A major step for HCV research

The only natural host of the hepatitis C virus (HCV) is humans. Model organisms for laboratory studies, especially mice, cannot be infected which makes the search for a vaccine against HCV extremely difficult because the protective effect cannot be tested directly. In order to understand why the virus cannot infect mice and to enable the development of new animal models, researchers at TWINCORE in Hannover have generated an adapted virus variant that can infect mouse liver cells in vitro. They have now published their work in the ‘Journal of Hepatology Reports’.
 

The world health organization estimates that 50 million people are chronically infected with hepatitis C virus. Although the virus has been the subject of intense research since its discovery 35 years ago and efficient therapies have been available for about ten years, the infectious disease remains a major health issue worldwide. Approximately 1 million people are newly infected with the virus every year and there are more than 250,000 HCV-related deaths. An effective vaccine could help to address the problem, but has not yet been developed, partly because efficacy studies in laboratory animals - usually mice - with HCV are not possible. The virus only infects humans and chimpanzees. Understanding why the virus does not infect mice and how this barrier can be overcome is therefore an important question in HCV research.

In previous work in New York and Madrid, Dr Julie Sheldon, a scientist at the Institute for Experimental Virology and first author of the study, has already investigated HCV variants that were better adapted to human cell cultures. ‘Here, we now describe the first HCV variant that can infect mouse liver cells and also replicate there,’ says Sheldon. To achieve this, she and her colleagues took advantage of a characteristic of HCV: ‘HCV is an RNA virus that generates a very large population of variants due to a high rate of replication and mutation,’ says Sheldon. ‘This diversity allows the virus to quickly adapt to changing environment conditions and enabled us to adapt the virus to infect mouse cells.’

The new HCV variant replicates very efficiently in liver cells isolated from mice,‘ says Sheldon. A total of 35 changes in the virus’ proteins were responsible for this. These are about 1% of the possible positions - the virus is still 99% identical to the original virus. ‘However, the infection only works if two essential human cell entry factors, CD81 and occludin, are present on the surface of the mouse cells and if the innate immune response of the cells is restricted - either genetically or by an inhibitor.’

In further experiments, the scientists combined the various mutations in a so-called molecular clone. This molecular clone was used to find out which mechanism the virus used to cross the species barrier: ‘Both the structural and non-structural proteins contained mutations that led to increased specific infectivity and higher replication,’ says Dr Melina Winkler, second author of the study. ‘Although mutations in the envelope proteins contribute to the adaptation, they are not solely responsible for the phenotype.’

The virus' adaptation to mouse cells, which has been demonstrated here for the first time, opens up completely new possibilities for research. “This has brought us a major step closer to developing a mouse model for HCV,” says Prof Thomas Pietschmann, Director of the Institute of Experimental Virology at TWINCORE. ’The development of a vaccine has also failed so far because we did not have an animal model. Thanks to our new findings, this is now within reach.’
 

Funded by:

German Centre for Infection Research (DZIF) Grant: Development of an HCV in vIvo  vaccine challenge model (Delphi-Vaccine)

 ERC Starting Grant: 281473 VIRAFRONT: Viral frontiers – species barriers of hepatitis C virus replication 
 

Publication:

Adapted hepatitis C virus clone infects innate immunity deficient mouse hepatocytes with minimal human HCV entry factors

Julie Ann Sheldon, Melina Winkler, Qinggong Yuan, Nicola Frericks, Richard John Phillip Brown, Csaba Miskey, Natascha Gödecke, Sara Behme, Katharina Rox, Giorgia Mysegades, Florian Vondran, Dagmar Wirth, Thomas Pietschmann

JHEP Report, 2025, in press

https://doi.org/10.1016/j.jhepr.2025.101328