KFO 129:  Mechanisms for Development of Resistance and Optimisation of Antiviral Strategies of Hepatitis C Virus Infection Comprising Integrative Biomathematical and Bioinformatical Models

• Subject Area: Medicine
• Term: from 2005 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5397647

This Clinical Research Unit comprises research projects from different disciplines including clinical medicine, biomathematics, bioinformatics, structural biology, immunology, virology, and pharmaceutical chemistry to characterise resistance to hepatitis C therapy and to develop new treatments approaches. Inflammation of the liver caused by chronic infection with the hepatitis C virus (HCV) affects more than 170 million patients throughout the world including 500,000 to 800,000 patients in Germany. After many years of infection chronic hepatitis C can proceed to severe liver diseases. Unfortunately, sustained virologic response rates to currently available anti-HCV treatments are only about 50 to 60 percent. Many new drugs, especially inhibitors of the HCV NS3 serine protease and the RNA-dependent RNA polymerase, are currently under preclinical and early clinical evaluation. Therefore models for predicting treatment response are highly desirable. Additionally, efficient and reliable prediction algorithms of treatment response early after initiation of therapy may lead to individualised optimisation of treatment schedules in clinical practise.
A solution of these challenges may be derived from viral kinetics and genetics. Research projects on viral kinetics and HCV sequence analyses form the central part of this Clinical Research Unit. Two projects apply bioinformatical methods. One on the prediction of protein structure and function and the other one on the analysis of associations between HCV genetic variability and treatment response. Further projects basing on immunology and virology examine viral evolution and antiviral immune response. Finally, two projects focus on the analysis of protein structure by x-ray crystallography and the structural characterisation of protein-protein complexes as well as on design, synthesis, and evaluation of potential drugs, especially binding, function, and enzyme inhibitors. In addition to these research projects, the Clinical Research Unit provides interdisciplinary training structures and joint support of young researchers by clinicians and basic researchers.

• DFG Programme: Clinical Research Units

Projects

• Analyse von Wirtsfaktoren hinsichtlich der HCV-Rekombination und Pathogenese (Applicant Grässer, Friedrich A. )
• Assoziation von extra- und intrazellulären Virustatikakonzentrationen mit deren antiviralen Wikungen bei chronischer Hepatitis C (Applicant Lötsch, Jörn )
• Bioinformatische Struktur- und Interaktionsanalysen bei HCV (Applicant Albrecht, Mario )
• Bioinformatische und -statistische HCV-Sequenzanalyse (Applicant Welsch, Christoph )
• Charakterisierung des additiven antiviralen Effekts von Ribavirin (Applicants Hofmann, Wolf Peter ;  Mihm, Ulrike )
• Chemische und strukturelle Charakterisierung der HCV Hüllproteine E1 und E2 (Applicant Scheidig, Axel J. )
• HCV Sequenzanalysen und Therapieresistenzmechanismen (Applicant Sarrazin, Christoph M. )
• Stochastische Modelle zur Hepatitis C Virus -und Quasispezieskinetik (Applicant Herrmann, Eva )
• Synthese und Wirkstoffdesign -Hemmung des CD81-vermittelten Hepatitis C-Virus Zelleintritts (Applicant Hartmann, Rolf )
• Zentralprojekt zur Koordinierung und wiss. Unterstützung der KFO 129 (Applicant Zeuzem, Stefan )

• Spokesperson: Professor Dr. Stefan Zeuzem
• Leader: Professorin Dr. Eva Herrmann