2003
DOI: 10.1128/jvi.77.8.4703-4709.2003
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Translational Compensation of a Frameshift Mutation Affecting Herpes Simplex Virus Thymidine Kinase Is Sufficient To Permit Reactivation from Latency

Abstract: Herpes simplex virus thymidine kinase is important for reactivation of virus from its latent state and is a target for the antiviral drug acyclovir. Most acyclovir-resistant isolates have mutations in the thymidine kinase gene; however, how these mutations confer clinically relevant resistance is unclear. Reactivation from explanted mouse ganglia was previously observed with a patient-derived drug-resistant isolate carrying a single guanine insertion within a run of guanines in the thymidine kinase gene. Despi… Show more

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Cited by 40 publications
(72 citation statements)
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“…Nevertheless, there is considerable evidence that much of the TK activity of G8 mutants is a result of ribosomal frameshifting (12,16,20). Plaque autoradiography provides no evidence for reversion of G8 mutants in cell culture (14,17). Full-length TK expression has been observed in G8 mutant-infected cells and has been recapitulated in an in vitro rabbit reticulocyte lysate translation system, where it was shown to be due to translational rather than other mechanisms (20).…”
mentioning
confidence: 93%
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“…Nevertheless, there is considerable evidence that much of the TK activity of G8 mutants is a result of ribosomal frameshifting (12,16,20). Plaque autoradiography provides no evidence for reversion of G8 mutants in cell culture (14,17). Full-length TK expression has been observed in G8 mutant-infected cells and has been recapitulated in an in vitro rabbit reticulocyte lysate translation system, where it was shown to be due to translational rather than other mechanisms (20).…”
mentioning
confidence: 93%
“…Plaque autoradiography was performed by modifying a previously described protocol (14). The modifications were that the dishes were seeded with 4 ϫ 10 5 143B cells 24 h prior to addition of an inoculum of 200 PFU of virus/dish and that radiolabeling was carried out for 20 h in the presence of 5 Ci/ml of [ 3 H]thymidine.…”
Section: Cells and Virusesmentioning
confidence: 99%
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“…In fact, the site of insertion was a guanine-rich sequence in the mRNA suitable as a frameshifting signal, resulting in realignment of the reading frame (50) and production of normal TK protein at 1-2% of wild-type translation (49). These levels were sufficient for HSV reactivation from latency but not high enough for virus susceptibility to acyclovir treatment (51,52). Taking advantage of this system, a model conventional influenza nucleoprotein epitope in tandem with the OVA SIINFEKL peptide was engineered downstream of the TK element (48).…”
Section: Molecular Mechanisms Involved In Translational Frameshiftingmentioning
confidence: 99%