Structural biology of the hepatitis B virus: from assembly towards design of therapeutics

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Despite the availability of a vaccine, a third of the world population has been infected with hepatitis B during their lifetime and more than 240 million people have developed a chronic infection, leaving them at high risk of developing hepatocellular carcinoma, cirrhosis and liver failure. Available drugs cannot clear the virus and escape mutations pose challenges to vaccination. A diversification of antiviral strategies is desirable targeting both virus entry and replication, in particular capsid assembly and envelopment, as well as host cell factors that sustain the virus. A prerequisite for the rational design of therapeutics is a detailed structural framework of all viral components. Despite extensive characterization of the hepatitis B virion, no unifying concept exists how the envelope, the capsid and the genome interact and assemble to yield functional viral particles at the atomic scale. One obstacle in the structural biology of this virus is its intrinsic heterogeneity, transient interactions, and dynamics, which are potentially relevant for function. We will employ nuclear magnetic resonance techniques jointly in solution and the immobilized state to monitor envelope and capsid proteins, nucleic acids and drug molecules, localizing sites of interaction and establishing how such interactions trigger structural and dynamical changes throughout the virions. In particular, our key research interests will be to rationalize the structural organization of the envelope proteins and their attachment to the capsid, to determine the structure of major surface epitope – the basis of the Hepatitis B vaccine – and to characterize the conformational and spatial dynamics of flexible segments as well as the packaging of the viral genome within the capsid. The long-term goal of this project will be to derive a structural model of the complete virion during all stages of the viral life cycle, uniting data from crystallography and cryo electron microscopy with insight into dynamics and interactions from magnetic resonance. Such a model will not only allow to rationalize virion maturation but also to predict potential interventions disturbing assembly and breaking signaling networks, which will enable the rational design of molecules that interfere with the viral life cycle for hepatitis B prevention and therapy. We will collaborate with virologists and researching medical scientists in order to maximize the translational impact of the project.