Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The virological, clinical and electrophysiological manifestations of acute and experimentally reactivated infections of the rabbit central nervous system (CNS) and trigeminal ganglia have been studied after intranasal infection with herpes simplex virus type 1 (strain KOS-63). All animals shed virus in nasal secretions during the acute phase of infection. Although no rabbits developed clinical signs during the acute phase of infection, mild electroencephalographic (EEG) abnormalities consistent with viral invasion of the CNS were seen. KOS-63 produced only occasional gross and histopathologic herpetic lesions of the CNS and was very rarely recovered from the brain. These results indicate that KOS-63 was poorly neuroinvasive and only mildly neurovirulent during the acute phase of infection. However, KOS-63 did establish latency within the CNS and trigeminal ganglia of infected rabbits as demonstrated by in situ hybridization and by recovery of virus from co-cultivation cultures, but not from cell-free homogenates of nervous tissue. Cyclophosphamide and dexamethasone injections were used to reactivate latent CNS and trigeminal ganglionic infections. Following injection of the drugs, no animal shed virus in nasal secretions or developed obvious clinical or EEG changes. However, KOS-63 was recovered from co-cultivation cultures of brain and trigeminal ganglia at greater frequency following drug injection than during latency. These results indicate that KOS-63 was only poorly susceptible to drug-induced reactivation. In vivo experiments confirmed that the apparent poor neuroinvasiveness and weak neurovirulence of KOS-63 was not due to viral temperature-sensitive defects, deficient production of viral thymidine kinase, or abnormal defects in viral DNA polymerase function.
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PMID:The weakly virulent herpes simplex virus type 1 strain KOS-63 establishes peripheral and central nervous system latency following intranasal infection of rabbits, but poorly reactivates in vivo. 132 37

We used a model involving acute and latent herpes simplex virus (HSV) infections of mouse superior cervical ganglia to assess in vivo neuronal infections with two thymidine kinase-deficient (TK-) mutants of HSV type 1. Despite replication of the TK- HSV strains at the site of inoculation in the eyes, little if any viral replication occurred in the superior cervical ganglia, as assessed by the viral titers of ganglion homogenates, viral antigens in tissue sections, and histopathological evidence of cytopathology or inflammation. Cyclophosphamide-induced immunosuppression and treatment with 6-hydroxydopamine, which enhanced productive infections of superior cervical ganglia with TK+ HSV did not induce TK- HSV ganglionic infections. Latent TK- HSV infections were not detected by cocultivation of ganglion explants. Efforts to infect ganglia in culture after they were removed from animals indicated that superior cervical ganglia, and particularly their neuronal elements, resisted productive TK- HSV infection. These results supported the hypothesis that viral thymidine kinase facilitates acute and reactivated productive HSV infections of neurons.
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PMID:Resistance of peripheral autonomic neurons to in vivo productive infection by herpes simplex virus mutants deficient in thymidine kinase activity. 627 21

The goal of this work was to identify potential host immune responses to thymidine kinase (TK) suicide gene-modified tumors undergoing chemoablation induced by the prodrug ganciclovir (GCV). The aims were to measure the efficacy and specificity of immunity induced against unmodified tumor, to identify qualitative or quantitative changes in the host response to TK+ tumors undergoing chemoablation that may contribute to the induction of antitumor immunity, and to compare critically the induction of immunity by chemoablation of TK-modified tumors with that of other methods of immunization in this tumor model and in response to other well-defined model antigens. Animals treated with TK+ tumors and GCV developed specific resistance to rechallenge with unmodified tumor. GCV induced significant tumor necrosis, which was associated with a pronounced host cell infiltrate composed of polymorphonuclear cells, both CD4+ and CD8+ T lymphocytes, and increased intratumoral IL-12. Cyclophosphamide-treated mice exhibited no such host response despite the induction of tumor necrosis. CTL responses to defined antigens in TK+ cells were greater in animals treated with prodrug than were those in animals not treated with prodrug but harboring live TK+ cells. Similar degrees of immunity were produced by immunization with irradiated cells.
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PMID:Ganciclovir chemoablation of herpes thymidine kinase suicide gene-modified tumors produces tumor necrosis and induces systemic immune responses. 975 29