Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.1.21 (thymidine kinase)
7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several enzymatic activities involved in the biosynthetic pathways of nucleotides, including thymidine kinase, which has been used as a biochemical marker in studies of gene transfer, are induced by herpes simplex virus (HSV). The utility of additional markers prompted us to reanalyze the effects of HSV infection on the activities of two other enzymes for which direct selective methods can be devised: dCMP deaminase and CDP reductase. For this purpose, mutant Chinese hamster (lA1) cells devoid of dCMP deaminase activity or Syrian hamster (BHK-21/C13) cells were infected by HSV type 1 or 2, and the activities of thymidine kinase, dCMP deaminase, and CDP reductase were measured in the cell extracts. The reported induction of thymidine kinase and CDP reductase by HSV was confirmed, whereas the stimulation of dCMP deaminase activity could not be observed. For both cell lines, the HSV-induced CDP reductase differed from the host enzyme by sensitivity to inhibition by both dTTP and dATP. This property should be helpful in developing a selection system for this activity.
...
PMID:Aanlysis of dCMP deaminase and CDP reductase levels in hamster cells infected by herpes simplex virus. 20 9

The phosphorylation of arabinofuranosylthymine (araThd) has been studied both in non-infected cells and in those infected with herpes simplex virus (HSV-1, Lennette; HSV-1, IES and HSV-2, D-316). In these experiments, HSV strains were used which either contain (Lennette, TK+ and D-316 TK+) or lack (IES, TK-) the capacity to induce pyrimidine deoxyribonucleoside kinase. It was found that extracellularly administered araThd is phosphorylated to ara TTP via araTMP and araTDP in both non-infected and in HSV-infected cells. The phosphorylating capacity is more than tenfold lower in non-infected cells than in infected cells. Interestingly, cells infected with the TK- strain have a tenfold higher phosphorylating capacity than normal, uninfected cells, a fact which might indicate that host cell deoxythymidine kinase is induced during HSV infection. AraTMP is incorporated into cellular DNA but not into HSV DNA. This finding is in contrast to observations with arabinofuranosyladenine, which is incorporated into both cellular and HSV DNA. In vitro experiments with HSV-induced DNA polymerase show that araTTP strongly inhibits the enzyme activity. Therefore we conclude that the inhibition of HSV DNA polymerase by araTTP (formed intracellularly from araThd) is the explanation for the observed antiviral activity of araThd.
...
PMID:Phosphorylation of arabinofuranosylthymine in non-infected and herpesvirus (TK+ and TK-)-infected cells. 22 22

Herpes simplex virus (HSV) resistant to acyclovir can produce persistent mucocutaneous ulcerative disease in patients with the acquired immunodeficiency syndrome (AIDS). The incidence of clinically significant acyclovir-resistant HSV disease has dramatically increased since the advent of the AIDS epidemic. The primary mechanism of acyclovir resistance is induction of viral mutants defective or deficient in thymidine kinase, the viral-encoded enzyme, which catalyzes the rate-limiting step in the triphosphorylation of acyclovir to its active form (acyclovir triphosphate). Foscarnet, a potent inhibitor of HSV DNA polymerase, does not require phosphorylation for its antiviral activity. This compound has been found to be effective in the treatment of acyclovir-resistant HSV infection by several investigators. A recently completed dose-comparative trial of foscarnet in AIDS patients with acyclovir-resistant HSV has confirmed the safety and efficacy of two doses of foscarnet (40 mg/kg every 8 or 12 hours) in the treatment of this disease, as well as providing preliminary evidence supporting the utility of foscarnet maintenance therapy in delaying recurrence of HSV lesions. Analysis of data from this trial has been complicated by the tremendous variability in lesion size at initiation of therapy, making any statistically valid comparison of treatment regimens almost impossible. A further trial in AIDS patients with acyclovir-resistant HSV infection has been designed to define better the role of foscarnet maintenance and, in light of evidence that a significant proportion of initial recurrences are due to acyclovir-sensitive HSV, to examine the potential utility of acyclovir maintenance following foscarnet induction therapy.
...
PMID:Foscarnet treatment of acyclovir-resistant herpes simplex virus infection in patients with acquired immunodeficiency syndrome: preliminary results of a controlled, randomized, regimen-comparative trial. 153 Dec 85

Resistance to acyclovir in vitro in herpes simplex virus (HSV) isolates has been associated with failure of acyclovir therapy in immunosuppressed patients, and the frequency of reports of clinical resistance in patients with human immunodeficiency virus (HIV) infection is increasing. The primary mechanism of clinical resistance is mutation, producing deficiency in the virus-specified thymidine kinase. A number of case reports and patient series have suggested the efficacy of foscarnet in the treatment of acyclovir-resistant HSV infection in HIV-infected patients. In a recent AIDS Clinical Trials Group study comparing the efficacy of vidarabine and foscarnet in this indication, foscarnet therapy was found to be associated with statistically significant reductions in time to complete healing of lesions, cessation of viral shedding, and 50% reduction in pain, and all patients randomized to receive foscarnet had complete re-epithelialization of lesions. The majority of initial recurrences of herpetic lesions in patients in this study were susceptible to acyclovir; however, all patients ultimately experienced a recurrence due to acyclovir-resistant HSV. A trial comparing acyclovir suppression, foscarnet maintenance therapy, and no chronic antiviral therapy after successful initial treatment of acyclovir-resistant HSV infection would be useful in defining the optimal management of recurrent disease.
...
PMID:Treatment of acyclovir-resistant herpes simplex virus infections in patients with AIDS. 160 61

Using as antigens fusion proteins expressed in bacteria, we have generated polyclonal antisera specific for the herpes simplex virus (HSV) type 1 DNA polymerase. A variety of immunologic, genetic, and biochemical assays were used to characterize these antisera and demonstrate their specificity for the HSV DNA polymerase. Using these antisera, measurements of the synthesis and accumulation of HSV DNA polymerase in infected Vero cells were made. Peak rates of polymerase synthesis were observed at 4 h postinfection, as much as 2 h before peak levels of polymerase mRNA accumulation. At all times examined, the HSV DNA polymerase polypeptide was found to be synthesized at a lower rate per mRNA than the viral thymidine kinase, with this difference being especially dramatic at later times. Infected-cell RNA isolated at 2 and 6 h postinfection directed the synthesis of similar amounts of polymerase polypeptide per polymerase transcript in rabbit reticulocyte lysates, indicating that polymerase transcripts are inherently as translatable at both times. An HSV mutant in which sequences including a short upstream open reading frame in the HSV DNA polymerase transcript were deleted specified polymerase mRNA whose translational efficiency was no more than marginally greater than that of the wild-type virus. These results demonstrate that polymerase expression is regulated by inefficient translation mediated by sequences other than the short upstream open reading frame and that this leads to an early shutoff of polymerase synthesis during HSV infection.
...
PMID:Translational regulation of herpes simplex virus DNA polymerase. 169 12

Herpes simplex virus (HSV) thymidine kinase (TK) expression and the HSV TK gene have been evaluated in studies of gene control, as well as in animal and human studies of viral pathogenesis, including HSV latency. In investigations of the biological role of HSV TK, enzyme expression was noted to be important for HSV infection of nonreplicating cells in culture; and, in experimental animal studies, HSV TK was shown to be important for in vivo latent infection of sensory ganglion neurons. Latency in these studies was determined by the ability of HSV to reactivate from sensory ganglion explants. In recent studies, investigators sought to determine whether the role HSV TK expression plays in latency is primarily in the establishment and maintenance of latency or in the reactivation process. Following infection of experimental animals with HSV TK-deficient mutants, the presence of HSV in ganglia was detected in complementation, rescue, and molecular biological studies. Results suggest that HSV TK expression may be important for HSV reactivation from latency. This was supported by in situ hybridization investigations. In the latter studies, HSV latency associated transcript (LAT) was present in ganglion neurons, although reactivation of HSV from such ganglia was defective. LAT-expressing, reactivation-defective infections established by TK mutants of HSV are considered examples of incomplete latency. From the present review, it appears that HSV TK expression, particularly TK expression of HSV-1, is important for the reactivation of latent HSV infection of sensory ganglion neurons, probably because of limited neuronal TK expression and absent replication capacity of these cells.
...
PMID:Role of herpes simplex virus thymidine kinase expression in viral pathogenesis and latency. 185 Nov 46

Herpes simplex virus (HSV) latency in sensory ganglion neurons is well documented, but the existence of extraneuronal corneal latency is less well defined. To investigate the possibility of extraneuronal latency during ocular HSV infection, corneal specimens from 18 patients with quiescent herpes simplex keratitis (HSK) were obtained at the time of keratoplasty. Polymerase chain reaction (PCR) amplification followed by southern blot hybridization with a radiolabeled oligonucleotide probe was done to detect the presence of HSV-1 genome in these human corneal samples. Two pairs of oligonucleotides from the region of the HSV thymidine kinase (TK) gene and the latency-associated transcript (LAT) gene were used as primers in the PCR amplification. The DNA sequences from either the TK or the LAT gene were identified in 15 of 18 HSK corneas (83%). These results demonstrate that the HSV genome was retained, at least in part, in human corneas during quiescent HSV infection, giving further support to the concept of corneal extraneuronal latency.
...
PMID:Detection of herpes simplex virus thymidine kinase and latency-associated transcript gene sequences in human herpetic corneas by polymerase chain reaction amplification. 185 32

The phosphonylmethoxyalkyl derivative (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) was evaluated for its in vivo efficacy in several model infections for herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) and thymidine kinase-deficient (TK-) HSV-1 in mice. In hairless mice infected intracutaneously with HSV-1 or HSV-2, HPMPC completely suppressed all manifestations of the disease (skin lesions, paralysis of the hind legs, and mortality) if it was administered topically at a concentration of as low as 0.1, 0.3, or 1%. Similarly, HPMPC completely suppressed TK- HSV-1 infection in athymic nude mice if it was administered topically at 0.1 or 0.3% or intraperitoneally at 100 or 250 mg/kg/day. HPMPC was also effective against intraperitoneal HSV infection if it was given orally at a dose of 50 mg/kg/day or higher. In mice inoculated intracerebrally with HSV-2, intraperitoneal HPMPC treatment achieved a significant and dose-dependent protection at doses ranging from 5 to 400 mg/kg/day. The protective effect of HPMPC (at 200 mg/kg/day) was accompanied by a complete inhibition of virus multiplication in the brain. In all models of infections studied, the efficacy of HPMPC proved to be superior to that of acyclovir. The most remarkable feature of HPMPC was that a single administration of the compound, even as late as 4 days after infection, conferred significant protection against HSV-1 or HSV-2 infection. Topical or systemic HPMPC treatment is efficacious in murine models of HSV-1, HSV-2, and TK- HSV infections.
...
PMID:Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine in various models of herpes simplex virus infection in mice. 206 75

Latent reactivateable herpes simplex virus (HSV) infections of sensory neurons of peripheral ganglia are most plausibly the source of clinical herpetic recurrences. The establishment of latency is the result of a concert of both viral and cellular factors such as the neuroinvasiveness of the virus, the relative density of receptors binding virus to the nerve cell plasma membrane, the permissiveness of the infection, including the axonal transport of the viral nucleocapsids, and the restriction of virus replication. Several hypotheses have been presented suggesting various mechanisms for the restriction of the HSV infection of the neuron. Thus, for instance the the importance of thymidine kinase negative mutants, hypermethylation of viral DNA and the existence of latency-associated viral genes have been discussed. Activation of the latent infection to a virus-producing lytic infection by means of superinfection with a replication-incompetent mutant is probably a result of genetic complementation. Reactivation by means of superinfection with replication-competent virus seems dependent upon the multiplicity of the superinfecting virus and more than one copy of the virus genome is required for the initiation of the reactivating process. These observations would be consistent with the overcoming of a cellularly controlled restriction of the latent infection. The cellular control of latency which can be impaired mechanically and chemically seems particularly important for the maintenance of latent HSV infection. However, recent observations indicate that reactivation of latent HSV infection is also associated with the expression of a latency-related viral gene (LAT), whereas establishment of the latency apparently is influenced by other properties determined by the genome of the virus, as well as by the capacity of the cell to restrict the lytic infection.
...
PMID:Biological and molecular aspects on herpes simplex virus latency. 217 37

We compared the levels of gene expression obtained after herpes simplex virus (HSV) superinfection of cell lines containing integrated human beta-interferon (IFN) or chloramphenicol acetyltransferase (CAT) genes under the control of HSV immediate-early (IE) or delayed-early class promoters. DNA-transfected mouse Ltk+ cell lines harboring coselected IE175-IFN or thymidine kinase (TK)-IFN hybrid genes gave only low basal expression of human IFN. However, infection of both cell types with HSV type 1 or HSV type 2 produced abundant synthesis of IFN-specific RNA and biologically active IFN protein product. The IE175-IFN cell lines consistently gave 20- to 150-fold increases in IFN titers, and several TK-IFN cell lines yielded 100- to 500-fold induction. In the IE175-IFN cells, expression of IFN RNA also increased up to 200-fold and was detectable within 30 to 60 min after virus infection. Qualitatively similar results were obtained with hybrid G418-resistant Ltk- or Vero cell lines containing coselected IE175-CAT and TK-CAT constructs, except that there was relatively high basal expression of IE175-CAT. All three sets of IE cell lines (but not the delayed-early cell lines) responded to virus infection both in the presence of cycloheximide and with mutants defective in IE gene expression, demonstrating specific trans-activation by the pre-IE virion factor. In contrast, activation in the TK hybrid cell types required viral gene expression and the presence of a functional IE175 gene product. Up to 30-fold amplification in the copy number of the resident IFN or CAT DNA sequences also occurred within 20 h after HSV infection in IE175 hybrid cells but not in TK hybrid cells. Amplification was abolished either by treatment with phosphonacetate or by superinfection with a ts mutant unable to synthesize viral DNA, demonstrating specific HSV activation of the viral DNA replication origin (oriS) present in the IE hybrid constructs.
...
PMID:Differential activation of hybrid genes containing herpes simplex virus immediate-early or delayed-early promoters after superinfection of stable DNA-transfected cell lines. 241 16


1 2 3 4 Next >>

---