Disease relevance of UL30

• The herpes simplex virus-1 DNA polymerase is a heterodimer of Mr 190,000 which consists of the products of the UL30 (Pol) and UL42 genes [1].
• Although one man was HBeAg positive on the first occasion, both men were considered of low infectivity, being anti-HBe positive, negative for serum DNA polymerase activity, and negative for serum hepatitis B virus (HBV) DNA when their second partners presented with fulminant hepatitis B [2].
• Loss of DNA polymerase, the hepatitis B e antigen, and the serum hepatitis B virus DNA was similar in all three groups [3].
• Progressive esophagitis from acyclovir-resistant herpes simplex. Clinical roles for DNA polymerase mutants and viral heterogeneity [4]?
• The ts6 mutation and the 2'ndgR-1 mutation within the viral DNA polymerase locus have been physically mapped by marker rescue and generation of HSV-1/HSV-2 intertypic recombinants [5].

High impact information on UL30

• Herpes simplex virus infections are the cause of significant morbidity, and currently used therapeutics are largely based on modified nucleoside analogs that inhibit viral DNA polymerase function [6].
• There was a rise in DNA polymerase activity and HBsAg titer with a fall in serum aspartate aminotransferase values during treatment [7].
• Upon discontinuing therapy, DNa polymerase activity fell dramatically in all 3 patients who completed their course of prednisone and became undetectable in 1 [7].
• The 3.3-kbp BamHI fragment containing most of the DNA polymerase gene from isolate 615.8 was purified and used to successfully transfer both acyclovir and foscarnet resistance [4].
• Acquisition of in-vitro acyclovir resistance was associated with progression of clinical disease, as well as with maintenance of pathogenicity in an animal model and at least one mutation in viral DNA polymerase [4].

Chemical compound and disease context of UL30

• Acyclovir-resistant herpes simplex virus infection due to altered DNA polymerase [8].
• In the 7 hepatitis B e antigen-positive patients, adenine arabinoside produced a fall in DNA polymerase activity during treatment [9].
• Resistance to 2'NDG by HSV-2 ts6 can be overcome in the presence of combinations of 2'NDG and phosphonoacetic acid, indicating drug synergism within the viral DNA polymerase locus [5].
• A herpes simplex virus type 2 (HSV-2) mutant TS6 (strain HG52) induces a heat-labile viral DNA polymerase at the nonpermissive temperature and is markedly resistant to 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-guanine [2'-nor-2'-deoxyguanosine; 2'NDG] [5].
• Mutations in hepatitis B DNA polymerase associated with resistance to lamivudine do not confer resistance to adefovir in vitro [10].

Biological context of UL30

• These data suggest that many patients with chronic type B hepatitis eventually have a spontaneous remission in clinical and biochemical evidence of active disease, usually heralded or accompanied by the disappearance of HBeAg and DNA polymerase [11].
• The oris binding protein, detectable only in nuclear extracts of infected cells, shows the same time course of appearance as the herpesvirus-induced DNA polymerase and the DNA binding protein ICP8 [12].
• The effects of mutations on enzyme kinetics could be explained by using a model of an alpha-like DNA polymerase active site bound to primer/template and inhibitor [13].
• The plasmid containing Xba I F can be replaced by two smaller plasmids, one of which contains only the gene for the HSV-encoded DNA polymerase, and the other of which contains only the gene for the major DNA binding protein (ICP8) [14].
• Resistance of herpes simplex virus to 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine: physical mapping of drug synergism within the viral DNA polymerase locus [5].

Anatomical context of UL30

• The mutated protein was as active as wildtype (wt) UL30 in a DNA polymerase assay in which activated calf thymus DNA was used as template [15].
• Processive DNA replication by the DNA polymerase isolated from HSV-1-infected Vero cells or the recombinant DNA polymerase-UL42 protein complex requires that the single-stranded DNA be coated with saturating levels of ICP8 [16].
• Recently it was found that some of them also have effects on proliferating eukaryotic cells (Neftel, K.A. and Hübscher, U. (1987) Antimicrob. Agents Chemother. 31, 1657-1661), and one such effect was shown to be the inhibition of DNA polymerase alpha (Huynh Do,U., Neftel, K.A., Spadari, S. and Hübscher, U. (1987) Nucl. Acids Res. 15, 10495-10506) [17].
• An inhibitor of viral TK or an inhibitor of viral DNA polymerase greatly decreased viral lytic gene expression in trigeminal ganglion tissue latently infected with wild-type virus and explanted in culture [18].
• In addition, this compound shows significant inhibition of DNA synthesis in isolated nuclei obtained from adenovirus-infected or uninfected cells and is a potent inhibitor of HeLa cell DNA polymerase alpha [19].

Associations of UL30 with chemical compounds

• This replication occurred most actively late after infection and could be shown to be inhibited by low concentrations of phosphonoacetate known to inhibit the HSV-specified viral DNA polymerase selectively [20].
• In vitro, ACV triphosphate inhibits herpesvirus DNA polymerase by means of binding, incorporation into primer/template, and dead-end complex formation in the presence of the next deoxynucleoside triphosphate [13].
• In summary, phosphorothioate oligonucleotides could be anti-template inhibitors of HSV DNA polymerase [21].
• Thus, the inhibition of HSV DNA polymerase by PMEApp appears to involve chain termination after its incorporation into DNA [22].
• The anti-HSV-2 DNA polymerase activity was related to the base composition of the analogs, with the order of potency: deoxycytidine greater than thymidine greater than deoxyadenosine, for compounds with equal chain length [21].

Other interactions of UL30

• Resistance of herpes simplex virus to acycloguanosine: role of viral thymidine kinase and DNA polymerase loci [23].
• Comparing the transcription mapping with marker rescue data suggests that the genes for glycoprotein B, DNA-binding protein, DNA polymerase, and nucleocapsid protein p40 are expressed as 3.3-, 4.2-, 4.3- or 4.2- or both, and 2.4-kilobase mRNAs, respectively [24].

Analytical, diagnostic and therapeutic context of UL30

• The 28-mer phosphorothioate oligodeoxycytidine (S-(dC)28) has been reported previously to be a strong inhibitor of herpes simplex virus type 2 (HSV-2) DNA polymerase and HSV-2 growth in cell culture [25].
• Thus, DEAE-cellulose and phosphocellulose chromatography were used in combination with affinity chromatography to purify DNA polymerase from herpes simplex virus type 1- and type 2-infected cells [26].
• Consistent with the Northern blot analysis, no RNA specific for the early DNA polymerase gene or the late gC gene was detected by in situ hybridization nor could the polypeptide for the gC gene be seen by immunofluorescence [27].
• Fine mapping and molecular cloning of mutations in the herpes simplex virus DNA polymerase locus [28].
• We used indirect immunofluorescence to examine the factors determining the intranuclear location of herpes simplex virus (HSV) DNA polymerase (Pol) in infected cells [29].

References