Herpes Simplex Viruses: Mechanisms of DNA Replication

Weller, Sandra K.; Coen, Donald M.

doi:10.1101/cshperspect.a013011

Cited by 193 publications

(185 citation statements)

References 94 publications

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“…Many chromatin components are involved in the balance between heterochromatic suppression of the viral genome and the euchromatin transition that promotes the expression of viral genes (6). HSV-1 infection also causes extensive reorganization of cellular structures, with nuclear changes including margination of chromatin, enlargement of the nucleus, formation of replication compartments, disruption of the nuclear lamina and nucleoli, and cytoplasmic changes including disruption of the Golgi apparatus and microtubules and genetic damage to mitochondria (4,8,9). HSV-1 infection also impacts cellular metabolism, in part by diverting the central carbon metabolism toward production of pyrimidine nucleotide components (10).…”

Section: Herpes Simplex Virus (Hsv-1)mentioning

confidence: 99%

“…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.…”

Section: Herpes Simplex Virus (Hsv-1)mentioning

confidence: 99%

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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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Section: Herpes Simplex Virus (Hsv-1)mentioning

confidence: 99%

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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“…For more detailed information on genome organization and replication of particular viruses, please refer to comprehensive reviews, e.g. for herpes simplex virus [54], poxvirus [55] and adenovirus [56]. Before amplification and expression of the viral genome can take place, it must be made accessible by uncoating.…”

Section: Viral Life Cyclementioning

confidence: 99%

Fighting Cancer with Mathematics and Viruses

Santiago¹,

Heidbuechel²,

Kandell³

et al. 2017

Preprint

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After decades of research, oncolytic virotherapy has recently advanced to clinical application, and currently a multitude of novel agents and combination treatments are being evaluated for cancer therapy. Oncolytic agents preferentially replicate in tumor cells, inducing tumor cell lysis and complex anti-tumor effects, such as innate and adaptive immune responses and the destruction of tumor vasculature. With the availability of different vector platforms and the potential of both genetic engineering and combination regimens to enhance particular aspects of safety and efficacy, the identification of optimal treatments for patient subpopulations or even individual patients becomes a top priority. Mathematical modeling can provide support in this arena by making use of experimental and clinical data to generate hypotheses about the mechanisms underlying complex biology and, ultimately, predict optimal treatment protocols. Increasingly complex models can be applied to account for therapeutically relevant parameters such as components of the immune system. In this review, we describe current developments in oncolytic virotherapy and mathematical modeling to discuss the benefit of integrating different modeling approaches into biological and clinical experimentation. Conclusively, we propose a mutual combination of these fields of research for more efficient development and effective treatments.

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“…Further U L 29 negatively regulates the transcription of β proteins post viral DNA replication [69][70][71][72]. HSV DNA replicates via a theta mechanism initially and continues via sigma or rolling-circle mechanism [73]. Post DNA replication L/γ genes are transcribed, which mainly include viral structural components [74].…”

Section: Viral Replicationmentioning

confidence: 99%

Update On Emerging Antivirals For The Management Of Herpes Simplex Virus Infections: A Patenting Perspective

Vadlapudi¹,

Vadlapatla²,

Mitra³

2013

Recent Patents on Anti-Infective Drug Discovery

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Herpes simplex virus (HSV) infections can be treated efficiently by the application of antiviral drugs. The herpes family of viruses is responsible for causing a wide variety of diseases in humans. The standard therapy for the management of such infections includes acyclovir (ACV) and penciclovir (PCV) with their respective prodrugs valaciclovir and famciclovir. Though effective, long term prophylaxis with the current drugs leads to development of drug-resistant viral isolates, particularly in immunocompromised patients. Moreover, some drugs are associated with dose-limiting toxicities which limit their further utility. Therefore, there is a need to develop new antiherpetic compounds with different mechanisms of action which will be safe and effective against emerging drug resistant viral isolates. Significant advances have been made towards the design and development of novel antiviral therapeutics during the last decade. As evident by their excellent antiviral activities, pharmaceutical companies are moving forward with several new compounds into various phases of clinical trials. This review provides an overview of structure and life cycle of HSV, progress in the development of new therapies, update on the advances in emerging therapeutics under clinical development and related recent patents for the treatment of Herpes simplex virus infections.

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Herpes Simplex Viruses: Mechanisms of DNA Replication

Cited by 193 publications

References 94 publications

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

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

Fighting Cancer with Mathematics and Viruses

Update On Emerging Antivirals For The Management Of Herpes Simplex Virus Infections: A Patenting Perspective

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