Disease relevance of ORF36

• The HVS reading frames identified by this method included homologs of the major capsid polypeptides, glycoprotein H, the major nonstructural DNA-binding protein, thymidine kinase, and the homolog of the regulatory gene product of the BMLF1 reading frame of EBV [1].
• Plaque reduction assays demonstrate that the SVV TK is active based on the susceptibility of SVV to acyclovir treatment and that SVV is less sensitive to acyclovir than VZV and herpes simplex virus (HSV-1) in infected Vero cells [2].
• Identification and analysis of the simian varicella virus thymidine kinase gene [2].
• The thymidine kinase (TK) of herpesviruses, in contrast to cellular TKs, phosphorylates a variety of substrates including antiherpetic nucleoside analogues [2].
• A similar reversion rate was observed using the Varicella-zoster virus TK gene [3].

High impact information on ORF36

• To this end we have targeted a construct containing a Herpes simplex virus thymidine kinase (TK) gene into the ribosomal DNA array of procyclic T. brucei [3].
• TK+ trypanosomes, however, reverted to a ganciclovir resistant phenotype at a rate of 10(-6) per cell-generation [3].
• Loss of TK activity was not due to detectable DNA rearrangements or a decrease in TK mRNA [3].
• The viral thymidine kinase gene as a tool for the study of mutagenesis in Trypanosoma brucei [3].
• This selectivity is due to the ability of these viruses to code for a viral thymidine kinase capable of phosphorylating acyclovir to a monophosphate; this capability is essentially absent in uninfected cells [4].

Chemical compound and disease context of ORF36

• METHODS: To study the potential involvement of mitochondria in the ganciclovir nucleotide cytotoxicity, we used adenovirus-mediated gene transfer to express herpes simplex virus thymidine kinase in rat liver and administered ganciclovir 2 days post-infection [5].
• BRL 39123 was inactive against an HSV-1 strain which does not express thymidine kinase activity, but a DNA polymerase mutant selected for resistance to ACV was sensitive to BRL 39123 (IC50, 1.5 micrograms/ml) [6].
• A transient assay system was used to identify varicella-zoster virus (VZV)-encoded genes whose products are able to activate the expression of an early gene promoter, the thymidine kinase (tk) promoter, and a late gene promoter, and the glycoprotein I (gpI) promoter [7].
• Thymidine plaque autoradiography of thymidine kinase-positive and thymidine kinase-negative herpesviruses [8].
• Inactivity of the bicyclic pyrimidine nucleoside analogues against simian varicella virus (SVV) does not correlate with their substrate activity for SVV-encoded thymidine kinase [9].

Biological context of ORF36

• The complete nucleotide sequence of the BglII "m" fragment revealed two large open reading frames in addition to the thymidine kinase gene [10].
• The open reading frame lying immediately 3' of the thymidine kinase gene has a predicted translation product with the features of a large glycoprotein [10].
• Identification of the 5' end of the SVV TK transcript by primer extension analysis allowed a comparison of the SVV and VZV TK promoter regions indicating extensive conservation of the DNA sequence and transcription factor binding sites [2].
• The specific phosphorylation by the HSV- and VZV-induced TK also explains the marked cytostatic activity of BVDU against tumor cells that have been transduced by the viral TK genes [11].
• We constructed plasmids with mutations in ORF61 and tested them for their ability to inhibit trans-activator (VZV genes 4 and 62)-mediated activation of the viral thymidine kinase promoter-chloramphenicol acetyltransferase construct [12].

Anatomical context of ORF36

• Noninfected and varicella-zoster virus (VZV)-infected human foreskin fibroblasts were examined for thymidine kinase activity [13].
• The 5-iodo compound (2, CC(50) 25 +/- 7 microM) was more efficient than ganciclovir (GCV, CC(50) 75 +/- 35 microM) in inhibiting growth of HSV1-TK transfected cells and less inhibitory than GCV toward TK(-) cells, whereas compound 3 inhibited transfected and nontransfected cell lines in a relatively similar dose-dependent manner [14].
• The COS 1 cells expressing VZV TK were shown to be susceptible to all compounds tested [15].
• Ganciclovir nucleotides accumulate in mitochondria of rat liver cells expressing the herpes simplex virus thymidine kinase gene [5].
• Clinical and angiographic follow-up, and serial thymidine kinase activity levels in the cerebrospinal fluid suggested a self-limiting course of the virus-induced vasculopathy [16].

Associations of ORF36 with chemical compounds

• This resulted in TK activity 30-50-fold above background and in susceptibility to the nucleoside analogues ganciclovir, ethyl-deoxyuridine and 1-[2-deoxy,2-fluoro-8-D-arabinofuranosyl]-5-iodouracil, all of which have no effect on wild-type trypanosomes [3].
• These enzymes were presumed to be thymidine kinase, deoxycytidine kinase, and uridine kinase [13].
• ACV, PCV, and BVDU protected the epithelium against cytopathic effect induced by wild-type viruses in a concentration-dependent manner, while treatment with CDV and PFA proved protective against the cytodestructive effects induced by both TK+ and TK- strains [17].
• Acyclovir-resistant VZV isolates were deficient in thymidine kinase (TK) or induced a TK with altered substrate specificity; all isolates were susceptible to foscarnet [18].
• It belongs to a class of purine arabinosides whose anti-VZV activity in vitro correlates with substrate utilization by the VZV-encoded thymidine kinase (TK) (D. R. Averett, G. W. Koszalka, J. A. Fyfe, G. B. Roberts, D. J. M. Purifoy, and T. A. Krenitsky, Antimicrob Agents Chemother. 35:851-857, 1991) [19].

Analytical, diagnostic and therapeutic context of ORF36

• The three compounds were also tested in vitro as prodrugs used in a gene therapy context on three osteosarcoma cell lines, either deficient in TK (TK(-)), nontransduced, or stably transduced with HSV1 TK [14].
• Ganciclovir is widely applied for anti-herpetic treatment, cytomegalovirus prophylaxis after organ transplantation, and, more recently, in experimental gene therapy to eradicate cycling cells that express the herpes simplex virus thymidine kinase gene [5].
• Autoradiography indicated that TK- virus retained the TK- phenotype after replication in vivo [8].
• Latency of a thymidine kinase-negative pseudorabies vaccine virus detected by the polymerase chain reaction [20].
• In addition, immunoprecipitation of truncated proteins synthesized in vitro suggested the possible involvement of the region between amino acid residues 101 and 168 from the amino terminus of the VZV TK molecule in the formation of structures necessary for antigenicity [21].

References