Herpes simplex virus thymidine kinase expression in infection of the trigeminal ganglion

Tenser, Richard B.; Dunstan, Marie E.

doi:10.1016/0042-6822(79)90021-7

Cited by 150 publications

(94 citation statements)

References 19 publications

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“…A widely accepted hypothesis (14)(15)(16) for the role of tk in these stages of HSV pathogenesis is that tk is required for the establishment of infection of ganglionic neurons. However, it has not been technically possible until recently to distinguish between a requirement for tk during establishment of infection and a requirement at later stages such as reactivation from latency or a requirement during earlier events such as transport of viral DNA to neuronal nuclei (for review, see ref.…”

Section: Infection Of Mammalian Hosts By Herpes Simplex Virus (Hsv)mentioning

confidence: 99%

Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate.

Coen

Kosz-Vnenchak

Jacobson

et al. 1989

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

339

306

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Herpes simplex virus infection of mammalian hosts involves lytic replication at a primary site, such as the cornea, translocation by axonal transport to sensory ganglia and replication, and latent infection at a secondary site, ganglionic neurons. The virus-encoded thymidine kinase, which is a target for antiviral drugs such as acyclovir, is not essential for lytic replication yet evidently is required at the secondary site for replication and some phase of latent infection. To determine the specific stage in viral pathogenesis at which this enzyme is required, we constructed virus deletion mutants that were acyclovir resistant and exhibited no detectable thymidine kinase activity. After corneal inoculation of mice, the mutants replicated to high titers in the eye but were severely impaired for acute replication in trigeminal ganglia and failed to reactivate from ganglia upon cocultivation with permissive cells. Nevertheless, latency-associated transcripts were expressed in neuronal nuclei of ganglia from mutantinfected mice and superinfection of the ganglia with a second virus rescued the latent mutant virus. Thus, contrary to a widely accepted hypothesis, the thymidine kinase-negative mutants established latent infections, implying that neither thymidine kinase activity nor ganglionic replication is necessary for establishment of latency. Rather, thymidine kinase appears to be necessary for reactivation from latency. These results suggest that acyclovir-resistant viruses could establish latent infections in clinical settings and have implications for the use of genetically engineered herpesviruses to deliver foreign genes to neurons.

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Section: Infection Of Mammalian Hosts By Herpes Simplex Virus (Hsv)mentioning

confidence: 99%

Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate.

Coen

Kosz-Vnenchak

Jacobson

et al. 1989

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

339

306

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“…28 % amino acid sequence homology with the VZV dPK, and neither enzyme is essential for virus replication in vitro. These enzymes are, however, important for the activation of certain antiviral drugs (Elion et al, 1977) and may be important in the pathogenesis of infection (Field & Wildy, 1978;Tenser & Dunstan, 1979). The most effective antiviral agent currently available for VZV infections is the guanosine analogue acyclovir, which is phosphorylated preferentially by the VZV dPK.…”

Section: Introductionmentioning

confidence: 99%

“…Since the dPK is not essential for virus replication in tissue culture, this conservation suggests that the VZV dPK gene may be important in aspects of infection in vivo. Studies of animal models of HSV infection suggest that the HSV TK may be involved in neurovirulence and also may be important in the establishment of latency (Field, 1982;Price & Khan, 1981;Tenser & Dunstan, 1979;Tenser & Edris, 1987;Tenser et al, , 1981. The high level of VZV dPK conservation also facilitated the recognition of mutations that were likely to be responsible for the loss of dPK activity in the acyclovir-resistant strains studied, since there were single changes between wt parents and drugresistant mutants derived from them.…”

mentioning

confidence: 99%

Molecular Analysis of the Pyrimidine Deoxyribonucleoside Kinase Gene of Wild-type and Acyclovir-resistant Strains of Varicella-Zoster Virus

Sawyer

Inchauspé

Biron

et al. 1988

Journal of General Virology

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SUMMARYThe pyrimidine deoxyribonucleoside kinase (dPK) genes from five wild-type and four acyclovir-resistant varicella-zoster virus (VZV) strains were studied. One of the acyclovir-resistant strains was isolated from a patient receiving chronic acyclovir therapy. Acyclovir-resistant strains expressed the 1.8 kb VZV dPK transcript but lacked dPK activity. To determine the basis for the lack of enzyme activity the dPK gene from each strain was cloned and its DNA sequence determined. The VZV dPK gene was found to be highly conserved among strains, with greater than 99 % nucleotide and amino acid homology. Each acyclovir-resistant VZV strain differed from its wildtype parent in only a single amino acid. The dPK genes from the acyclovir-resistant strains contained either point mutations near the putative thymidine-binding site of the enzyme or ones that resulted in the premature termination of protein synthesis. Single point mutations were sufficient to render these strains dPK-negative and highly resistant to acyclovir. The molecular basis for acyclovir resistance at the dPK locus of VZV is similar to that previously noted to render herpes simplex viruses resistant to acyclovir.

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“…It is generally accepted that TK-deficient viruses have low neurovirulence (Field & Darby, 1980;Field & Wildy, 1978;Tenser et al, 1981;Sibrack et al, 1982b) and are unable to reactivate from latency (Tenser & Dunstan, 1979;Coen et al, 1989;Efstathiou et al, 1989;Jacobson et al, 1993). Periodically, however, reports have emerged that describe individual TK-deficient isolates which appear to challenge these principles, i.e.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a neurovirulent aciclovir-resistant variant of herpes simplex virus

Grey

Sowa

Collins

et al. 2003

Journal of General Virology

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Herpes simplex virus thymidine kinase expression in infection of the trigeminal ganglion

Cited by 150 publications

References 19 publications

Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate.

Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate.

Molecular Analysis of the Pyrimidine Deoxyribonucleoside Kinase Gene of Wild-type and Acyclovir-resistant Strains of Varicella-Zoster Virus

Characterization of a neurovirulent aciclovir-resistant variant of herpes simplex virus

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