Molecular biology of HBV

Research focus

Chronic hepatitis B virus (HBV) infections and the resulting liver diseases are serious medical problems and available therapies of limited efficacy. The development of new or the improvement of existing therapeutic concepts on a rational basis requires a deep knowledge of the biology of HBV on a molecular level. The virus is the prototype of the family hepadnaviridae characterized by several unique features. For example, hepadnaviruses are very species specific and efficiently replicate only in hepatocytes, they have the smallest DNA genome among enveloped DNA viruses (only appr. 3 kb) which is generated by reverse transcription. The whole circular genome is covered by four open reading frames which overlap extensively with each other. Important questions about the HBV biology are still unresolved and our understanding of potential antiviral targets insufficient. The group investigates the specific research topics of the molecular biology of hepatitis B viruses listed below.

Envelopment of the nucleocapsid

The virus particle is formed by the envelopment of a cytoplasmic icosahedral capsid containing the viral genome with viral envelope proteins at an internal cellular membrane. This budding process translocates the capsid across the cellular membrane and allows the release of the infectious virus from the cell by its secretion machinery. A very tight and specific interaction between the capsid surface and cytoplasmic domains of viral membrane proteins is required for and probably drives the envelopment process. We try to describe the molecular surfaces of capsid and envelope involved in the budding process. These structures are potential antiviral targets, and we intend to generate small molecules specifically blocking the HBV capsid-envelope interaction.

Maturation of the nucleocapsid

During HBV capsid formation a viral RNA molecule is packaged in the lumen together with a viral reverse transcriptase. This early, RNA containing, "immature" capsid is incompetent for budding. By reverse transcription of the RNA molecule in the capsid lumen the viral DNA genome is generated. The capsid is then named "mature" and becomes competent for envelopment. We want to understand the molecular difference between immature and mature capsids and how this envelopment signal is generated.

Biogenesis of subviral particles

The small HBV envelope protein S is initially synthesized as a transmembrane protein and has the unique feature to efficiently form subviral spherical lipoprotein particles of appr. 20 nm diameter. These particles are generated and secreted from S expressing cells without the need of other viral factors. They are used as the current vaccine against hepatitis B. We want to understand the molecular mechanisms leading from the transmembrane S protein to the secreted lipoprotein particles.