Disease relevance of UL23

• We also report that, in mice and rabbits in vivo, the compound is effective against both local and systemic infections with herpes simplex virus type 1, including herpetic keratitis caused by a TK- mutant which is resistant to the classical anti-herpes drugs [1].
• CONCLUSION: Foscarnet may be an effective treatment for severe mucocutaneous disease due to acyclovir-resistant, TK-negative strains of HSV-2 [2].
• Chicken ovalbumin gene fused to a herpes simplex virus alpha promoter and linked to a thymidine kinase gene is regulated like a viral gene [3].
• For suicide gene therapy, VP22 activity was demonstrated under hypoxia by coupling VP22 to the HSV thymidine kinase (HSVtk) [4].
• (iii) HSV-1(HFEM)tsB7 induced the alpha-TK gene chimeras at the nonpermissive (39 degrees C) temperature; at 39 degrees C the parental HSV-1(HFEM)tsB7 capsids accumulate at nuclear pores and do not release viral DNA [5].

High impact information on UL23

• PATIENTS: Four patients with AIDS who developed progressive ulcerative mucocutaneous lesions of the genitals, perineum, perianal region, or finger due to acyclovir-resistant, thymidine-kinase (TK)-negative strains of HSV-2 [2].
• In addition to secondary lymphoid tissue and bone marrow, HSV-specific plasma cells were detected in spinal cords of mice up to 10 months after intravaginal inoculation with a thymidine kinase-deficient HSV-2 strain and in lumbosacral ganglia and spinal cords of guinea pigs inoculated with HSV-2 strain MS [6].
• Cloned HSV DNA fragments derived from various parts of the genome were cotransfected into BHK cells together with chimaeric plasmids which contained the thymidine kinase gene under IE control [7].
• In cells converted from TK- to TK+ phenotype, these chimeric genes are induced by infection with homologous TK- virus [5].
• Nucleotide sequence of the herpes simplex virus type 2 thymidine kinase gene [8].

Chemical compound and disease context of UL23

• Moreover, two of the most potent TK-2 inhibitors (18 and 26b) that also inhibit HSV-1 TK were able to reverse the cytostatic activity of 1-(beta-D-arabinofuranosyl)thymine (Ara-T) and ganciclovir in HSV-1 TK-expressing OST-TK-/HSV-1 TK+ cell cultures [9].
• 5'-Ethynylthymidine was less inhibitory against herpes simplex virus type 2 (strain 333)-induced thymidine kinase with a Ki of 0.38 microM and showed no inhibition against human cytosolic thymidine kinase under the conditions tested [10].
• Novel N1-substituted thymine derivatives related to 1-[(Z)-4-(triphenylmethoxy)-2-butenyl]thymine have been synthesized and evaluated against thymidine kinase-2 (TK-2) and related nucleoside kinases [i.e., Drosophila melanogaster deoxynucleoside kinase (Dm-dNK) and herpes simplex virus type 1 thymidine kinase (HSV-1 TK)] [9].
• Phosphorylation of four acyclic guanosine analogs by herpes simplex virus type 2 thymidine kinase [11].
• Four acyclic guanosine analogs, the (R) and (S) enantiomers of 9-(3,4-dihydroxybutyl)guanine, 9-(4-hydroxybutyl)guanine, and acyclovir were compared in enzyme kinetic experiments, using purified herpes simplex virus type 2 thymidine kinase [11].

Biological context of UL23

• (Cell 24:555-565, 1981) have shown that chimeric genes constructed by fusion of 5' noncoding leader and upstream sequences of alpha genes to the 5' noncoding leader and structural sequences of the viral thymidine kinase (TK), a beta gene, are regulated as alpha genes upon recombination into the viral genome [5].
• Sites of integration of herpes simplex virus type-2 thymidine kinase gene in human chromosomes [12].
• Compounds with a hexamethylene spacer (18, 26b, 31) displayed the highest inhibitory values against TK-2 (IC50 = 0.3-0.5 microM) [9].
• Contributions of thymidine kinase (TK) mutations to acyclovir (ACV) resistance were evaluated in herpes simplex virus type 1 recombinant viruses generated using a set of overlapping cosmids and plasmids [13].
• A recurrent isolate was resistant to acyclovir and lacked thymidine kinase activity on the basis of a frameshift mutation in the thymidine kinase (tk) gene [14].

Anatomical context of UL23

• A murine model of genital infection with a thymidine kinase-deficient (tk-) strain of herpes simplex virus type 2 (HSV-2) was utilized to examine the development of the local T cell response in the genital mucosa and draining genital lymph nodes (gLN) [15].
• Intranasal herpes simplex virus type 2 inoculation causes a profound thymidine kinase dependent cerebral inflammatory response in the mouse hindbrain [16].
• Following primary inoculation with attenuated thymidine kinase-deficient (TK(-)) HSV-2, B cell-deficient (microMT) mice developed a local viraemia and transient genital inflammation, suggesting a role for B cells in the innate control of local infection and inflammation [17].
• To detect and localize a herpes simplex virus type 2 (HSV-2) thymidine kinase gene sequence in paraffin sections of brains and trigeminal ganglia of infected mice, an in situ polymerase chain reaction (ISPCR) protocol was developed [18].

Associations of UL23 with chemical compounds

• Compound 26b competitively inhibited TK-2 with respect to thymidine and uncompetitively with respect to ATP [9].
• N1-substituted thymine derivatives as mitochondrial thymidine kinase (TK-2) inhibitors [9].
• Polyamine depletion and cell cycle manipulation in combination with HSV thymidine kinase/ganciclovir cancer gene therapy [19].
• The resistant clone was deficient in thymidine kinase (TK) activity and a nucleotide substitution, thymine for cytosine, at position 153 was identified in its TK gene [20].
• This differs from the results for CV where only idoxuridine and bromodeoxyuridine appeared to be activated, putatively by the type II TK expressed by this virus [21].

Analytical, diagnostic and therapeutic context of UL23

• (iv) The alpha-TK gene chimeras were not induced by infection with spontaneous TK- mutants of pseudorabies virus and bovine mammillitis virus or with human cytomegalovirus or adenovirus type 2 or by exposure to lysates of HSV-1-infected cells from which the virus was removed by centrifugation [5].
• A polymerase chain reaction (PCR) employing primers flanking a region of the HSV thymidine kinase gene common to both HSV-1 and HSV-2 was used to detect HSV in the CSF [22].
• We used a variety of techniques, including two-color flow cytometry and cytotoxicity assays to detect the presence of TK in the non-producing cells [23].
• In the present studies, we demonstrate that intravaginal vaccination with an attenuated strain of this virus, which possesses a partial deletion of the thymidine kinase gene, rapidly induced durable immunity to lethal intravaginal challenge with wild-type virus [24].
• When examined the immunofluorescence staining patterns of RXP/tk fusion proteins in transfected COS7 cells, the RXP chimeras revealed a conservation of the trafficking activity of RXP [25].

References