Geng Qibin, Navaratnarajah Chanakha K, Zhang Wei
Institute for Molecular Virology, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA.
Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA.
Int J Mol Sci. 2025 Aug 27;26(17):8323. doi: 10.3390/ijms26178323.
Sindbis virus (SINV), a prototype of the Alphavirus genus (family ), is a globally distributed arbovirus causing febrile rash and debilitating arthritis in humans. Viral structural proteins-capsid (C), E1, and E2-are fundamental to the virion's architecture, mediating all stages from assembly to host cell entry and pathogenesis, thus representing critical targets for study. This review consolidates the historical and current understanding of SINV structural biology, tracing progress from early microscopy to recent high-resolution cryo-electron microscopy (cryo-EM) and X-ray crystallography. We detail the virion's precise = 4 icosahedral architecture, composed of a nucleocapsid core and an outer glycoprotein shell. Key functional roles tied to protein structure are examined: the capsid's dual capacity as a serine protease and an RNA-packaging scaffold that interacts with the E2 cytoplasmic tail; the E1 glycoprotein's function as a class II fusion protein driving membrane fusion; and the E2 glycoprotein's primary role in receptor binding, which dictates cellular tropism and serves as the main antigenic target. Furthermore, we connect these molecular structures to viral evolution and disease, analyzing how genetic variation among SINV genotypes, particularly in the E2 gene, influences host adaptation, immune evasion, and the clinical expression of arthritogenic and neurovirulent disease. In conclusion, the wealth of structural data on SINV offers a powerful paradigm for understanding alphavirus biology. However, critical gaps persist, including the high-resolution visualization of dynamic conformational states during viral entry and the specific molecular determinants of chronic disease. Addressing these challenges through integrative structural and functional studies is paramount. Such knowledge will be indispensable for the rational design of next-generation antiviral therapies and broadly protective vaccines against the ongoing threat posed by SINV and related pathogenic alphaviruses.
辛德毕斯病毒（SINV）是甲病毒属（病毒科）的原型，是一种全球分布的虫媒病毒，可导致人类发热性皮疹和使人衰弱的关节炎。病毒结构蛋白——衣壳（C）、E1和E2——对病毒粒子的结构至关重要，介导从组装到宿主细胞进入及发病机制的所有阶段，因此是研究的关键靶点。本综述整合了对SINV结构生物学的历史和当前认识，追溯了从早期显微镜技术到近期高分辨率冷冻电子显微镜（cryo-EM）和X射线晶体学的进展。我们详细阐述了病毒粒子精确的T = 4二十面体结构，它由一个核衣壳核心和一个外部糖蛋白壳组成。研究了与蛋白质结构相关的关键功能作用：衣壳作为丝氨酸蛋白酶和与E2细胞质尾巴相互作用的RNA包装支架的双重能力；E1糖蛋白作为驱动膜融合的II类融合蛋白的功能；以及E2糖蛋白在受体结合中的主要作用，受体结合决定细胞嗜性并作为主要抗原靶点。此外，我们将这些分子结构与病毒进化和疾病联系起来，分析SINV基因型之间的遗传变异，特别是E2基因中的变异，如何影响宿主适应性、免疫逃避以及致关节炎和神经毒性疾病的临床表达。总之，关于SINV的大量结构数据为理解甲病毒生物学提供了一个强大的范例。然而，关键差距仍然存在，包括病毒进入过程中动态构象状态的高分辨率可视化以及慢性病的特定分子决定因素。通过综合结构和功能研究应对这些挑战至关重要。这些知识对于合理设计针对SINV和相关致病性甲病毒持续威胁的下一代抗病毒疗法和广泛保护性疫苗将不可或缺。
