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)

Resistance of herpes simplex virus to acyclovir is a problem of growing clinical importance. Acyclovir-resistance can be due either to mutations in the viral thymidine kinase gene or in the viral DNA polymerase gene. Although clinical resistance has most frequently been associated with thymidine kinase alterations, heterogeneity in clinical isolates has not been addressed frequently. The potential for such heterogeneity has been emphasized by a report describing a pathogenic clinical isolate containing within its population at least one thymidine kinase-proficient DNA polymerase mutant as well as mutants exhibiting thymidine kinase-deficiency (Sacks, et al., 1989). We provide here additional characterization of this isolate and speculations regarding its significance.
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PMID:Heterogeneity of a herpes simplex virus clinical isolate exhibiting resistance to acyclovir and foscarnet. 132 2

Acyclovir (ACV)-resistant herpes simplex virus type 2 (HSV-2) was isolated from a patient with acquired immunodeficiency syndrome after long-term but intermittent ACV therapy. These thymidine kinase-defective isolates were sensitive in vitro to foscarnet. While combined therapy with ACV and interferon produced only partial clinical improvement, the in vitro effect of this combination against an ACV-resistant isolate from the patient was strongly synergistic. A short course (10-12 days) of intravenous foscarnet controlled severe ulceration, and clinical improvement lasted 6 months. After recurrence and further courses of foscarnet, however, the patient responded poorly, and subsequent HSV isolates were resistant to both ACV and foscarnet and hypersensitive to aphidicolin.
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PMID:Altered sensitivity to antiviral drugs of herpes simplex virus isolates from a patient with the acquired immunodeficiency syndrome. 216 40

Four patients with human immunodeficiency virus (HIV) infection who received chronic oral acyclovir therapy for suppression of recurrent varicella zoster or herpes simplex virus infection developed persistent disseminated hyperkeratotic papules that failed to heal with intravenous or high-dose oral acyclovir therapy. Varicella zoster virus, resistant to acyclovir in vitro, was isolated from skin lesions of all four patients. Three patients were adults in whom the acquired immunodeficiency syndrome (AIDS) had been diagnosed 12 to 20 months before isolation of acyclovir-resistant varicella zoster virus. The fourth patient was a perinatally HIV-infected child who developed primary varicella infection at age 7 years when profoundly immunosuppressed (absolute CD4+ lymphocyte count less than 50 cells/microL). Mean antiviral susceptibilities (ED50 values) of the four clinical isolates compared with the ED50 values of the reference strain Oka were 85 compared with 3.3 mumol/L for acyclovir, 1.4 compared with 0.8 mumol/L for vidarabine, and 123 compared with 117 mumol/L for foscarnet. When assayed by [125I]-dC plaque autoradiography, 90% to 100% of the viral isolate populations had altered or no measurable thymidine kinase function. Acyclovir-resistant varicella zoster virus infection may complicate long-term oral acyclovir administration in patients with AIDS and may be associated with the appearance of atypical hyperkeratotic papules.
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PMID:Acyclovir-resistant varicella zoster virus infection after chronic oral acyclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS). 229 95

Infections caused by herpes simplex virus (HSV) are a significant source of morbidity in immunocompromised patients. Acyclovir is often used prophylactically and therapeutically in patients with human immunodeficiency virus infection. The emergence of acyclovir-resistant strains of HSV capable of causing disease has been recognized. We report a case in which a thymidine kinase-deficient mutant of HSV caused extensive disease in a patient with AIDS. This case emphasizes that virus recovered from nonhealing lesions should be submitted for further study, which may advance our understanding of the interaction between host defense and drug-resistant strains.
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PMID:Mucocutaneous dissemination of acyclovir-resistant herpes simplex virus in a patient with AIDS. 254 44

A series of clinical isolates of herpes simplex virus type 2 were taken from a patient with chronic lymphocytic leukemia. Acyclovir (ACV) susceptibility assays revealed that some isolates were resistant to ACV and cross-resistant to ganciclovir but not to phosphonoacetic acid. The nature of the resistance was examined further. A number of cloned variants were generated, and thymidine kinase and DNA polymerase assays were carried out. Variants that were resistant to ACV were found to be thymidine kinase deficient. Evidence for alteration in the DNA polymerase was not found when ACV triphosphate or phosphonoacetic acid was used as the inhibitor. In vivo studies with the plaque-purified viruses showed that ACV resistance was associated with a reduced neurovirulence. In a zosteriform model, virus resistant to ACV was unable to induce secondary spread in the same dermatome, to invade the peripheral nervous system or the central nervous system, or to establish latent infections.
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PMID:Biological and biochemical characterization of clinical isolates of herpes simplex virus type 2 resistant to acyclovir. 254 86

Acyclovir (9-/2-hydroxyethoxymethyl/guanine) enhanced the plaque formation of HSV and VZV at subinhibitory dose and inhibited at higher concentration but not in thymidine kinase deficient viruses. The enhancement was neutralized by thymidine. Induction of viral thymidine kinase activity was not affected with ACV. These results suggest that the enhancement may be mediated by viral thymidine kinase.
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PMID:Enhancement of plaque formation of herpes simplex virus (HSV) and varicella-zoster virus (VZV) by subinhibitory dose of acyclovir (ACV). 257 98

Acyclovir (aciclovir) is a nucleoside antiviral drug with antiviral activity in vitro against members of the herpes group of DNA viruses. As an established treatment of herpes simplex infection, intravenous, oral and to a lesser extent topical formulations of acyclovir provide significant therapeutic benefit in genital herpes simplex and recurrent orofacial herpes simplex. The effect of acyclovir therapy is maximised by early initiation of treatment, especially in non-primary infection which tends to have a less protracted course than the primary episode. Long term prophylactic oral acyclovir, in patients with frequent episodes of genital herpes simplex, totally suppresses recurrences in the majority of subjects; as with other infections responding to acyclovir, viral latency is not eradicated and pretreatment frequencies of recurrence return after discontinuation of treatment. Caution should accompany the prophylactic use of acyclovir in the general population, due to the theoretical risk of the emergence of viral strains resistant to acyclovir and other agents whose mechanism of action is dependent on viral thymidine kinase. Intravenous acyclovir is the treatment of choice in biopsy-proven herpes simplex encephalitis in adults, and has also been successful in the treatment of disseminated herpes simplex in pregnancy and herpes neonatorium. Intravenous and oral acyclovir protect against dissemination and progression of varicella zoster virus infection, but do not protect against post-herpetic neuralgia. In immunocompromised patients, intravenous, oral and topical acyclovir shorten the clinical course of herpes simplex infections while prophylaxis with oral or intravenous dosage forms suppresses reactivation of infection during the period of drug administration. Ophthalmic application of 3% acyclovir ointment rapidly heals herpetic dendritic corneal ulcers and superficial herpetic keratitis. Thus, despite an inability to eradicate latent virus, acyclovir administered in therapeutic or prophylactic fashion is now the standard antiviral therapy in several manifestations of herpes simplex virus infection, and indeed represents a major advance in this regard. With the exception of varicella zoster virus infections, early optimism concerning the use of the drug in diseases due to other herpes viruses has generally not been supported in clinical investigations.
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PMID:Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. 265 90

In a mature newborn the symptoms of a disseminated HSV infection were evident at the 6th day of life. Later on bleeding occurred as a result of severe consumption coagulopathy. During treatment with Acyclovir the bleeding situation was controlled by fibrinogen replacement. The infant survived and is under normal psychologic and motorical development now. The treatment result is taken for the good virostatic efficacy of Acyclovir. It inhibits the DNA polymerases and therefore the DNA replication within the herpes viruses selectively. This high degree of selectivity is caused by its selective penetration into the infected cells, its faster transformation by the viral thymidine kinase as well as by its stronger affinity for HSV coded polymerase in detail. The diagnosis had been confirmed by detection of herpes viruses within the blister fluid and cerebrospinal fluid as well as by serological findings.
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PMID:[Generalized herpesvirus infection with severe consumption coagulopathy in a newborn infant]. 270 90

A screening program for antiviral drugs begun at Burroughs Wellcome in the 1960s resulted in the discovery of acyclovir in 1974. Preclinical investigation brought the drug to clinical trials in 1977 and the first form of the drug (topical) was available to physicians in 1982. Activity of acyclovir is greatest against herpes 1 and herpes 2, less against varicella zoster, still less against Epstein-Barr, and very little against cytomegalovirus. Acyclovir is an antiviral agent only after it is phosphorylated in infected cells by a viral-induced thymidine kinase. Acyclovir monophosphate is phosphorylated to diphosphate and triphosphate forms by cellular enzymes in the infected host cell where the drug is concentrated. Acyclovir triphosphate inactivates viral deoxyribonucleic acid polymerase. Acyclovir incorporation into the growing viral deoxyribonucleic acid chain causes its termination. The antiviral process has relatively little effect on normal, uninfected cells. An important toxic effect of acyclovir is its potential to cause obstructive nephropathy. The drug is excreted primarily by the kidney, which may require smaller doses in patients with decreased kidney function. Oral dosages of acyclovir as recommended for herpes simplex are probably not adequate for varicella zoster infections.
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PMID:History, pharmacokinetics, and pharmacology of acyclovir. 282 40

Rat cytomegalovirus (RCMV) induces a cytosol thymidine kinase (TK) in G0-phase rat embryo fibroblasts (REF), but not in a TK deficient rat cell line (R-2), though virus titers in both cell types reached comparable levels. The results indicate that TK is neither virus-coded nor is required for a productive infection in R-2 cells. A deoxycytidine kinase (dCK) is induced in either growing or RCMV-infected REF and R-2 cells, suggesting that dCK is essential for both host-cell and viral DNA synthesis. A deoxyguanosine kinase (dGK) is detectable in low concentrations in either growing or G0-phase REF and R-2 cells suggesting that this enzyme is cell-cycle independent. In contrast, RCMV induces high persisting levels of dGK, particularly in R-2 cells, indicating that this enzyme is of crucial importance for viral DNA synthesis. By comparison of thermostabilities and electrophoretic mobilities (Rf for TK, dCK and dGK were 0.12; 0.97; and 0.54, respectively) the enzymes were found to be substrate specific but of cellular origin. In contrast to TK and dCK, only dGK is inhibited by Acyclovir (Ki = 320 microM). It is suggested that RCMV inducable dGK is an important enzyme determining the in vitro anti-CMV activity of Acyclovir.
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PMID:Rat cytomegalovirus induces cellular purine and pyrimidine nucleoside kinases in rat embryo fibroblasts and TK- rat-2 cells. Correlations with the antiviral activity of Acyclovir. 298 53


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