HCV/HIV-PI · The impact of HCV diversity on replication fitness and protease inhibitor sensitivity in HIV infected patients with chronic HCV

Hepatitis C virus (HCV) is a major cause of premature death due to cirrhosis and hepatocellular carcinoma in a large proportion of the world population (>25 million). Recently, advances in the development of new therapeutic compounds to treat HCV have revealed several potent inhibitors of the HCV serine protease, which have reached clinical trials. However HCV has a high genetic variability, not only between genotypes but also between quasispecies of an infected individual. In HIV coinfected patients the levels of complexity and diversity of the HCV protease gene variants and the resultant impact on HIV coinfection are unknown. The advent of HCV genotype 1b derived replicon systems has enabled measurement of HCV subgenomic RNA replication in a cell-based format and aided the development in the new therapeutic compounds. However these replicons are not representative of the genetic variability within the HCV genotypes, subtypes and quasispecies. In this project proposal we wish to clone HCV NS3 sequences derived from the sera of HIV infected patients with chronic HCV to address the impact of diversity on replication fitness and the drug sensitivity in a transient replication assay. The importance of HIV co-infection will also be investigated. The project will take place in the Center for the Study of Hepatitis C, New York, USA were the state of the art techniques are currently being used. In the returning phase the methodology and experience will be transferred to Europe at the Hospital Carlos III, Madrid, Spain an institute renown for its research in HIV and viral hepatitis co-infection. This project will help understanding the mechanism of HCV drug resistance and will provide relevant information for the design of new anti-HCV drugs