title: Valpromide Inhibits Lytic Cycle Reactivation of Epstein-Barr Virus.
abstract: Reactivation of Epstein-Barr virus (EBV) from latency into the lytic phase of its life cycle allows the virus to spread among cells and between hosts. Valproic acid (VPA) inhibits initiation of the lytic cycle in EBV-infected B lymphoma cells. While VPA blocks viral lytic gene expression, it induces expression of many cellular genes, because it is a histone deacetylase (HDAC) inhibitor. Here we show, using derivatives of VPA, that blockade of EBV reactivation is separable from HDAC inhibition. Valpromide (VPM), an amide derivative of valproic acid that is not an HDAC inhibitor, prevented expression of two EBV genes, BZLF1 and BRLF1, that mediate lytic reactivation. VPM also inhibited expression of a viral late gene, but not early genes, when BZLF1 was exogenously expressed. Unlike VPA, VPM did not activate lytic expression of Kaposi's sarcoma-associated herpesvirus. Expression of cellular immediate-early genes, such as FOS and EGR1, is kinetically upstream of the EBV lytic cycle. VPM did not activate expression of these cellular immediate-early genes but decreased their level of expression when induced by butyrate, an HDAC inhibitor. VPM did not alter expression of several other cellular immediate-early genes, including STAT3, which were induced by the HDAC inhibitors in cells refractory to lytic induction. Therefore, VPM selectively inhibits both viral and cellular gene expression. VPA and VPM represent a new class of antiviral agents. The mechanism by which VPA and VPM block EBV reactivation may be related to their anticonvulsant activity.
  
  
  OBJECTIVE
  Epstein-Barr virus, (EBV), a human tumor virus, establishes a life-long latent infection. Reactivation of EBV into the lytic phase of its life cycle allows the virus to spread. Previously, we showed that EBV reactivation was blocked by valproic acid (VPA), an inhibitor of cellular histone deacetylases (HDACs). VPA alters the expression of thousands of cellular genes. In this study, we demonstrate that valpromide (VPM), an amide derivative of valproic acid that is not an HDAC inhibitor, prevented initiation of the EBV lytic cycle. VPA induced lytic reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV), but VPM did not. Unlike VPA, VPM did not activate cellular immediate-early gene expression. VPM is a new type of antiviral agent. VPM will be useful in probing the mechanism of EBV lytic reactivation and may have therapeutic application.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Gorres
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Daigle
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Sudharshan
authors.initials: S
authors.lastname: Mohanram
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Grace E
authors.initials: GE
authors.lastname: McInerney
authors.affiliation: Department of Microbiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Lyons
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut, USA Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut, USA george.miller@yale.edu.
authors.forename: George
authors.initials: G
authors.lastname: Miller
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000821:virology; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors; D015534:Trans-Activators / Q000037:antagonists & inhibitors; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D014775:Virus Activation / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C068382:BRLF1 protein, Human herpesvirus 4; C063676:BZLF1 protein, Herpesvirus 4, Human; D017874:Immediate-Early Proteins; D015534:Trans-Activators; D014635:Valproic Acid; C004651:dipropylacetamide