Centre for Biosystems Science and Engineering, Indian Institute of Science, Bangalore 560012, Karnataka, India.
Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, Karnataka, India.
J R Soc Interface. 2021 Nov;18(184):20210401. doi: 10.1098/rsif.2021.0401. Epub 2021 Nov 10.
Life cycle processes of positive-strand (+)RNA viruses are broadly conserved across families, yet they employ different strategies to grow in the cell. Using a generalized dynamical model for intracellular (+)RNA virus growth, we decipher these life cycle determinants and their dependencies for several viruses and parse the effects of viral mutations, drugs and host cell permissivity. We show that poliovirus employs rapid replication and virus assembly, whereas the Japanese encephalitis virus leverages its higher rate of translation and efficient cellular reorganization compared to the hepatitis C virus. Stochastic simulations demonstrate infection extinction if all seeding (inoculating) viral RNA degrade before establishing robust replication critical for infection. The probability of this productive cellular infection, 'cellular infectivity', is affected by virus-host processes and defined by early life cycle events and viral seeding. An increase in cytoplasmic RNA degradation and delay in vesicular compartment formation reduces infectivity, more so when combined. Synergy among these parameters in limiting (+)RNA virus infection as predicted by our model suggests new avenues for inhibiting infections by targeting the early life cycle bottlenecks.
正链(+)RNA 病毒的生命周期过程在不同家族中广泛保守，但它们在细胞内生长时采用不同的策略。我们使用一种通用的细胞内(+)RNA 病毒生长动力学模型，解析了这些生命周期决定因素及其对几种病毒的依赖性，并解析了病毒突变、药物和宿主细胞易感性的影响。我们发现脊髓灰质炎病毒采用快速复制和病毒组装的策略，而日本脑炎病毒则利用其较高的翻译率和有效的细胞重组能力，与丙型肝炎病毒相比。随机模拟表明，如果所有的种子(接种)病毒 RNA 在建立感染所需的稳健复制之前降解，就会导致感染的消灭。这种有效的细胞感染的可能性，即“细胞感染性”，受到病毒-宿主过程的影响，并由早期生命周期事件和病毒接种来定义。我们的模型预测，细胞质 RNA 降解增加和囊泡区室形成延迟会降低感染性，两者结合时更是如此。这些参数之间的协同作用限制了(+)RNA 病毒的感染，这表明通过靶向早期生命周期瓶颈来抑制感染可能有新的途径。
