Michael Schindler

Characterization of the Hepatitis-C-Virus glycoprotein interactions with cellular entry receptors

Principle Investigator:

Dr. Michael Schindler, Heinrich-Pette-Institute (HPI)

Background:

The flavivirus hepatitis C (HCV) is a major cause of chronic liver disease that has infected an estimated number of 170 million people worldwide. While several promising drug candidates are currently evaluated in the clinic, there is still no protective vaccine available. HCV entry seems to be a slow and multistep process that involves binding of the viral E1/E2 glycoprotein heterodimers to several cellular components. Those include the glycosaminoglycan heparan-sulphate, the low density lipoprotein receptor (LDL-R), the scavenger receptor class B type I (SR-B1), the tetraspanin CD81 and the tight junction forming protein claudin-1 (CLDN1) as well as occludin. Currently, virtually nothing is known about the defined interactions of the HCV E1/E2 proteins with its cellular receptors. The goal of our project is to characterize these interactions in order to understand the sequential binding and entry process of HCV. In more detail, we will take advantage of the cumulated expertise regarding structural biology and protein expression that is available within the participating PIs of this graduate school. First of all there is a strong background in recombinant protein expression and purification, which is necessary for downstream structural applications. Furthermore, we have the opportunity to analyze the interaction of HCV with its cellular receptors by various state of the art techniques eg NMR, biacore (surface plasmon resonance) and FRET. Most importantly, we will validate the in vitro generated data with the HCV cell culture system that uses fully replication competent virus and is established in our laboratory. In sum, we will identify and characterize interactions of the HCV envelope proteins with their cellular receptors. This knowledge is essential to map E1/E2 epitopes which are necessary for the infection process and will be of fundamental importance for the development of vaccines and interfering drugs.  

Homepage Schindler:

http://www.hpi-hamburg.de/forschung/abteilungen-forschungsgruppen/viruspathogenese.html

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