An Entropic Safety Catch Controls Hepatitis C Virus Entry and Antibody Resistance
An Entropic Safety Catch Controls Hepatitis C Virus Entry and Antibody Resistance
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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
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Stejskal L
中科院分区：
文献类型：
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作者：
Stejskal L
E1和E2（E1 E2）是丙型肝炎病毒（HCV）的融合蛋白，不同于迄今为止描述的任何其他病毒，并且HCV进入/融合的详细分子机制仍然未知。E2的高变区-1（HVR-1）是一个假定的内在无序的蛋白质尾。在这里，我们证明了HVR-1具有自抑制功能，抑制E1 E2对游离病毒体的活性，这取决于其构象熵。因此，HVR-1类似于防止过早触发E1 E2活性的安全栓。至关重要的是，这种机制被细胞表面的宿主受体相互作用关闭，以允许进入。降低HVR-1构象熵的突变或HVR-1的基因缺失会关闭安全捕获，产生高反应性HCV，其表现出增强的病毒进入，但热不稳定，对中和抗体非常敏感。因此，HVR-1安全捕获控制病毒进入的效率，并保持对中和抗体的抗性。这一发现为HCV在面对持续免疫攻击时持续存在的能力提供了解释，并代表了一种可能在其他病毒融合机制中发现的新的调节机制。
E1 and E2 (E1E2), the fusion proteins of Hepatitis C Virus (HCV), are unlike that of any other virus yet described, and the detailed molecular mechanisms of HCV entry/fusion remain unknown. Hypervariable region-1 (HVR-1) of E2 is a putative intrinsically disordered protein tail. Here, we demonstrate that HVR-1 has an autoinhibitory function that suppresses the activity of E1E2 on free virions; this is dependent on its conformational entropy. Thus, HVR-1 is akin to a safety catch that prevents premature triggering of E1E2 activity. Crucially, this mechanism is turned off by host receptor interactions at the cell surface to allow entry. Mutations that reduce conformational entropy in HVR-1, or genetic deletion of HVR-1, turn off the safety catch to generate hyper-reactive HCV that exhibits enhanced virus entry but is thermally unstable and acutely sensitive to neutralising antibodies. Therefore, the HVR-1 safety catch controls the efficiency of virus entry and maintains resistance to neutralising antibodies. This discovery provides an explanation for the ability of HCV to persist in the face of continual immune assault and represents a novel regulatory mechanism that is likely to be found in other viral fusion machinery.