Fifty-eight million individuals worldwide are affected by chronic hepatitis C virus (HCV) infection, a primary driver of liver cancer for which no vaccine is available¹. The HCV envelope proteins E1 and E2 form a heterodimer (E1/E2), which is the target for neutralizing antibodies². However, the higher-order organization of these E1/E2 heterodimers, as well as that of any Hepacivirus envelope protein complex, remains unknown. Here we determined the cryo-electron microscopy structure of two E1/E2 heterodimers in a homodimeric arrangement. We reveal how the homodimer is established at the molecular level and provide insights into neutralizing antibody evasion and membrane fusion by HCV, as orchestrated by E2 motifs such as hypervariable region 1 and antigenic site 412, as well as the organization of the transmembrane helices, including two internal to E1. This study addresses long-standing questions on the higher-order oligomeric arrangement of Hepacivirus envelope proteins and provides a critical framework in the design of novel HCV vaccine antigens.

全球有 5800 万人受到慢性丙型肝炎病毒 (HCV) 感染的影响，这是肝癌的主要驱动因素，目前尚无疫苗可用于治疗¹ 。 HCV 包膜蛋白 E1 和 E2 形成异二聚体 (E1/E2)，它是中和抗体的靶标² 。然而，这些 E1/E2 异二聚体以及任何肝炎病毒包膜蛋白复合物的高级组织仍然未知。在这里，我们确定了同二聚体排列中的两个 E1/E2 异二聚体的冷冻电子显微镜结构。我们揭示了同型二聚体是如何在分子水平上建立的，并提供了对 HCV 中和抗体逃避和膜融合的见解，如高变区 1 和抗原位点 412 等 E2 基序以及跨膜螺旋的组织，包括两个位于 E1 内部。这项研究解决了有关肝炎病毒包膜蛋白高阶寡聚排列的长期存在的问题，并为新型丙型肝炎病毒疫苗抗原的设计提供了关键框架。