Strain and rupture of HIV-1 capsids during uncoating.
Strain and rupture of HIV-1 capsids during uncoating.
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DOI：
10.1073/pnas.2117781119
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发表时间：
2022-03-08
影响因子：
11.1
通讯作者：
Voth GA
中科院分区：
文献类型：
--
作者：
Yu A;Lee EMY;Briggs JAG;Ganser-Pornillos BK;Pornillos O;Voth GA
HIV-1的成熟衣壳是瞬时稳定的复合物，其在成熟期间在病毒基因组周围自组装，并且脱壳以释放整合前复合物，其在宿主细胞基因组中存档病毒的双链DNA拷贝。然而，关于艾滋病毒核心如何破裂的详细观点仍然缺乏。在这里，我们阐明的物理特性，涉及衣壳破裂使用大规模的全原子分子动力学模拟和冷冻电子断层扫描相结合。我们发现，在衣壳上的固有应变形成高度相关的图案沿着衣壳表面，沿着裂纹传播。衣壳刚性也随着高应变而增加。我们的研究结果提供了病毒衣壳脱壳的基本见解。HIV-1的病毒复制依赖于富勒烯形状的衣壳将遗传物质运送到受感染细胞的细胞核深处。衣壳稳定性与辅因子的存在有关，包括与衣壳中发现的孔结合的肌醇六磷酸（IP 6）。使用对完整病毒粒子（包含IP 6和核糖核蛋白复合物）中冷冻电子断层扫描（cryo-ET）成像的HIV-1核心进行广泛的全原子分子动力学模拟，我们发现衣壳晶格上有明显的条纹图案。这些辅因子的存在也增加了衣壳的刚性。衣壳蛋白（CA）的构象分析表明，CA适应应变的局部弯曲远离结构解析使用X射线晶体学和冷冻ET。然后，进行内源性逆转录的HIV-1核心的冷冻ET表明，在机械失效之前，衣壳中的晶格应变增加，并且衣壳通过沿着沿着高应变区域的裂纹扩展而破裂。这些结果揭示了HIV-1衣壳的特性参与其关键的拆卸过程。
The mature capsids of HIV-1 are transiently stable complexes that self-assemble around the viral genome during maturation, and uncoat to release preintegration complexes that archive a double-stranded DNA copy of the virus in the host cell genome. However, a detailed view of how HIV cores rupture remains lacking. Here, we elucidate the physical properties involved in capsid rupture using a combination of large-scale all-atom molecular dynamics simulations and cryo-electron tomography. We find that intrinsic strain on the capsid forms highly correlated patterns along the capsid surface, along which cracks propagate. Capsid rigidity also increases with high strain. Our findings provide fundamental insight into viral capsid uncoating. Viral replication in HIV-1 relies on a fullerene-shaped capsid to transport genetic material deep into the nucleus of an infected cell. Capsid stability is linked to the presence of cofactors, including inositol hexakisphosphates (IP6) that bind to pores found in the capsid. Using extensive all-atom molecular dynamics simulations of HIV-1 cores imaged from cryo-electron tomography (cryo-ET) in intact virions, which contain IP6 and a ribonucleoprotein complex, we find markedly striated patterns of strain on capsid lattices. The presence of these cofactors also increases rigidity of the capsid. Conformational analysis of capsid proteins (CA) show CA accommodates strain by locally flexing away from structures resolved using X-ray crystallography and cryo-ET. Then, cryo-ET of HIV-1 cores undergoing endogenous reverse transcription demonstrates that lattice strain increases in the capsid prior to mechanical failure and that the capsid ruptures by crack propagation along regions of high strain. These results uncover HIV-1 capsid properties involved in their critical disassembly process.
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影响因子：
2.9
作者：
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通讯作者：
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DOI：
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影响因子：
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通讯作者：
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