Varicella-zoster virus (VZV) is a medically important human herpesvirus that causes chickenpox and shingles, but its cell-associated nature has hindered structure studies. Here we report the cryo-electron microscopy structures of purified VZV A-capsid and C-capsid, as well as of the DNA-containing capsid inside the virion. Atomic models derived from these structures show that, despite enclosing a genome that is substantially smaller than those of other human herpesviruses, VZV has a similarly sized capsid, consisting of 955 major capsid protein (MCP), 900 small capsid protein (SCP), 640 triplex dimer (Tri2) and 320 triplex monomer (Tri1) subunits. The VZV capsid has high thermal stability, although with relatively fewer intra- and inter-capsid protein interactions and less stably associated tegument proteins compared with other human herpesviruses. Analysis with antibodies targeting the N and C termini of the VZV SCP indicates that the hexon-capping SCP—the largest among human herpesviruses—uses its N-terminal half to bridge hexon MCP subunits and possesses a C-terminal flexible half emanating from the inner rim of the upper hexon channel into the tegument layer. Correlation of these structural features and functional observations provide insights into VZV assembly and pathogenesis and should help efforts to engineer gene delivery and anticancer vectors based on the currently available VZV vaccine.

水痘-带状疱疹病毒 (VZV) 是一种医学上重要的人类疱疹病毒，可引起水痘和带状疱疹，但其与细胞相关的性质阻碍了结构研究。在这里，我们报告了纯化的 VZV A 衣壳和 C 衣壳的冷冻电子显微镜结构，以及病毒粒子内含 DNA 的衣壳。源自这些结构的原子模型表明，尽管 VZV 包含的基因组比其他人类疱疹病毒的基因组小得多，但它具有类似大小的衣壳，由 955 个主要衣壳蛋白 (MCP)、900 个小衣壳蛋白 (SCP)、640三重二聚体 (Tri2) 和 320 个三重单体 (Tri1) 亚基。VZV 衣壳具有较高的热稳定性，尽管与其他人类疱疹病毒相比，衣壳内和衣壳间的蛋白质相互作用相对较少，相关的外皮蛋白也不太稳定。对针对 VZV SCP N 和 C 末端的抗体进行的分析表明，人类疱疹病毒中最大的六邻体 SCP 使用其 N 端一半来桥接六邻体 MCP 亚基，并具有从内部发出的 C 端柔性部分上六邻体通道的边缘进入外皮层。这些结构特征和功能观察的相关性提供了对 VZV 组装和发病机制的见解，应该有助于基于当前可用的 VZV 疫苗来设计基因传递和抗癌载体。