Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, United Kingdom.
Institute of Structural and Molecular Biology, Birkbeck College, London, United Kingdom.
Elife. 2022 Jul 7;11:e71854. doi: 10.7554/eLife.71854.
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.
E1 和 E2（E1E2）是丙型肝炎病毒（HCV）的融合蛋白，与其他任何已描述的病毒都不同，HCV 进入/融合的详细分子机制仍不清楚。E2 的高变区-1（HVR-1）是一种假定的固有无序蛋白尾巴。在这里，我们证明 HVR-1 具有自动抑制功能，可抑制游离病毒粒子上的 E1E2 活性；这依赖于其构象熵。因此，HVR-1 类似于安全扣，可防止 E1E2 活动过早触发。至关重要的是，这种机制会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 的遗传缺失，会关闭安全扣，从而产生超反应性 HCV，表现出增强的病毒进入能力，但热稳定性差且对中和抗体高度敏感。因此，HVR-1 安全扣控制病毒进入的效率，并维持对中和抗体的抗性。这一发现解释了 HCV 如何在持续的免疫攻击下持续存在，并代表了一种可能存在于其他病毒融合机制中的新型调节机制。
