Productive herpesvirus lytic replication in primary effusion lymphoma cells requires S-phase entry

Robert Hollingworth, Grant S. Stewart, Roger J. Grand

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)
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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.
Original languageEnglish
Pages (from-to)873-883
JournalJournal of General Virology
Volume101
Issue number8
Early online date5 Jun 2020
DOIs
Publication statusPublished - Aug 2020

Bibliographical note

Funding Information:
This project was funded by a Cancer Research UK PhD studentship. We would also like to thank Katie Grand for charitable donations.

Keywords

  • herpesvirus
  • cell cycle
  • DNA damage response
  • HHV-8
  • KSHV
  • palbociclib
  • lytic replication
  • S phase and replication stress
  • Lytic replication
  • Palbociclib
  • S phase
  • Replication stress
  • Cell cycle
  • Herpesvirus
  • Humans
  • Lymphoma, Primary Effusion/virology
  • DNA Replication/genetics
  • Gene Expression Regulation, Viral/genetics
  • Virus Latency/genetics
  • S Phase/genetics
  • Cell Line
  • Virus Activation/genetics
  • DNA, Viral/genetics
  • Virus Replication/genetics
  • Herpesvirus 8, Human/genetics
  • G1 Phase/genetics
  • Herpesviridae/genetics

ASJC Scopus subject areas

  • Virology

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