Gammaherpesviruses establish lifelong latent infection in B lymphocytes and are the causative agent of several B-cell malignancies and lymphoproliferative disorders. While a quiescent latent infection allows these pathogens to evade immune detection, initiation of an alternative lifecycle stage, known as lytic replication, is an essential step in the production and dissemination of infectious progeny. Although cessation of cellular proliferation is an eventual consequence of lytic induction, exactly how gammaherpesviruses manipulate the cell cycle prior to amplification of viral DNA remains under debate. Here we show that the onset of Kaposi's sarcoma-associated herpesvirus (KSHV) lytic reactivation in B cells leads to S-phase accumulation and that exit from G1 is required for efficient viral DNA replication. We also show that lytic replication leads to an S-phase-specific activation of the DNA damage response (DDR) that is abrogated when lytic replication is restricted to G0/G1. Finally, we observe that expression of early lytic viral genes results in cellular replication stress with increased stalling of DNA replication forks. Overall, we demonstrate that S-phase entry is important for optimal KSHV replication, that G1 arresting compounds are effective inhibitors of viral propagation, and that lytic-induced cell-cycle arrest could occur through the obstruction of cellular replication forks and subsequent activation of the DDR.

中文翻译：

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原发性渗出性淋巴瘤细胞中生产性疱疹病毒的裂解复制需要S期进入。

伽马疱疹病毒在B淋巴细胞中建立终身潜伏感染，并且是几种B细胞恶性肿瘤和淋巴增生性疾病的病因。虽然静态潜伏感染使这些病原体能够逃避免疫检测，但替代生命周期阶段（称为裂解复制）的启动是感染性子代生产和传播的关键步骤。尽管停止细胞增殖是裂解诱导的最终结果，但是伽马疱疹病毒在病毒DNA扩增之前如何操纵细胞周期仍存在争议。在这里，我们显示B细胞中卡波西氏肉瘤相关疱疹病毒（KSHV）裂解激活的发作导致S期积累，从G1退出是有效的病毒DNA复制所必需的。我们还显示，裂解复制导致DNA损伤反应（DDR）的S期特异性激活，而裂解复制仅限于G0 / G1时，DNA损伤反应将被废止。最后，我们观察到早期裂解性病毒基因的表达导致细胞复制压力增加，DNA复制叉停滞。总体而言，我们证明S期进入对于最佳KSHV复制非常重要，G1阻滞化合物是病毒繁殖的有效抑制剂，裂解诱导的细胞周期阻滞可能通过阻塞细胞复制叉和随后的激活而发生。 DDR。我们观察到早期裂解性病毒基因的表达导致细胞复制压力增加，DNA复制叉停滞。总的来说，我们证明了S期进入对于KSHV的最佳复制非常重要，G1阻滞化合物是病毒繁殖的有效抑制剂，并且裂解诱导的细胞周期阻滞可能通过阻塞细胞复制叉和随后的激活而发生。 DDR。我们观察到早期裂解性病毒基因的表达导致细胞复制压力增加，DNA复制叉停滞。总的来说，我们证明了S期进入对于KSHV的最佳复制非常重要，G1阻滞化合物是病毒繁殖的有效抑制剂，并且裂解诱导的细胞周期阻滞可能通过阻塞细胞复制叉和随后的激活而发生。 DDR。