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.

Mood stabilizers inhibit cytomegalovirus infection

“…Although both VPA and VPD attenuate reactivation from latency of Epstein Barr virus [18], VPA enhances the infectivity and replication of a large variety of other viruses including HIV [19], vesicular stomatitis virus (VSV) [20], Kaposi’s sarcoma-associated herpes virus [21], herpes simplex viruses [22, 23], human herpes virus 6 [24], and hCMV [25–27] through a mechanism involving HDAC inhibition. These virus-enhancing effects are exerted at doses therapeutic for anti-epileptic and mood stabilizing purposes [28–30], thus raising concerns over the use of VPA in congenitally CMV-infected neonates experiencing seizures and in AIDS patients with CMV- and HIV-mediated neurological disorders [31].…”

Review: Biological and Pharmacological Basis of Cytolytic Viral Activation in EBV-Associated Nasopharyngeal Carcinoma

“…factors, which have specific binding motifs on the Zp and Rp promoters, respectively [63,64]. For information, phorbol-esters, which have long been known to induce lytic EBV activation in lymphoid cells, are direct pharmacological agonists of PKCs [65].…”

“…Activation of NF-κB has been reported to stabilize latency in various γ-herpesviruses [69]. Stat3 is also reported to stabilize latency in EBV-infected cells [63]. However, the influence of inflammatory factors on EBV latency in NPC cells has not been well documented.…”

Epigenetic Treatment of Persistent Viral Infections

“…Curiously, although butyrate's activating effect on the EBV lytic cycle was attributed to its roles as an epigenetic regulator and a histone deacetylase (HDAC) inhibitor [Ghosh et al, ], valproic acid (VPA; Figure ), which is a close analogue that is also an HDAC inhibitor, instead suppresses EBV lytic cycle reactivation [Gorres et al, ]. To account for the differential effect of VPA versus butyrate on EBV reactivation, Gorres et al [] posit that the repressive activity of VPA on the EBV lytic cycle may be independent of its HDAC properties.…”

“…Curiously, although butyrate's activating effect on the EBV lytic cycle was attributed to its roles as an epigenetic regulator and a histone deacetylase (HDAC) inhibitor [Ghosh et al, ], valproic acid (VPA; Figure ), which is a close analogue that is also an HDAC inhibitor, instead suppresses EBV lytic cycle reactivation [Gorres et al, ]. To account for the differential effect of VPA versus butyrate on EBV reactivation, Gorres et al [] posit that the repressive activity of VPA on the EBV lytic cycle may be independent of its HDAC properties. VPA is a weaker HDAC inhibitor than is butyrate (52% HDAC inhibition vs 82% at 1 mM concentrations, respectively [Gilbert et al, ; Manal et al, ; Stilling et al, ]), and although the amide derivative of butyric acid [butyramide (Figure ), which is not an HDAC inhibitor] shows no effect on the EBV lytic cycle, the corresponding amide derivative of VPA [valproamide (Figure ) also not an HDAC inhibitor] nonetheless retains the acid's suppressive properties.…”