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

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。这些是HCV大流行传播的原因，也是疫苗开发最相关的毒株。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否增强自然的nAb反应？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：

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: