Systems Biology of Virus-Host Interactions

Date

Feb 9, 2012

Time

2:30 PM - 3:30 PM

Speaker

Lars Kaderali

Affiliation

Institute for Medical Informatics and Biometry (IMB), TU Dresden

Series

IMB - Seminar

Language

en

Main Topic

Medizin

Other Topics

Biologie, Medizin, Informatik

Description

Hepatitis C virus (HCV) infection is a major global health problem, with 170 million chronically infected individuals worldwide. A main obstacle in treatment is the insidious course of the disease; HCV infection persists in about 80% of patients and is mostly asymptomatic. However, these persons are at high risk to develop liver cirrhosis and hepatocellular carcinoma, making HCV the leading cause of liver transplantation in Europe. There is no vaccine available against HCV, and standard of care treatment with ribavirin and pegylated interferon induces long-term responses in only 50% of patients, and is associated with severe side effects. While several new anti-HCV compounds are in phase 1 or 2 trials, the development of efficient antiviral drugs is still limited by our poor understanding of the intracellular replication of HCV and its interactions with the host cell. We use a combination of mathematical modeling, machine learning and bioinformatics approaches to elucidate cellular processes involved in viral infection and viral replication. Based on genome-wide RNA interference experiments, we study host processes exploited by the virus. Machine learning approaches are used to map identified genes to their respective cellular processes. Last but not least, quantitative, dynamic mathematical modeling of the intracellular replication is used to study the replication kinetics, using systems of differential equations. By integrating these approaches, our aim is to gain a deeper understanding of HCV-host interactions, and ultimately to identify new potential drug targets. We will show results of this approach to understand virus-host interactions, and elucidate the intracellular HCV replication kinetics. Our results specifically show that the participation of host proteins is an essential factor in the formation of intracellular vesicles, the location of RNA genome replication formation. Differences in replication efficiency that is experimentally observed can be explained by differences in the abundance of a host factor involved in this process. Furthermore, our model predicts that HCV fails to replicate successfully without the protection inside the replication vesicles, showing the importance of intra-vesicle replication. This is the first time the initial dynamics of HCV replication has been modeled based on time resolved data. Our model may thus provide the basis to better understand the highly dynamic initial steps after infection, and to study in particular the initial race between immune response and successful viral replication.

Last modified: Jan 24, 2012, 3:26:59 PM