Valpromide Inhibits Lytic Cycle Reactivation of Epstein-Barr Virus.

Kelly L Gorres,Sudharshan Mohanram,Derek Daigle,George Miller,Grace E Mcinerney,Danielle E Lyons,Diane E Griffin

doi:10.1128/mbio.00113-16

Abstract

ABSTRACTReactivation 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.

Highlights

Epstein-Barr virus (EBV), a human gammaherpesvirus, causes infectious mononucleosis and other lymphoproliferative diseases
We found that VPM blocks the expression of two cellular immediate-early (IE) genes, FOS and EGR1, which are involved in EBV lytic reactivation
To determine whether the blockade of EBV reactivation by valproic acid (VPA) correlated with its histone deacetylase (HDAC) inhibitory activity, we studied VPM (2-propyl-pentanamide), the carboximide derivative of VPA (Fig. 1)

Summary

Introduction

Epstein-Barr virus (EBV), a human gammaherpesvirus, causes infectious mononucleosis and other lymphoproliferative diseases. Medium-chain fatty acids, including valproic acid (VPA), block reactivation of the EBV lytic cycle caused by inducing agents in Burkitt lymphoma cells [2]. Since butyrate and VPA are HDAC inhibitors, they each change the expression of thousands of genes This makes the identification and characterization of specific genes required for either activating or repressing EBV lytic reactivation difficult. We sought to determine whether the ability of VPA to block EBV reactivation is dependent on its property of inhibiting HDACs. we examined valpromide (VPM), an analog in which the carboxylic acid of VPA is replaced with an amide (Fig. 1). Unlike VPA, VPM did not induce the lytic cycle of a related gammaherpesvirus, Kaposi sarcoma-associated herpesvirus (KSHV)

Methods

Results

Conclusion