Investigating the intrinsic link between hepatitis C virus entry and sensitivity to neutralising antibodies.

研究丙型肝炎病毒进入与中和抗体敏感性之间的内在联系。

• 批准号: 1764982
• 金额: --
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1764982
• 关键词: Investigating; intrinsic; link; between; hepatitis

Hepatitis C virus (HCV) establishes a chronic infection in ~80% of cases, this feature is largely attributable to the array of immune countermeasures exhibited by the virus, including various neutralising antibody (nAb) evasion mechanisms. Current evidence suggests that nAb evasion incurs a fitness cost to the virus by making virus entry less efficient. As such, HCV is likely to perform a balancing between opposing selection pressures: the necessity to evade nAbs vs the benefits of efficient entry. We are investigating the molecular mechanisms that underlie this evolutionary antagonism. The project is comprised of three phases:1) Quantifying the relationship between virus entry and nAb sensitivity.We have identified a pair of closely related HCV variants one of which is highly resistant to nAbs, whereas the other is highly sensitive. We hypothesize that these differences in nAb sensitivity will be accompanied by changes in entry efficiency. We will investigate this using an array of virus entry assays combined with mathematical modeling analysis by a collaborator. This will allow us to measure the fitness cost associated with nAb evasion.2) Investigate the link between nAb evasion and virus entry using clinically relevant patient derived viruses.Having established the tools to evaluate virus entry efficiency we will focus our investigation on a range of diverse patient derived viruses. In particular, we are interested in the founder strains of HCV that transmit between individuals. These are responsible for the propagation of the HCV pandemic and are the most relevant strains for vaccine development. We will study whether these viruses have particular hallmarks, in virus entry or nAb evasion. For instance, do founder viruses favor efficient entry over nAb evasion? 3) Can perturbing the efficiency of virus entry augment the natural nAb response?Hepatitis C virus (HCV) establishes a chronic infection in ~80% of cases, this feature is largely attributable to the array of immune countermeasures exhibited by the virus, including various neutralising antibody (nAb) evasion mechanisms. Current evidence suggests that nAb evasion incurs a fitness cost to the virus by making virus entry less efficient. As such, HCV is likely to perform a balancing between opposing selection pressures: the necessity to evade nAbs vs the benefits of efficient entry. We are investigating the molecular mechanisms that underlie this evolutionary antagonism. The project is comprised of three phases:

丙型肝炎病毒（HCV）在约80%的病例中建立慢性感染，这一特征在很大程度上归因于病毒表现出的一系列免疫对抗，包括各种中和抗体（nAb）逃避机制。目前的证据表明，nAb逃避通过使病毒进入效率降低而对病毒产生适应性成本。因此，HCV可能在相反的选择压力之间进行平衡：逃避nAb的必要性与有效进入的好处。我们正在研究这种进化拮抗作用的分子机制。该项目包括三个阶段：1）量化病毒进入和nAb敏感性之间的关系。我们已经确定了一对密切相关的HCV变体，其中一个对nAb高度耐药，而另一个则高度敏感。我们假设nAb敏感性的这些差异将伴随着进入效率的变化。我们将使用一系列病毒进入试验结合合作者的数学建模分析来研究这一点。这将使我们能够测量与nAb逃逸相关的适应性成本。2）使用临床相关的患者衍生病毒调查nAb逃逸和病毒进入之间的联系。在建立了评估病毒进入效率的工具之后，我们将集中调查一系列不同的患者衍生病毒。特别是，我们对个体之间传播的HCV创始株感兴趣。这些菌株是导致丙型肝炎病毒大流行传播的原因，也是与疫苗开发最相关的菌株。我们将研究这些病毒在病毒进入或nAb逃避方面是否具有特定的特征。例如，创始人病毒是否更喜欢有效进入而不是nAb逃避？3)干扰病毒进入的效率能增强天然nAb应答吗？丙型肝炎病毒（HCV）在约80%的病例中建立慢性感染，这一特征在很大程度上归因于病毒表现出的一系列免疫对抗，包括各种中和抗体（nAb）逃避机制。目前的证据表明，nAb逃避通过使病毒进入效率降低而对病毒产生适应性成本。因此，HCV可能在相反的选择压力之间进行平衡：逃避nAb的必要性与有效进入的好处。我们正在研究这种进化拮抗作用的分子机制。该项目包括三个阶段：

项目成果

Optimised cell systems for the investigation of hepatitis C virus E1E2 glycoproteins

用于研究丙型肝炎病毒 E1E2 糖蛋白的优化细胞系统

• DOI: 10.1101/2020.06.18.159442
• 发表时间: 2020
• 作者: Kalemera M

Optimized cell systems for the investigation of hepatitis C virus E1E2 glycoproteins.

• DOI: 10.1099/jgv.0.001512
• 发表时间: 2021-01
• 期刊: The Journal of general virology
• 作者: Kalemera MD;Capella-Pujol J;Chumbe A;Underwood A;Bull RA;Schinkel J;Sliepen K;Grove J
• 通讯作者: Grove J

An Entropic Safety Catch Controls Hepatitis C Virus Entry and Antibody Resistance

熵安全锁控制丙型肝炎病毒进入和抗体耐药性

• DOI: 10.1101/2020.11.11.377218
• 发表时间: 2020
• 作者: Stejskal L