1. Productive herpesvirus lytic replication in primary effusion lymphoma cells requires S-phase entry
- Author
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Grant S. Stewart, Robert Hollingworth, and Roger J.A. Grand
- Subjects
DNA Replication ,Gene Expression Regulation, Viral ,0301 basic medicine ,palbociclib ,replication stress ,DNA damage ,030106 microbiology ,Lymphoproliferative disorders ,KSHV ,Biology ,DNA damage response ,Virus Replication ,Cell Line ,03 medical and health sciences ,Immune system ,herpesvirus ,Large DNA Viruses ,Lymphoma, Primary Effusion ,Virology ,Replication (statistics) ,medicine ,Humans ,HHV-8 ,lytic replication ,Herpesviridae ,Animal ,G1 Phase ,DNA replication ,S phase ,Cell cycle ,medicine.disease ,Virus Latency ,030104 developmental biology ,Lytic cycle ,DNA, Viral ,Herpesvirus 8, Human ,cell cycle ,Virus Activation ,Primary effusion lymphoma ,Research Article - Abstract
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.
- Published
- 2020