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

丙型肝炎病毒基因型3 NS5A蛋白：对直接作用抗病毒药物的耐药性和功能分析

基本信息

批准号：
MR/S001026/1
负责人：
Mark Harris
金额：
$ 69.26万
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FS001026%2F1
关键词：
Hepatitis virus genotype NS5A protein

项目摘要

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.

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。最近已经开发出了一些非常有效的抗病毒药物，可以治愈感染者，但这些药物很昂贵，而且病毒可能会产生抗药性。因此，有必要更好地了解病毒是如何生长和引起疾病的，药物是如何起作用的，并最终开发出更多的抗病毒药物。丙型肝炎病毒是一种非常易变的病毒，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，这是世界上第二大最常见的基因型，约占30%。2000万)的HCV病例。基因3型在中低收入国家最为常见，占44%的病例，特别是南亚（巴基斯坦、印度和泰国）70%的丙型肝炎病毒感染为基因3型。与此一致的是，基因3型在西欧部分地区也很普遍，在英国占HCV病例的44%。这一点很重要，因为与其他基因型相比，基因3型感染与肝病进展更快、糖尿病、脂肪肝和肝癌发病率更高以及死亡率更高相关。基因3型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该基因型。我们试图解决这一知识的缺乏，特别是关注一种病毒蛋白NS5A，它已经在其他基因型中被证明是病毒生长和疾病所必需的，并且是一些新药的靶标。我们将利用我们在研究其他基因型的NS5A方面的专业知识，以及我们和其他人开发的在细胞培养中培养基因型3病毒的新系统，来研究为什么它对药物如此耐药，以及NS5A如何与细胞相互作用。我们希望这些研究能够揭示为什么基因3型如此不同，并为感染该基因型HCV的患者开发新的治疗策略提供机会。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

NS5A domain I antagonises PKR to facilitate the assembly of infectious hepatitis C virus particles.

DOI：
10.1371/journal.ppat.1010812
发表时间：
2023-02
期刊：
PLoS pathogens
影响因子：
6.7
作者：
通讯作者：

A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir.

DOI：
10.1099/jgv.0.001496
发表时间：
2021-01
期刊：
The Journal of general virology
影响因子：
0
作者：
Fernandes Campos GR;Ward J;Chen S;Bittar C;Vilela Rodrigues JP;Martinelli ALC;Souza FF;Pereira LRL;Rahal P;Harris M
通讯作者：
Harris M

Positive strand RNA viruses differ in the constraints they place on the folding of their negative strand

正链RNA病毒对其负链折叠的限制有所不同

DOI：
10.1101/2022.02.01.478670
发表时间：
2022
期刊：
影响因子：
0
作者：
Herod M
通讯作者：
Herod M

Corrigendum: A novel substitution in NS5A enhances resistance of hepatitis C virus genotype 3 to daclatasvir.

DOI：
10.1099/jgv.0.001582
发表时间：
2021-03
期刊：
The Journal of general virology
影响因子：
0
作者：
Fernandes Campos GR;Ward J;Chen S;Bittar C;Vilela Rodrigues JP;Candolo Martinelli AL;Souza FF;Leira Pereira LR;Rahal P;Harris M
通讯作者：
Harris M

Effect of proteins isolated from Brazilian snakes on enterovirus A71 replication cycle: An approach against hand, foot and mouth disease