Tackling the HCV Life Cycle with Mathematical Modeling – Decoding the Enigma

Hepatitis C Virus (HCV) is the causative agent of Hepatitis C. An estimated 71 Mio. people worldwide are chronically infected, leading to roughly 400.000 deaths a year from liver cirrhosis or hepatocellular carcinoma (HCC) (WHO, 2017). In Europe, except for Greece and Russia, HCV is the major cause of HCC, accounting for almost 50% of cases in Germany from 2000 – 2014 (de Martel et al., 2015). For few years now, highly potent drugs giving cure rates of almost 100% are available; however, access is limited to the developed world and by extremely high costs and resistance mutants are on the rise. Together with the low number of patients aware of their infection (20%), the estimated global disease burden by HCV and HCV-driven HCC therefore is supposed to increase in the near future (Sibley et al., 2015). Given the mentioned treatment limitations and risks as well as the many still open questions in viral persistence, immune evasion, and tumorigenesis, there is high need for further research.

We study HCV infection of hepatoma cells and follow its replication in a highly time-resolved and quantitative manner. We extended a previously developed and published mathematical model of intracellular HCV replication (Binder et al., 2013) to now cover the whole viral life cycle, including infection, particle production, and spread. Our model is able to accurately simulate viral replication dynamics in vitro and will now be used to address questions with high biological complexity that cannot be approached in a single experiment, e.g. the mode of action of direct-acting antivirals used in the clinics or IFN-α which triggers an intricate antiviral response in the host cell. Furthermore, our model can help to gain a better understanding of viral persistence and viral immune evasion strategies.

Binder, M., Sulaimanov, N., Clausznitzer, D., Schulze, M., Huber, C.M., Lenz, S.M., Schloder, J.P., Trippler, M., Bartenschlager, R., Lohmann, V., et al. (2013). Replication vesicles are load- and choke-points in the hepatitis C virus lifecycle. PLoS pathogens 9, e1003561.

de Martel, C., Maucort-Boulch, D., Plummer, M., and Franceschi, S. (2015). World-wide relative contribution of hepatitis B and C viruses in hepatocellular carcinoma. Hepatology 62, 1190 – 1200.

WHO, 2017 – http://www.who.int/hepatitis/publications/global-hepatitis-report2017/en/; retrieved Oct 24th, 2018