The molecular basis of herpes simplex virus latency

Nicoll, Michael P.; Proença, João T.; Efstathiou, Stacey

doi:10.1111/j.1574-6976.2011.00320.x

Cited by 226 publications

(224 citation statements)

References 209 publications

(311 reference statements)

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“…Hence, infection of new neurons and commitments to latency could occur at any time during this interval. Several reports indicate that various factors are recruited to the viral genome in the course of the commitment phase (47)(48)(49)(50)(51)(52)(53)(54). iii) Several potentially important questions arise from the observations that in ganglia harboring latent R111 recombinant virus at the end of the commitment phase (between 14 and 30 d after corneal inoculation), there was a less than twofold decrease in viral DNA but a 10-to 100-fold decrease in LAT and miRNAs relative to the levels detected in ganglia harboring WT virus.…”

Section: Discussionmentioning

confidence: 99%

HSV carrying WT REST establishes latency but reactivates only if the synthesis of REST is suppressed

Zhou

Roizman

2013

Proc. Natl. Acad. Sci. U.S.A.

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HSVs transit from vigorous replication at the portal of entry into the body to a latent state in sensory neurons in which only noncoding (e.g., latency-associated transcript) and micro-RNAs are expressed. In productive infection, viral genes must be sequentially derepressed at two checkpoints. A leading role in the repression of viral genes is carried out by histone deacetylase (HDAC)/corepressor element-1 silencing transcription factor (CoREST)/lysinespecific demethylase1(LSD1)/RE1-silencing transcription factor (REST) repressor complex (HCLR). Previously, we reported that to define the role of the components of the HCLR complex in the establishment of latency, we constructed recombinant virus (R112) carrying a dominant-negative REST that bound response elements in DNA but could not recruit repressive proteins. This recombinant virus was unable to establish latency. In the current studies, we constructed a virus (R111) carrying WT REST with a WT genome. We report the following findings: (a) R111 readily established latent infection in trigeminal ganglia; however, although the amounts of viral DNAs in latently infected neurons were similar to those of WT virus, the levels of latency-associated transcript and micro-RNAs were 50-to 100-fold lower; (b) R111 did not spontaneously reactivate in ganglionic organ cultures; however, viral genes were expressed if the synthesis of REST was blocked by cycloheximide; and (c) histone deacetylase inhibitors reactivated the WT parent but not the R111 recombinant virus. The results suggest that REST plays a transient role in the establishment of latency but not in reactivation and suggest the existence of at least two phases at both establishment and reactivation.NGF | protein synthesis

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Section: Discussionmentioning

confidence: 99%

HSV carrying WT REST establishes latency but reactivates only if the synthesis of REST is suppressed

Zhou

Roizman

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The HSV-1 genome is a double-stranded DNA molecule that replicates in the host cell nucleus (1). HSV-1 initially infects epithelial cells as a lytic infection, and then enters peripheral neurons where it establishes latency (2,3). Processes such as viral transcription, viral DNA synthesis, virion assembly and DNA packaging take place in discrete virus-induced structures within the nucleus called replication compartments (1,4).…”

Section: Herpes Simplex Virus (Hsv-1)mentioning

confidence: 99%

Time-resolved Global and Chromatin Proteomics during Herpes Simplex Virus Type 1 (HSV-1) Infection

Kulej

Avgousti

Sidoli

et al. 2017

Molecular & Cellular Proteomics

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Herpes simplex virus (HSV-1) lytic infection results in global changes to the host cell proteome and the proteins associated with host chromatin. We present a system level characterization of proteome dynamics during infection by performing a multi-dimensional analysis during HSV-1 lytic infection of human foreskin fibroblast (HFF) cells. Our study includes identification and quantification of the host and viral proteomes, phosphoproteomes, chromatin bound proteomes and post-translational modifications (PTMs) on cellular histones during infection. We analyzed proteomes across six time points of virus infection (0, 3, 6, 9, 12 and 15 h post-infection) and clustered trends in abundance using fuzzy c-means. Globally, we accurately quantified more than 4000 proteins, 200 differently modified histone peptides and 9000 phosphorylation sites on cellular proteins. In addition, we identified 67 viral proteins and quantified 571 phosphorylation events (465 with high confidence site localization) on viral proteins, which is currently the most comprehensive map of HSV-1 phosphoproteome. We investigated chromatin bound proteins by proteomic analysis of the high-salt chromatin fraction and identified 510 proteins that were significantly different in abundance during infection. We found 53 histone marks significantly regulated during virus infection, including a steady increase of histone H3 acetylation (H3K9ac and H3K14ac). Our data provide a resource of unprecedented depth for human and viral proteome dynamics during infection. Collectively, our results indicate that the proteome composition of the chromatin of HFF cells is highly affected during HSV-1 infection, and that phosphorylation events are abundant on viral proteins. We propose that our epi-proteomics approach will prove to be important in the characterization of other model infectious systems that involve changes to chromatin composition. Molecular & Cellular Proteomics 16: 10.1074/mcp.M116.065987, S92-S107, 2017. Herpes simplex virus (HSV-1)1 leads to a contagious and persistent infection that affects about 95% of the human population. The HSV-1 genome is a double-stranded DNA molecule that replicates in the host cell nucleus (1). HSV-1 initially infects epithelial cells as a lytic infection, and then enters peripheral neurons where it establishes latency (2, 3). Processes such as viral transcription, viral DNA synthesis, virion assembly and DNA packaging take place in discrete virus-induced structures within the nucleus called replication compartments (1, 4). These processes are temporally regulated by the viral cascades of immediate-early (IE), early (E), and late (L) gene expression. The IE proteins are primarily responsible for counteracting intrinsic host defenses and for activating expression of early-phase genes (1). Early viral pro-

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“…Trigeminal and sacral ganglia are the regions where HSV-1 and HSV-2 viruses most frequently remain latent. Recurrent genital herpes infection usually occurs as a result of reactivation of the virus remaining latent in sacral root ganglia [9,17,22]. Many factors such as traumas, inlammatory diseases, ultraviolet, menstruation, immune suppression, fatigue, and psychological stress may lead to reactivation of the latent virus.…”

Section: Pathophysiologymentioning

confidence: 99%

Genital Herpes

Emre¹,

Akkus²

2017

Fundamentals of Sexually Transmitted Infections

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Genital herpes simplex virus (HSV) infections are among the most commonly seen sexually transmited infections in the world. Genital herpes is a serious health problem because the infection continues through life with remissions and relapses, it causes recurring painful ulcers, and there is no known cure for it. The real prevalence of the genital herpes infection is unknown due to asymptomatic cases. The majority of infected individuals are not aware of the infection due to short duration of symptoms and signs or its asymptomatic nature. The clinical presentation of genital herpes shows certain differences in terms of the primary atack following the irst encounter with the virus and recurrent atacks. There is a strong relationship between HSV-2 positivity and human immunodeiciency virus (HIV). A serious complication of genital herpes in the mother during pregnancy, neonatal herpes, has a mortality risk of 60% if not treated. Antiviral therapy is safe and efective, for both episodic treatment and chronic suppression of HSV. Epidemiology, clinical presentation, laboratory, and treatment options of genital herpes are summarized in this chapter.

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The molecular basis of herpes simplex virus latency

Cited by 226 publications

References 209 publications

HSV carrying WT REST establishes latency but reactivates only if the synthesis of REST is suppressed

HSV carrying WT REST establishes latency but reactivates only if the synthesis of REST is suppressed

Time-resolved Global and Chromatin Proteomics during Herpes Simplex Virus Type 1 (HSV-1) Infection

Genital Herpes

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