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

丙型肝炎病毒（HCV）是一种重要的人类病原体，据估计，全世界有7000万人感染这种病毒。最近已经开发了一些非常有效的抗病毒药物，可以治愈感染者，但是这些药物价格昂贵，并且病毒可以改变以产生耐药性。因此，有必要更好地了解病毒如何生长和引起疾病，药物如何起作用，并最终开发更多的抗病毒药物。HCV是一种非常多变的病毒，已鉴定出7种不同的毒株（称为基因型1-7）。该项目的重点是基因型3，第二个最常见的基因型世界各地约占30%（约。2000万）的HCV病例。基因型3在中低收入国家（LMIC）中最常见，占病例的44%，特别是南亚（巴基斯坦，印度和泰国）70%的HCV感染是基因型3。与此一致，基因型3在西欧部分地区也很流行，占英国HCV病例的44%。这一点很重要，因为与其他基因型相比，基因型3感染与肝脏疾病的更快进展，糖尿病，脂肪肝和肝癌的发病率更高以及死亡率更高有关。基因型3患者也表现出对新药的高水平耐药性，限制了治疗选择。基因型3和其他基因型之间的差异还不是很清楚，主要是因为直到最近还没有良好的实验室系统来研究这种基因型。我们试图解决这种知识的缺乏，特别是关注一种病毒蛋白NS 5A，它在其他基因型中被证明是病毒生长和疾病所需的，也是一些新药的靶点。我们将利用我们在其他基因型中研究NS 5A的专业知识，以及我们和其他人开发的在细胞培养物中培养基因型3病毒的新系统，来研究为什么它对药物如此耐受以及NS 5A如何与细胞相互作用。我们希望这些研究将阐明基因型3为何如此不同，并为感染该基因型HCV的患者提供开发新治疗策略的机会。

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.