Name: Ralf Bartenschlager
Institution: Heidelberg University Hospital & German Cancer Research Center
Could you tell me a little bit about your research and what it entails?
As a molecular biologist by training I am very much interested in how viruses manipulate and exploit host cells to achieve efficient virus production, how viruses can overcome intrinsic and inducible antiviral defences to establish persistent infections and by which mechanisms viral infections induce pathogenesis, most notably cancer. In the past ~20 years, all these interests were centered on the hepatitis C virus (HCV) and the work in my laboratory focuses on three main areas:
- In the past we concentrated on the establishment and improvement of cell culture systems for HCV, because they are essential to study the replication cycle of this virus and to develop antiviral drugs. Nowadays, we take advantage of these systems and try to understand how HCV exploits cellular pathways such as autophagy and lipid metabolism for efficient replication and virus production. Moreover, HCV is a perfect model to study basic aspects of protein – lipid interactions because the complete viral replication cycle takes place on the surface of intracellular membranes.
- Most HCV infections persist. This is unusual for an RNA virus and we want to find out which tricks HCV uses to overcome innate and adaptive immune responses. While in the past these studies relied on cell based systems, with the advent of highly efficient antiviral therapy to treat HCV infections it became possible to study the reconstitution of HCV-specific antiviral immunity in infected patients. In this way we hope to gain further insights into how viruses other than HCV, establish persistent infections.
- HCV is one out of seven human-pathogenic viruses linked to cancer. In fact, around 25% of hepatocellular carcinomas arise in the context of an HCV infection (and an additional 50% is linked to HBV infection). We want to understand how HCV contributes to cancer development, which seems to be mediated by indirect mechanisms (notably chronic inflammation) and by direct viral effects such as perturbation of distinct cellular pathways.
In the last few years we expanded our studies to the hepatitis B virus (HBV) as well as the so-called flaviviruses such as Dengue virus and Zika virus, where we address similar questions with the aim to learn from the similarities and differences between HCV and these viruses.
How did you come to be interested in viral hepatitis?
This happened by chance. As a student in biology at Heidelberg University, I was very interested in viruses, what they are, how they replicate and how they make people sick. Fortunately, a world leader in hepatitis virus research, Prof. Heinz Schaller, worked at the Center of Molecular Biology on Heidelberg campus. So I ended up as a PhD student in his lab, learnt a lot about viruses, especially HBV, how to conduct experiments and how to do scientific research. I enjoyed it a lot but by the time I had finished my PhD, I searched for a new topic. It happened that by this time, the first molecular HCV clone was published and so the choice to move on with this virus during the next step of my career was pretty obvious.
What do you see as the biggest accomplishment in your field in the past few years?
Many important accomplishments have been made, but to my opinion, the one that stands out is the development of antiviral therapy that eradicates the virus in ~95% and more of treated people, within 12 weeks or even less. This is most remarkable considering HCV as chronic infection. It is the result of a strong and highly committed HCV research community that paved the way for drug development, but also the result of clever drug design and brave scientists who followed unconventional ideas. Amongst all the highly potent drugs in clinical use, the NS5A inhibitors are most remarkable to me. They were identified by high-throughput cell-based screening, are the most potent drugs ever made against a virus and had never been on our radar, because NS5A lacks enzymatic activity and therefore was initially considered as non-druggable. Nowadays pretty much every drug combination given to patients contains one NS5A inhibitor.
What do you see as the main challenges for research in your field in the coming years?
With the advent of highly potent drugs HCV is considered to be done. However, this only applies to a very ideal situation, i.e. to patients who are aware of their infection (most people are not), who have access to therapy and can afford it. Unfortunately, this is the vast minority of people. Moreover, the risk to develop hepatocellular carcinoma persists even after HCV eradication, but this risk very much depends on how much liver disease has progressed by the time of therapy. Finally, reinfections with HCV are common and therefore virus eradication in high-risk groups will be difficult. In the light of these clinical and public health challenges a prophylactic vaccine would be most helpful, but interests to develop them are low for economic reasons and because of major technical challenges. Therefore, I think that HCV will keep us busy for many years to come, even though many funding agencies have a different view.
What personal career achievement are you most proud of? Why?
I think the development of the first cell culture model is the most important contribution that my research group could make to the field. I remember the depression that came up in the early years of HCV research when we were running out of ideas what to do with this virus in the absence of systems to propagate it and how to get it propagated in easy to culture cells. This first culture model, established by Volker Lohmann in my laboratory helped us to survive in these difficult days and gave both us and the HCV research community a new perspective.