112:. Upon initial infection, herpes simplex virus (HSV) causes acute lytic infection of epithelial cells, usually at either genital or orolabial mucous membranes. During this initial infection, the virus also infects local nerve cells, such as in the trigeminal ganglion in the case of HSV-1. HSV enters the cell when its membrane fuses with the cellular membrane, releasing tegument proteins and the naked capsid into the cytoplasm. The capsid travels to a nuclear pore, likely along cytoskeletal microtubules. The HSV genome is then injected into the nucleus where it is assembled with histones and undergoes chromatin remodeling, thus inducing latency.
25:
311:, which is responsive to stressors such as heat shock, ultraviolet radiation, and cytokine production. Activation of JNK leads to the expression of viral genes of all temporal classes (immediate early, early, and late) by phosphorylating H3, effectively bypassing the latent repression markers (methylation). Next, the
174:, which interrupt the viral replication cycle. These drugs since have been developed commercially and are subsequently prescribed depending on factors such as the immune status of the host, the site of infection, and whether the infection is primary (initial infection) or recurrent (recurring symptoms).
324:
Mammalian viral treatment within the scope of epigenetics is a relatively novel approach that has only seen theoretical or laboratory significance, and as such, advancements in chromatin-based viral therapy relies on advancement in knowledge of viral-host chromatin dynamics and interplay. Two major
236:
As seen by most mainstream antiviral agents, the mechanism of treatment for HSV historically is via the inhibition of viral replication using nucleotides that inhibit DNA polymerase. The specificity in targeting for viral polymerases is dependent on the drug used, which in turn is dependent on the
132:
persistence, common generalities too can be ascribed. Generally, the long-term latency of a mammalian virus is a dynamic interaction between it and the host cell's antiviral immunity. The establishment, maintenance, and reactivation of the infection cycle (reversibility) largely relies on cellular
281:
methyltransferase which can methylate previously unmethylated DNA, such as that of viral genomes. DNMT3A is recruited to viral genomes by viral proteins such as the Kaposi's
Sarcoma herpesvirus (KSHV) protein LANA, and VP26 and VP5 in herpes simplex virus 1 (HSV-1). Methylation of gene promoters
245:
Epigenetic down-regulation of viral gene expression is likely a result, at least in part, of the evolutionary arms race in which a cellular host attempts to silence viral DNA, such as through chromatin remodeling. However, some viruses have evolved to twist this process to their own advantage by
123:
Latent infection is described as the dormancy of a virus, by which proliferation of viral particles cease, yet the viral genome still remains incorporated as reservoirs within the cell. Although diversity among viruses' latent phase exist, ranging from selective viral gene expression (e.g., HSV
355:
The Ezh1/2 inhibitors GSK126, GSK343, and UNC1999 as well as astemizole, which interferes with Ezh1/2 association in PRC, were shown by
Arbuckle et al. to limit HSV immediate early gene expression and the number of transcriptionally active viral genomes during lytic infection. This resulted in
249:
Upon initial infection, viral genomes are not associated with histones. Typical double-stranded DNA viruses that infect eukaryotic cells insert their genome into the cell nucleus, where cellular machinery necessary for DNA replication and transcription is present (the notable exceptions are
87:
As of 2012, an estimated 3.7 billion people globally were infected with oral herpes simplex virus (HSV-1), and 417 million were living with genital herpes (HSV-2) worldwide (World Health
Organization, 2018). In severe cases, HSV infection can cause corneal scarring and blindness from herpes
232:
Foscarnet does not rely on TK phosphorylation, and is thus potent against TK-deficient HSV isolates which otherwise form a resistant to TK-dependent drug mechanisms. Docosanol (Abreva) blocks initial viral entry via inhibition of fusion between the host plasma membrane and HSV envelope.
384:
affects gene expression by changing mRNA splicing, stability, and translation. These changes favor viral gene expression, though the mechanism for this effect is not known. Importantly, mA has been proposed to inhibit host immune recognition of viral RNAs. Inhibition of mA addition by
269:
There are several known examples of viral recruitment of cellular proteins to chromatin for histone modification, particularly in herpesviridae. (Polycomb complex recruitment by LAT, VP16 recruits OCT1 and HCF1, which in turn recruit histone demethylases JMJD2s and LSD1, etc).
224:
Penciclovir is similar to aciclovir in mechanism, except that penciclovir is a guanosine analog. Penciclovir triphosphate is 100-fold less potent in inhibiting viral DNA polymerase, yet also remains in infected cells at higher concentrations and for longer periods of time.
359:
Ezh1/2 inhibitors also activate cellular antiviral pathways. Specifically, in cells treated with Ezh1/2 inhibitors, greater numbers of promyelocytic leukemia (PML) foci, which are involved with repression of gene expression, were seen, along with upregulation of
266:, and ATRX. In particular, Daxx and ATRX assemble viral DNA around histone 3, forming heterochromatin and silencing viral gene expression. Viral responses have evolved to either degrade or modify this heterochromatin, such as repurposing to induce latency.
246:
establishing latency. Latent proviral DNA exists as heterochromatin in the host nucleus, evading cellular defenses. Four epigenetic processes have been well described: chromatin assembly, histone modifications, DNA methylation, and regulatory RNA.
120:. During latency, most viral genes are silenced, and infected individuals are asymptomatic. More importantly, during latency, proviral DNA is hidden from the immune system, making treatment extremely difficult, if not impossible.
169:
HSV infections have been medically recorded in literature for centuries, but its antiviral treatment has been developed only over the past 50 years. The framework for antiviral HSV treatment began with the experimental use of
315:
translation of VP16 results in the temporal regulation of these genes; VP16 associates with Oct-1 and with viral promoters to regulate transcription. Reactivation results in lytic infection of proximal epithelial cells.
141:
Antiviral drug development has been a complex process utilizing several different fields to synthesize single methods of treatment. As of May 2018 there are about 50 drugs approved for human use against viruses such as
1186:
Bader JP, Brown NR, Chiang PK, Cantoni GL (September 1978). "3-Deazaadenosine, an inhibitor of adenosylhomocysteine hydrolase, inhibits reproduction of Rous sarcoma virus and transformation of chick embryo cells".
389:
hydrolase inhibitor) has been shown to have broad antiviral applications. Therapies utilizing specific mA may be very effective against nuclear viruses without toxicity to the host, though this research is new.
254:, which remain in the cytoplasm). Once viral DNA enters the nucleus, it colocalizes with promyelocytic leukaemia nuclear bodies (PML-NBs), regions rich in proteins associated with antiviral pathways such as
297:
proteins to lytic cycle-associated genes on the viral genome. This results in the methylation of cytosines within the promoter region of genes associated with lytic cycle processes. In the
352:), which functions to repress gene transcription by propagating a H3K27 trimethylation. Ezh1/2 has been implicated in suppression of viral replication during lytic infection.
368:. These pathways are not specific to HSV; treatment with Ezh1/2 inhibitors reduced infection of multiple viral pathogens, including human cytomegalovirus, adenovirus, and
482:
304:, the non-coding RNA EBER2 has been implicated in gene regulation. EBER2 recruits PAX5, a transcription factor, to immediate-early genes to promote latency.
290:
325:
therapies that target epigenetic machinery have been proposed for treatment of viral infections: inhibition of Ezh1/2 and mA addition to viral mRNA.
116:
DNA viruses in particular make use of cellular epigenetic mechanisms in their life cycle, particularly prior to replication, during a virus'
993:"Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens"
743:"Disruption of host antiviral resistances by gammaherpesvirus tegument proteins with homology to the FGARAT purine biosynthesis enzyme"
458:
1098:"Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA"
293:, the Latency-Associated Transcripts (LATs), which are non-coding RNAs, are thought to play an important role in recruiting host
88:
keratitis, central nervous system infections, and even death in immunocompromised individuals such as neonates and HIV patients.
124:
expression of latency associated transcripts) to complete lack of expression, incorporation into the cell's genome (such as in
255:
1222:
de Clercq E, Montgomery JA (March 1983). "Broad-spectrum antiviral activity of the carbocyclic analog of 3-deazaadenosine".
294:
839:
Cliffe AR, Arbuckle JH, Vogel JL, Geden MJ, Rothbart SB, Cusack CL, Strahl BD, Kristie TM, Deshmukh M (December 2015).
841:"Neuronal Stress Pathway Mediating a Histone Methyl/Phospho Switch Is Required for Herpes Simplex Virus Reactivation"
133:
epigenetic processes in this dynamic and thus opens a discussion for viral treatment via an epigenetic perspective.
670:"History and progress of antiviral drugs: From acyclovir to direct-acting antiviral agents (DAAs) for Hepatitis C"
341:
668:
Bryan-Marrugo OL, Ramos-Jiménez J, Barrera-Saldaña H, Rojas-Martínez A, Vidaltamayo R, Rivas-Estilla AM (2015).
1139:"RNAs Containing Modified Nucleotides Fail To Trigger RIG-I Conformational Changes for Innate Immune Signaling"
308:
205:
aciclovir into its monophosphate form, which is subsequently phosphorylated to active aciclovir triphoshate by
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Arbuckle JH, Gardina PJ, Gordon DN, Hickman HD, Yewdell JW, Pierson TC, Myers TG, Kristie TM (August 2017).
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301:
283:
386:
406:
Knipe DM, Cliffe A (March 2008). "Chromatin control of herpes simplex virus lytic and latent infection".
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represses gene expression, which has several functions in maintaining latency and even reactivation in
1262:
206:
166:. A large amount of viral research in the field of epigenetics has been done on specifically on HSV.
81:
792:"MicroRNA miR-BART20-5p stabilizes Epstein-Barr virus latency by directly targeting BZLF1 and BRLF1"
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acts as a nucleoside analog which specifically target herpes virus-infected cells using viral
105:
890:"VP16 serine 375 is a critical determinant of herpes simplex virus exit from latency in vivo"
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DNA methylation can occur on viral genomes through recruitment of cellular machinery such as
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Brady RC, Bernstein DI (February 2004). "Treatment of herpes simplex virus infections".
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939:"The rise of epigenetic targets for the development of novel antivirals"
618:"Viral latency and its regulation: lessons from the gamma-herpesviruses"
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of aciclovir, which is thus converted to aciclovir in the liver.
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337:
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Durbin AF, Wang C, Marcotrigiano J, Gehrke L (September 2016).
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18:
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Sawtell NM, Triezenberg SJ, Thompson RL (December 2011).
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Reactivation in HSV requires the stress response enzyme
1096:
Karikó K, Buckstein M, Ni H, Weissman D (August 2005).
1047:
Kennedy EM, Courtney DG, Tsai K, Cullen BR (May 2017).
49:
39:
567:"Epigenetic Regulation of Viral Biological Processes"
453:(2nd ed.). Hoboken, NJ: John Wiley & Sons.
380:Methylation on the N position of adenosine (mA) on
741:Tsai K, Messick TE, Lieberman PM (October 2015).
790:Jung YJ, Choi H, Kim H, Lee SK (August 2014).
291:Kaposi's Sarcoma-associated herpesvirus (KSHV)
229:is the diacetyl ester prodrug of penciclovir.
217:Aciclovir triphosphate is the L-valine ester
8:
565:Balakrishnan L, Milavetz B (November 2017).
481:: CS1 maint: multiple names: authors list (
515:"Epigenetics and Genetics of Viral Latency"
340:(Ezh1/2) are two homologous enzymes of Ezh
16:Epigenetic modification of HSV genetic code
177:Popular, current antiviral agents include
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943:Expert Review of Anti-Infective Therapy
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100:of a virus typically consists of its
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504:
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209:, thus selectively inhibiting viral
451:Fundamentals of molecular virology
320:Potential therapeutic applications
14:
275:DNA methyltransferase 3A (DNMT3A)
356:suppression of lytic infection.
23:
720:10.1016/j.antiviral.2003.09.006
616:Speck SH, Ganem D (July 2010).
1:
309:c-Jun N-terminal kinase (JNK)
1236:10.1016/0166-3542(83)90011-6
1201:10.1016/0042-6822(78)90191-5
1115:10.1016/j.immuni.2005.06.008
937:Kristie TM (December 2012).
759:10.1016/j.coviro.2015.07.008
408:Nature Reviews. Microbiology
747:Current Opinion in Virology
385:3-deazaadenosine (DAA) (an
241:Viral epigenetic mechanisms
237:severity of the infection.
1284:
1049:"Viral Epitranscriptomics"
857:10.1016/j.chom.2015.11.007
634:10.1016/j.chom.2010.06.014
531:10.1016/j.chom.2016.04.008
906:10.1007/s13365-011-0065-y
687:10.1016/j.rmu.2015.05.003
513:Lieberman PM (May 2016).
342:histone methyltransferase
894:Journal of Neurovirology
449:H., Acheson, N. (2011).
362:interferon-alpha (IFN-α)
302:Epstein-Barr virus (EBV)
284:Epstein-Barr virus (EBV)
845:Cell Host & Microbe
622:Cell Host & Microbe
519:Cell Host & Microbe
38:, as no other articles
674:Medicina Universitaria
387:S-adenosylhomocysteine
348:repression complex 2 (
344:, and are part of the
1155:10.1128/mBio.00833-16
1009:10.1128/mbio.01141-17
376:Adenosine methylation
1065:10.1128/JVI.02263-16
808:10.1128/jvi.00721-14
382:messenger RNA (mRNA)
366:interleukin-8 (IL-8)
137:History of treatment
84:(HSV) genetic code.
82:herpes simplex virus
1053:Journal of Virology
796:Journal of Virology
420:10.1038/nrmicro1794
1224:Antiviral Research
955:10.1586/eri.12.143
708:Antiviral Research
57:for suggestions.
47:to this page from
329:Ezh1/2 inhibition
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199:thymidine kinase
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92:Infectious cycle
80:modification of
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201:(TK). Viral TK
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1263:Epigenetics
577:(11): 346.
289:In HSV and
252:pox viruses
227:Famciclovir
183:penciclovir
106:replication
1257:Categories
394:References
370:Zika virus
98:life cycle
78:epigenetic
53:; try the
40:link to it
753:: 30–40.
477:cite book
469:697768676
195:Aciclovir
191:docosanol
187:foscarnet
179:aciclovir
114:Lysogenic
43:. Please
1189:Virology
1173:27651356
1124:16111635
1102:Immunity
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1027:28811345
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346:Polycomb
295:Polycomb
130:episomal
110:shedding
62:May 2018
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