Project TP 1

(R. Bartenschlager)

Virological and immunological mechanisms of hepatitis C virus persistence

Hepatitis C virus (HCV) infections are characterized by a high rate of persistence. Although this phenomenon argues for viral strategies of immune evasion, the molecular mechanisms underlying inefficient virus control are still rather poorly defined. During the first funding period we established a cell culture system mimicking viral persistence and obtained evidence that HCV might exploit the stochastic of the interferon (IFN) response (Bauhofer et al., Gastroenterology 2012). Moreover, by using a siRNA based screen we identified effector proteins responsible for IFNα- and IFNγ-mediated suppression of HCV replication (Metz et al., Hepatology 2012). Finally, by using live cell imaging we found that HCV triggers induction of stress granules in an IFNα-dependent manner. Their assembly and disassembly is highly dynamic which is important for cell survival and thus, persistence (Ruggieri et al., Cell Host & Microbe 2012).

In the next funding period we aim to continue our characterization of viral and cellular conditions essential for persistence. We will follow two complementary projects. The first one aims at understanding the dynamics of the IFN response and its impact on virus spread. Building on the results described above we will continue our studies by using live cell imaging to analyze the stochastic of the IFN response and its relation to virus spread. A caveat is that cell lines that are HCV permissive do not produce IFN and therefore, IFN response can only be studied upon exogenous addition of the cytokine. Thus, an important aim of this subproject is to establish HCV-permissive cell lines that are capable of endogenous IFN production, thus mimicking more closely the in vivo situation. Data generated in either system are used to set up and validate a mathematical model describing the stochastic of the IFN-response and predicting the outcome of HCV infection, i.e. persistence or virus elimination. Importantly, results will be validated with patient samples. The second project deals with the role of pattern recognition receptors in HCV-mediated activation of the IFN response and its suppression by NS5A. Here we will study two aspects: first, what is the recognition mechanism of HCV by these receptors? Second, do HCV proteins suppress IFN production? The results of these studies will contribute to a better understanding of the strategies used by HCV to overcome innate immune responses.
© Dep. of Infectious Diseases, Molecular Virology. University of Heidelberg
Activation of Type I and III Interferon Response by Mitochondrial and Peroxisomal MAVS and Inhibition by Hepatitis C Virus.Bender S, Reuter A, Eberle F, Einhorn E, Binder M, Bartenschlager R. PLoS Pathog. 2015 Nov 20;11(11):e1005264.

Virus-specific CD4+ T Cells Have Functional and Phenotypic Characteristics of Follicular T-helper Cells in Patients With Acute and Chronic HCV Infections. Raziorrouh B, Sacher K, Tawar RG, Emmerich F, Neumann-Haefelin C, Baumert TF, Thimme R, Boettler T. Gastroenterology. 2015 Nov 13. pii: S0016-5085(15)01622-4.

Evidence that hepatitis B virus replication in mouse cells is limited by the lack of a host cell dependency factor. Lempp FA, Mutz P, Lipps C, Wirth D, Bartenschlager R, Urban S. J Hepatol. 2015 Nov 11. pii: S0168-8278(15)00736-9. doi: 10.1016/j.jhep.2015.10.030. [Epub ahead of print]