Strength in Diversity: Understanding the Pathways to Herpes Simplex Virus Reactivation

Overview

Journal Virology

Specialty Microbiology

Date 2018 Jul 18

PMID 30014861

Citations 67

Authors

Jon B Suzich

Anna R Cliffe

Affiliations

Soon will be listed here.

Abstract

Herpes simplex virus (HSV) establishes a latent infection in peripheral neurons and can periodically reactivate to cause disease. Reactivation can be triggered by a variety of stimuli that activate different cellular processes to result in increased HSV lytic gene expression and production of infectious virus. The use of model systems has contributed significantly to our understanding of how reactivation of the virus is triggered by different physiological stimuli that are correlated with recrudescence of human disease. Furthermore, these models have led to the identification of both common and distinct mechanisms of different HSV reactivation pathways. Here, we summarize how the use of these diverse model systems has led to a better understanding of the complexities of HSV reactivation, and we present potential models linking cellular signaling pathways to changes in viral gene expression.

Citing Articles

Management of Herpes Simplex Virus Reactivation Following Open Septorhinoplasty: A Case Report.

Alosaimi A, Assiri H Indian J Otolaryngol Head Neck Surg. 2025; 77(2):1046-1049.

PMID: 40065925 PMC: 11890691. DOI: 10.1007/s12070-024-05266-7.

The functions of herpesvirus shuttling proteins in the virus lifecycle.

Cao H, Wang M, Cheng A, Tian B, Yang Q, Ou X Front Microbiol. 2025; 16:1515241.

PMID: 39973925 PMC: 11837949. DOI: 10.3389/fmicb.2025.1515241.

Co-option of mitochondrial nucleic acid-sensing pathways by HSV-1 UL12.5 for reactivation from latent infection.

Krakowiak P, Flores M, Cuddy S, Whitford A, Dochnal S, Babnis A Proc Natl Acad Sci U S A. 2025; 122(4):e2413965122.

PMID: 39854226 PMC: 11789124. DOI: 10.1073/pnas.2413965122.

Herpetic Meningoencephalitis Complicating the Resection of a Vestibular Schwannoma: A Case Report.

Houdu J, Barron M, Civit T, Parietti-Winkler C Clin Case Rep. 2025; 13(1):e70050.

PMID: 39759188 PMC: 11695209. DOI: 10.1002/ccr3.70050.

Vistas in Signaling Pathways Implicated in HSV-1 Reactivation.

Papavassiliou K, Sofianidi A, Spiliopoulos F, Gogou V, Papavassiliou A Int J Mol Sci. 2024; 25(22).

PMID: 39596536 PMC: 11594712. DOI: 10.3390/ijms252212472.

References

Neumann D, Bhattacharjee P, Hill J . Sodium butyrate: a chemical inducer of in vivo reactivation of herpes simplex virus type 1 in the ocular mouse model. J Virol. 2007; 81(11):6106-10. PMC: 1900314. DOI: 10.1128/JVI.00070-07. View

Pourchet A, Modrek A, Placantonakis D, Mohr I, Wilson A . Modeling HSV-1 Latency in Human Embryonic Stem Cell-Derived Neurons. Pathogens. 2017; 6(2). PMC: 5488658. DOI: 10.3390/pathogens6020024. View

Halford W, Gebhardt B, Carr D . Mechanisms of herpes simplex virus type 1 reactivation. J Virol. 1996; 70(8):5051-60. PMC: 190459. DOI: 10.1128/JVI.70.8.5051-5060.1996. View

Creech C, Neumann D . Changes to euchromatin on LAT and ICP4 following reactivation are more prevalent in an efficiently reactivating strain of HSV-1. PLoS One. 2010; 5(11):e15416. PMC: 2973973. DOI: 10.1371/journal.pone.0015416. View

Ertel M, Cammarata A, Hron R, Neumann D . CTCF occupation of the herpes simplex virus 1 genome is disrupted at early times postreactivation in a transcription-dependent manner. J Virol. 2012; 86(23):12741-59. PMC: 3497617. DOI: 10.1128/JVI.01655-12. View

Kubat N, Tran R, McAnany P, Bloom D . Specific histone tail modification and not DNA methylation is a determinant of herpes simplex virus type 1 latent gene expression. J Virol. 2004; 78(3):1139-49. PMC: 321404. DOI: 10.1128/jvi.78.3.1139-1149.2004. View

Mo A, Mukamel E, Davis F, Luo C, Henry G, Picard S . Epigenomic Signatures of Neuronal Diversity in the Mammalian Brain. Neuron. 2015; 86(6):1369-84. PMC: 4499463. DOI: 10.1016/j.neuron.2015.05.018. View

Colgin M, Smith R, Wilcox C . Inducible cyclic AMP early repressor produces reactivation of latent herpes simplex virus type 1 in neurons in vitro. J Virol. 2001; 75(6):2912-20. PMC: 115917. DOI: 10.1128/JVI.75.6.2912-2920.2001. View

Yan D, Jin Y . Regulation of DLK-1 kinase activity by calcium-mediated dissociation from an inhibitory isoform. Neuron. 2012; 76(3):534-48. PMC: 3508676. DOI: 10.1016/j.neuron.2012.08.043. View

10.

Roosterman D, Goerge T, Schneider S, Bunnett N, Steinhoff M . Neuronal control of skin function: the skin as a neuroimmunoendocrine organ. Physiol Rev. 2006; 86(4):1309-79. DOI: 10.1152/physrev.00026.2005. View

11.

Bertke A, Patel A, Imai Y, Apakupakul K, Margolis T, Krause P . Latency-associated transcript (LAT) exon 1 controls herpes simplex virus species-specific phenotypes: reactivation in the guinea pig genital model and neuron subtype-specific latent expression of LAT. J Virol. 2009; 83(19):10007-15. PMC: 2748022. DOI: 10.1128/JVI.00559-09. View

12.

Thellman N, Triezenberg S . Herpes Simplex Virus Establishment, Maintenance, and Reactivation: In Vitro Modeling of Latency. Pathogens. 2017; 6(3). PMC: 5617985. DOI: 10.3390/pathogens6030028. View

13.

Divito S, Cherpes T, Hendricks R . A triple entente: virus, neurons, and CD8+ T cells maintain HSV-1 latency. Immunol Res. 2007; 36(1-3):119-26. DOI: 10.1385/IR:36:1:119. View

14.

Lee J, Raja P, Pan D, Pesola J, Coen D, Knipe D . CCCTC-Binding Factor Acts as a Heterochromatin Barrier on Herpes Simplex Viral Latent Chromatin and Contributes to Poised Latent Infection. mBio. 2018; 9(1). PMC: 5801469. DOI: 10.1128/mBio.02372-17. View

15.

Liang Y, Vogel J, Arbuckle J, Rai G, Jadhav A, Simeonov A . Targeting the JMJD2 histone demethylases to epigenetically control herpesvirus infection and reactivation from latency. Sci Transl Med. 2013; 5(167):167ra5. PMC: 4778723. DOI: 10.1126/scitranslmed.3005145. View

16.

Cho Y, Sloutsky R, Naegle K, Cavalli V . Injury-induced HDAC5 nuclear export is essential for axon regeneration. Cell. 2013; 155(4):894-908. PMC: 3987749. DOI: 10.1016/j.cell.2013.10.004. View

17.

Hirai S, Kawaguchi A, Suenaga J, Ono M, Cui D, Ohno S . Expression of MUK/DLK/ZPK, an activator of the JNK pathway, in the nervous systems of the developing mouse embryo. Gene Expr Patterns. 2005; 5(4):517-23. DOI: 10.1016/j.modgep.2004.12.002. View

18.

Kinchington P, St Leger A, Guedon J, Hendricks R . Herpes simplex virus and varicella zoster virus, the house guests who never leave. Herpesviridae. 2012; 3(1):5. PMC: 3541251. DOI: 10.1186/2042-4280-3-5. View

19.

Sawtell N, Thompson R . Herpes simplex virus and the lexicon of latency and reactivation: a call for defining terms and building an integrated collective framework. F1000Res. 2016; 5. PMC: 4995687. DOI: 10.12688/f1000research.8886.1. View

20.

Valtcheva M, Copits B, Davidson S, Sheahan T, Pullen M, McCall J . Surgical extraction of human dorsal root ganglia from organ donors and preparation of primary sensory neuron cultures. Nat Protoc. 2016; 11(10):1877-88. PMC: 5082842. DOI: 10.1038/nprot.2016.111. View