Reactivation of thymidine kinase-defective herpes simplex virus is enhanced by nucleoside

Richard B. Tenser, Andrew Gaydos, Kathleen A. Hay

Research output: Contribution to journalArticle

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Abstract

Herpes simplex virus (HSV) mutants defective for thymidine kinase expression (TK-) have been reported to establish latent infection of sensory ganglia of mice, in that HSV latency-associated transcript is expressed, but to be defective for reactivation. In the present study, the mechanism of defective reactivation by TK- HSV was investigated. Latent infection established by each of three reactivation-defective HSV type 1 mutants was studied. Reactivation in explant culture was markedly enhanced by the addition of thymidine (dTdR) to the explant culture medium. Without added dTdR, reactivation occurred in 0 of 32 ganglia, while when dTdR (200 μM) was present, reactivation occurred in 32 of 37 ganglia (86%). Reactivation was minimal or did not occur after treatment with other nucleosides; specificity for dTdR would suggest the importance of dTdR nucleotide levels rather than more general nucleotide pool imbalance. Enhanced reactivation by dTdR was dose dependent and was blocked by acyclovir. While some degree of inhibition of TK- HSV by acyclovir may he expected, the complete block of dTdR-enhanced reactivation was unexpected. This result may suggest that HSV is particularly vulnerable during initial reactivation events. The mechanism of dTdR-enhanced reactivation of TK- HSV was further evaluated during in vivo infection by TK- HSV. For mice infected with TK- HSV, virus was undetectable in ganglia 3 days later. However, for mice infected with TK- HSV and treated with dTdR, virus was readily detected (2.8 x 103 PFU per ganglion). This result suggested that in vivo treatment with dTdR enhanced replication of TK- HSV in ganglion neurons. In turn, this suggests that in latently infected ganglia, dTdR-enhanced reactivation of TK- HSV occurred as a result of viral replication in neurons following initial reactivation events.

Original languageEnglish (US)
Pages (from-to)1271-1276
Number of pages6
JournalJournal of virology
Volume70
Issue number2
StatePublished - Jan 29 1996

Fingerprint

Defective Viruses
thymidine kinase
herpes simplex
Thymidine Kinase
nucleosides
Simplexvirus
Nucleosides
viruses
Ganglia
Acyclovir
Nucleotides
Infection
mice
Virus Latency
explants
Sensory Ganglia
Viruses
Neurons
neurons
nucleotides

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Tenser, Richard B. ; Gaydos, Andrew ; Hay, Kathleen A. / Reactivation of thymidine kinase-defective herpes simplex virus is enhanced by nucleoside. In: Journal of virology. 1996 ; Vol. 70, No. 2. pp. 1271-1276.
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abstract = "Herpes simplex virus (HSV) mutants defective for thymidine kinase expression (TK-) have been reported to establish latent infection of sensory ganglia of mice, in that HSV latency-associated transcript is expressed, but to be defective for reactivation. In the present study, the mechanism of defective reactivation by TK- HSV was investigated. Latent infection established by each of three reactivation-defective HSV type 1 mutants was studied. Reactivation in explant culture was markedly enhanced by the addition of thymidine (dTdR) to the explant culture medium. Without added dTdR, reactivation occurred in 0 of 32 ganglia, while when dTdR (200 μM) was present, reactivation occurred in 32 of 37 ganglia (86{\%}). Reactivation was minimal or did not occur after treatment with other nucleosides; specificity for dTdR would suggest the importance of dTdR nucleotide levels rather than more general nucleotide pool imbalance. Enhanced reactivation by dTdR was dose dependent and was blocked by acyclovir. While some degree of inhibition of TK- HSV by acyclovir may he expected, the complete block of dTdR-enhanced reactivation was unexpected. This result may suggest that HSV is particularly vulnerable during initial reactivation events. The mechanism of dTdR-enhanced reactivation of TK- HSV was further evaluated during in vivo infection by TK- HSV. For mice infected with TK- HSV, virus was undetectable in ganglia 3 days later. However, for mice infected with TK- HSV and treated with dTdR, virus was readily detected (2.8 x 103 PFU per ganglion). This result suggested that in vivo treatment with dTdR enhanced replication of TK- HSV in ganglion neurons. In turn, this suggests that in latently infected ganglia, dTdR-enhanced reactivation of TK- HSV occurred as a result of viral replication in neurons following initial reactivation events.",
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Reactivation of thymidine kinase-defective herpes simplex virus is enhanced by nucleoside. / Tenser, Richard B.; Gaydos, Andrew; Hay, Kathleen A.

In: Journal of virology, Vol. 70, No. 2, 29.01.1996, p. 1271-1276.

Research output: Contribution to journalArticle

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N2 - Herpes simplex virus (HSV) mutants defective for thymidine kinase expression (TK-) have been reported to establish latent infection of sensory ganglia of mice, in that HSV latency-associated transcript is expressed, but to be defective for reactivation. In the present study, the mechanism of defective reactivation by TK- HSV was investigated. Latent infection established by each of three reactivation-defective HSV type 1 mutants was studied. Reactivation in explant culture was markedly enhanced by the addition of thymidine (dTdR) to the explant culture medium. Without added dTdR, reactivation occurred in 0 of 32 ganglia, while when dTdR (200 μM) was present, reactivation occurred in 32 of 37 ganglia (86%). Reactivation was minimal or did not occur after treatment with other nucleosides; specificity for dTdR would suggest the importance of dTdR nucleotide levels rather than more general nucleotide pool imbalance. Enhanced reactivation by dTdR was dose dependent and was blocked by acyclovir. While some degree of inhibition of TK- HSV by acyclovir may he expected, the complete block of dTdR-enhanced reactivation was unexpected. This result may suggest that HSV is particularly vulnerable during initial reactivation events. The mechanism of dTdR-enhanced reactivation of TK- HSV was further evaluated during in vivo infection by TK- HSV. For mice infected with TK- HSV, virus was undetectable in ganglia 3 days later. However, for mice infected with TK- HSV and treated with dTdR, virus was readily detected (2.8 x 103 PFU per ganglion). This result suggested that in vivo treatment with dTdR enhanced replication of TK- HSV in ganglion neurons. In turn, this suggests that in latently infected ganglia, dTdR-enhanced reactivation of TK- HSV occurred as a result of viral replication in neurons following initial reactivation events.

AB - Herpes simplex virus (HSV) mutants defective for thymidine kinase expression (TK-) have been reported to establish latent infection of sensory ganglia of mice, in that HSV latency-associated transcript is expressed, but to be defective for reactivation. In the present study, the mechanism of defective reactivation by TK- HSV was investigated. Latent infection established by each of three reactivation-defective HSV type 1 mutants was studied. Reactivation in explant culture was markedly enhanced by the addition of thymidine (dTdR) to the explant culture medium. Without added dTdR, reactivation occurred in 0 of 32 ganglia, while when dTdR (200 μM) was present, reactivation occurred in 32 of 37 ganglia (86%). Reactivation was minimal or did not occur after treatment with other nucleosides; specificity for dTdR would suggest the importance of dTdR nucleotide levels rather than more general nucleotide pool imbalance. Enhanced reactivation by dTdR was dose dependent and was blocked by acyclovir. While some degree of inhibition of TK- HSV by acyclovir may he expected, the complete block of dTdR-enhanced reactivation was unexpected. This result may suggest that HSV is particularly vulnerable during initial reactivation events. The mechanism of dTdR-enhanced reactivation of TK- HSV was further evaluated during in vivo infection by TK- HSV. For mice infected with TK- HSV, virus was undetectable in ganglia 3 days later. However, for mice infected with TK- HSV and treated with dTdR, virus was readily detected (2.8 x 103 PFU per ganglion). This result suggested that in vivo treatment with dTdR enhanced replication of TK- HSV in ganglion neurons. In turn, this suggests that in latently infected ganglia, dTdR-enhanced reactivation of TK- HSV occurred as a result of viral replication in neurons following initial reactivation events.

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