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Intracellular transport of viral structures

Research project
Active research
Project owner
Institute of Biomedicine

Short description

For pathogenesis, viruses must spread within the infected organism. They must multiply, become released and infect uninfected cells. The kinetic of these steps must be faster than the counteractions of the immune system. The aim of the projects is the understanding of rate-limiting factors using two model viruses: hepatitis B virus, which causes chronic infections leading to liver cirrhosis and liver cancer and adeno-associated viruses, which are do not cause any disease but which are used in gene therapy. The aims of the research projects are thus distinct: for hepatitis B virus the aim is for the efficiency of spread to be reduced, while the aim for adenoviruses is to increase their efficiency.

Hepatitis B viruses (HBV) are major pathogen accounting for 1 million deaths per year world-wide. The death toll comes from chronic infections, which lead to liver cirrhosis and liver failure and from liver cell carcinoma. HBV contains a partially double-stranded DNA, which is found inside the viral capsid, which is surrounded by the viral surface proteins. HBV infection is very efficient and replication occurs via reverse transcription of so-called pregenomic RNA, which is transcribed from a nuclear double stranded DNA. This nuclear DNA is stable and is not affected by current therapies, which target production of new virions. During infection, HBV has to transport its genome from the cell periphery into the nucleus also requiring that virus’s DNA becomes released from the capsids. As the capsid is required for transport of the genome to the nucleus, genome release must be coordinated and must occur at the end of the transport process through the cytoplasm. Despite of the importance for establishing and maintaining infection, very little is known about the driving forces and interactions leading to genome nor about the fate of the nuclear DNA. We analyze the underlying molecular interactions using methods from cell biology including time-lapse microscopy for better understanding the bottlenecks of the transport and subsequent repair processes, which convert virion’s partially double-stranded DNA to nuclear double stranded DNA.

 

Adeno-associated viruses (AAV) are not associated with any disease. They serve as platforms in gene therapy and there are currently two treatments of genetic diseases based on AAVs: Zolgensma™ is used against spinal muscular atrophy and Glybera™ against lipoprotein lipase deficiency. AAVs also replicate via nuclear DNA and – similarly to HBV - the genome has to be transported through the cytoplasm into the nucleus, which requires distinct transport steps mediated via the viral capsid. However, in contrast to HBV, AAVs are very inefficient and the intracellular transport steps appear to be rate-limiting. Our research on the molecular mechanisms of HBV transport and genome release are thus complemented with AAVs but with the aim of increasing efficiency.

 

Group members

Maria Johansson

Gustaf Rydell

Luisa Fernanda Bustamante Jaramillo