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, i...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Kelly L. Gorres, Derek Daigle, Sudharshan Mohanram, Grace E. McInerney, Danielle E. Lyons, George Miller
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/cf69ace380fa4a8f868716425cabda6e
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:cf69ace380fa4a8f868716425cabda6e
record_format	dspace
spelling	oai:doaj.org-article:cf69ace380fa4a8f868716425cabda6e2021-11-15T15:41:40ZValpromide Inhibits Lytic Cycle Reactivation of Epstein-Barr Virus10.1128/mBio.00113-162150-7511https://doaj.org/article/cf69ace380fa4a8f868716425cabda6e2016-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00113-16https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE 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.Kelly L. GorresDerek DaigleSudharshan MohanramGrace E. McInerneyDanielle E. LyonsGeorge MillerAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 2 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Kelly L. Gorres Derek Daigle Sudharshan Mohanram Grace E. McInerney Danielle E. Lyons George Miller Valpromide Inhibits Lytic Cycle Reactivation of Epstein-Barr Virus
description	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. IMPORTANCE 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.
format	article
author	Kelly L. Gorres Derek Daigle Sudharshan Mohanram Grace E. McInerney Danielle E. Lyons George Miller
author_facet	Kelly L. Gorres Derek Daigle Sudharshan Mohanram Grace E. McInerney Danielle E. Lyons George Miller
author_sort	Kelly L. Gorres
title	Valpromide Inhibits Lytic Cycle Reactivation of Epstein-Barr Virus
title_short	Valpromide Inhibits Lytic Cycle Reactivation of Epstein-Barr Virus
title_full	Valpromide Inhibits Lytic Cycle Reactivation of Epstein-Barr Virus
title_fullStr	Valpromide Inhibits Lytic Cycle Reactivation of Epstein-Barr Virus
title_full_unstemmed	Valpromide Inhibits Lytic Cycle Reactivation of Epstein-Barr Virus
title_sort	valpromide inhibits lytic cycle reactivation of epstein-barr virus
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/cf69ace380fa4a8f868716425cabda6e
work_keys_str_mv	AT kellylgorres valpromideinhibitslyticcyclereactivationofepsteinbarrvirus AT derekdaigle valpromideinhibitslyticcyclereactivationofepsteinbarrvirus AT sudharshanmohanram valpromideinhibitslyticcyclereactivationofepsteinbarrvirus AT graceemcinerney valpromideinhibitslyticcyclereactivationofepsteinbarrvirus AT danielleelyons valpromideinhibitslyticcyclereactivationofepsteinbarrvirus AT georgemiller valpromideinhibitslyticcyclereactivationofepsteinbarrvirus
_version_	1718427671570939904

Valpromide Inhibits Lytic Cycle Reactivation of Epstein-Barr Virus

Ejemplares similares