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The Epstein-Barr Virus Immunoevasins BCRF1 and BPLF1 Are Expressed by a Mechanism Independent of the Canonical Late Pre-initiation Complex

Mckenzie, Jessica ; Lopez-Giraldez, Francesc ; Delecluse, Henri-Jacques ; Walsh, Ann ; El-Guindy, Ayman ;Ling, Paul D. (editor)

PLoS Pathogens, 2016, Vol.12(11) [Peer Reviewed Journal]

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  • Title:
    The Epstein-Barr Virus Immunoevasins BCRF1 and BPLF1 Are Expressed by a Mechanism Independent of the Canonical Late Pre-initiation Complex
  • Author/Creator: Mckenzie, Jessica ; Lopez-Giraldez, Francesc ; Delecluse, Henri-Jacques ; Walsh, Ann ; El-Guindy, Ayman
  • Ling, Paul D. (editor)
  • Subjects: Research Article ; Biology And Life Sciences ; Biology And Life Sciences ; Biology And Life Sciences ; Biology And Life Sciences ; Biology And Life Sciences ; Biology And Life Sciences ; Biology And Life Sciences ; Biology And Life Sciences ; Biology And Life Sciences ; Biology And Life Sciences ; Biology And Life Sciences ; Biology And Life Sciences
  • Is Part Of: PLoS Pathogens, 2016, Vol.12(11)
  • Description: Subversion of host immune surveillance is a crucial step in viral pathogenesis. Epstein-Barr virus (EBV) encodes two immune evasion gene products, BCRF1 (viral IL-10) and BPLF1 (deubiquitinase/deneddylase); both proteins suppress antiviral immune responses during primary infection. The BCRF1 and BPLF1 genes are expressed during the late phase of the lytic cycle, an essential but poorly understood phase of viral gene expression. Several late gene regulators recently identified in beta and gamma herpesviruses form a viral pre-initiation complex for transcription. Whether each of these late gene regulators is necessary for transcription of all late genes is not known. Here, studying viral gene expression in the absence and presence of siRNAs to individual components of the viral pre-initiation complex, we identified two distinct groups of late genes. One group includes late genes encoding the two immunoevasins, BCRF1 and BPLF1, and is transcribed independently of the viral pre-initiation complex. The second group primarily encodes viral structural proteins and is dependent on the viral pre-initiation complex. The protein kinase BGLF4 is the only known late gene regulator necessary for expression of both groups of late genes. ChIP-seq analysis showed that the transcription activator Rta associates with the promoters of eight late genes including genes encoding the viral immunoevasins. Our results demonstrate that late genes encoding immunomodulatory proteins are transcribed by a mechanism distinct from late genes encoding viral structural proteins. Understanding the mechanisms that specifically regulate expression of the late immunomodulatory proteins could aid the development of antiviral drugs that impair immune evasion by the oncogenic EB virus. Author Summary Late proteins are expressed during the productive cycle of Epstein-Barr virus (EBV) after the onset of viral DNA replication. Many late proteins serve structural functions; they form the capsid shell around the viral genome or mediate attachment and fusion of the virus to the host cell. EBV also encodes two late proteins that suppress the immune system during primary infection. The current model suggests that transcription of all late genes is regulated by a common mechanism involving seven late gene regulators. Here, we demonstrate that late genes encoding two viral immune suppressants are transcribed by a mechanism different from that regulating late genes encoding structural proteins. Abolishing expression of the late immunomodulators without disrupting expression of the antigenic viral structural proteins could serve as an approach to block EBV de novo infection and its associated malignancies.
  • Identifier: ISSN: 1553-7366 ; E-ISSN: 1553-7374 ; DOI: 10.1371/journal.ppat.1006008 ; PMCID: 5113994 ; PMID: 27855219