient in reducing the virus load by several logs, only 20-30% of patients show sustained virological responses after withdrawal of the substances.[5] In addition, the drugs are expensive and prolonged therapies with nucleoside analogs results in the selection of resistant mutants.[6]

Soon after the discovery of HBV as the causative agent for hepatitis B in the mid-1960s, many attempts have been undertaken to study HBV replication in cell culture and to establish small animal models.[7] These approaches were successful as artificial delivery of DNA expressing genomic HBV RNA resulted in replication and proper assembly of virions that are infectious in chimpanzees.[8] However, the observation that only primary human hepatocytes (PHHs)[9] or Tupaia belangeri hepatocytes (PTHs)[10] but none of the established hepatoma cell lines supported de novo HBV infection hampered the investigation of the early infection events and led to the hypothesis that these cells might lack (a) factor(s) required for HBV entry. Following these observations, the generation of HBV-expressing stable cell lines or transgenic mice facilitated investigations on replication steps downstream HBV gene expression.[11,12,13,14] As alternatives, animal models, such as the duck HBV (DHBV) system[15] or the woodchuck HBV system[16] have been established. Many general features of the hepadnaviral intracellular replication steps have been successfully elucidated using these models; however, there are indications of profound differences to HBV regarding viral entry (for a recent review addressing this topic, see[7]).

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