Hepatitis C virus genotype 3 NS5A protein: resistance to direct acting antiviral agents and functional analysis

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Hepatitis C virus (HCV) is an important human pathogen and it is estimated that 70 million people worldwide are infected with this virus. Recently a number of very effective antiviral drugs have been developed that can cure infected individuals, however these are expensive and the virus can change to become resistant. Thus there is a need to better understand how the virus grows and causes disease, how the drugs work and ultimately to develop more antivirals. HCV is a very variable virus and 7 distinct strains (termed genotypes 1-7) have been identified. This project focusses on genotype 3, the second most common genotype worldwide accounting for approximately 30% (approx. 20 million) of HCV cases. Genotype 3 is the most common in low to middle income countries (LMIC), accounting for 44% of cases and in particular, 70% of HCV infections in South Asia (Pakistan, India and Thailand) are genotype 3. Consistent with this, genotype 3 is also prevalent in parts of Western Europe, and accounts for 44% of HCV cases in the UK. This is important as genotype 3 infection is associated with a more rapid progression of liver disease, a higher incidence of diabetes, fatty liver and liver cancer, and a higher mortality rate compared to other genotypes. Genotype 3 patients also exhibit high levels of resistance to the new drugs, limiting the treatment options. The differences between genotype 3 and other genotypes are not very well understood, mainly because until recently there were no good laboratory systems available to study this genotype. We seek to address this lack of knowledge in particular focusing on one viral protein, NS5A, which has been shown in other genotypes to be required for virus growth and disease, as well as being a target for some of the new drugs. We will use our expertise in studying NS5A in other genotypes, together with new systems developed by us and others to grow genotype 3 virus in cell culture, to ask why it is so resistant to the drugs and how NS5A interacts with the cell. We hope that these studies will shed light on why genotype 3 is so different, and provide opportunities to develop new therapeutic strategies for patients infected with this genotype of HCV.