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1
Sato, Hiroshi, Hiroki Kato, Haruyoshi Yamaza, Keiji Masuda, Huong Thi Nguyen Nguyen, Thanh Thi Mai Pham, Xu Han, Yuta Hirofuji, and Kazuaki Nonaka. "Engineering of Systematic Elimination of a Targeted Chromosome in Human Cells." BioMed Research International 2017 (2017): 1–5. http://dx.doi.org/10.1155/2017/6037159.
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Embryonic trisomy leads to abortion or congenital genetic disorders in humans. The most common autosomal chromosome abnormalities are trisomy of chromosomes 13, 18, and 21. Although alteration of gene dosage is thought to contribute to disorders caused by extra copies of chromosomes, genes associated with specific disease phenotypes remain unclear. To generate a normal cell from a trisomic cell as a means of etiological analysis or candidate therapy for trisomy syndromes, we developed a system to eliminate a targeted chromosome from human cells. Chromosome 21 was targeted by integration of a DNA cassette in HeLa cells that harbored three copies of chromosome 21. The DNA cassette included two inverted loxP sites and a herpes simplex virus thymidine kinase (HSV-tk) gene. This system causes missegregation of chromosome 21 after expression of Cre recombinase and subsequently enables the selection of cells lacking the chromosome by culturing in a medium that includes ganciclovir (GCV). Cells harboring only two copies of chromosome 21 were efficiently induced by transfection of a Cre expression vector, indicating that this approach is useful for eliminating a targeted chromosome.
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Zhang, Guohua, Husam Mohammad, Brad D. Peper, Srinivasa Raja, Steven P. Wilson, and Sarah M. Sweitzer. "Enhanced Peripheral Analgesia Using Virally Mediated Gene Transfer of the μ-Opioid Receptor in Mice." Anesthesiology 108, no. 2 (February 1, 2008): 305–13. http://dx.doi.org/10.1097/01.anes.0000299836.61785.79.
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Background The use of opioids to treat pain is often limited by side effects mediated through the central nervous system. The current study used a recombinant herpes simplex virus type 1 to increase expression of the mu-opioid receptor (muOR) in primary afferent neurons. The goal of this strategy was to enhance peripheral opioid analgesia. Methods Cutaneous inoculation with herpes simplex virus containing muOR complementary DNA (cDNA) in antisense (SGAMOR) or sense (SGMOR) orientation relative to a constitutive promoter, or complementary DNA for Escherichia coli lac Z gene as a control virus (SGZ) was used to modify the levels of muOR in primary afferents. The effects of altered muOR levels on peripheral analgesia were then examined. Results At 4 weeks after SGAMOR and SGMOR infection, decreased and increased muOR immunoreactivity was observed in ipsilateral dorsal hind paw skin, lumbar dorsal root ganglion cells, and superficial dorsal horns, respectively, compared with SGZ. This change in muOR expression in mice by SGAMOR and SGMOR was accompanied at the behavioral level with a rightward and leftward shift in the loperamide dose-response curve, respectively, compared with SGZ. Conclusions This gene therapy approach may provide an innovative strategy to enhance peripheral opioid analgesia for the treatment of pain in humans, thereby minimizing centrally mediated opioid side effects such as sedation and addiction.
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Whitley, Richard, and Joel Baines. "Clinical management of herpes simplex virus infections: past, present, and future." F1000Research 7 (October 31, 2018): 1726. http://dx.doi.org/10.12688/f1000research.16157.1.
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Infection with herpes simplex virus (HSV) types 1 and 2 is ubiquitous in the human population. Most commonly, virus replication is limited to the epithelia and establishes latency in enervating sensory neurons, reactivating periodically to produce localized recurrent lesions. However, these viruses can also cause severe disease such as recurrent keratitis leading potentially to blindness, as well as encephalitis, and systemic disease in neonates and immunocompromised patients. Although antiviral therapy has allowed continual and substantial improvement in the management of both primary and recurrent infections, resistance to currently available drugs and long-term toxicity pose a current and future threat that should be addressed through the development of new antiviral compounds directed against new targets. The development of several promising HSV vaccines has been terminated recently because of modest or controversial therapeutic effects in humans. Nevertheless, several exciting vaccine candidates remain in the pipeline and are effective in animal models; these must also be tested in humans for sufficient therapeutic effects to warrant continued development. Approaches using compounds that modulate the chromatin state of the viral genome to suppress infection and reactivation or induce enhanced antiviral immunity have potential. In addition, technologies such as CRISPR/Cas9 have the potential to edit latent viral DNA in sensory neurons, potentially curing the neuron and patient of latent infection. It is hoped that development on all three fronts—antivirals, vaccines, and gene editing—will lead to substantially less HSV morbidity in the future.
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Lim, Filip. "HSV-1 as a Model for Emerging Gene Delivery Vehicles." ISRN Virology 2013 (May 27, 2013): 1–12. http://dx.doi.org/10.5402/2013/397243.
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The majority of viral vectors currently used possess modest cargo capability (up to 40 kb) being based on retroviruses, lentiviruses, adenoviruses, and adenoassociated viruses. These vectors have made the most rapid transition from laboratory to clinic because their small genomes have simplified their characterization and modification. However, there is now an increasing need both in research and therapy to complement this repertoire with larger capacity vectors able to deliver multiple transgenes or to encode complex regulatory regions, constructs which can easily span more than 100 kb. Herpes Simplex Virus Type I (HSV-1) is a well-characterized human virus which is able to package about 150 kb of DNA, and several vector systems are currently in development for gene transfer applications, particularly in neurons where other systems have low efficiency. However, to reach the same level of versatility and ease of use as that of smaller genome viral vectors, simple systems for high-titer production must be developed. This paper reviews the major HSV-1 vector systems and analyses the common elements which may be most important to manipulate to achieve this goal.
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Caccuri, Francesca, Michele Sommariva, Stefania Marsico, Francesca Giordano, Alberto Zani, Arianna Giacomini, Cornel Fraefel, Andrea Balsari, and Arnaldo Caruso. "Inhibition of DNA Repair Mechanisms and Induction of Apoptosis in Triple Negative Breast Cancer Cells Expressing the Human Herpesvirus 6 U94." Cancers 11, no. 7 (July 18, 2019): 1006. http://dx.doi.org/10.3390/cancers11071006.
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Triple-negative breast cancer (TNBC) accounts for 15–20% of all breast cancers. In spite of initial good response to chemotherapy, the prognosis of TNBC remains poor and no effective specific targeted therapy is readily available. Recently, we demonstrated the ability of U94, the latency gene of human herpes virus 6 (HHV-6), to interfere with proliferation and with crucial steps of the metastatic cascade by using MDA-MB 231 TNBC breast cancer cell line. U94 expression was also associated with a partial mesenchymal-to-epithelial transition (MET) of cells, which displayed a less aggressive phenotype. In this study, we show the ability of U94 to exert its anticancer activity on three different TNBC cell lines by inhibiting DNA damage repair genes, cell cycle and eventually leading to cell death following activation of the intrinsic apoptotic pathway. Interestingly, we found that U94 acted synergistically with DNA-damaging drugs. Overall, we provide evidence that U94 is able to combat tumor cells with different mechanisms, thus attesting for the great potential of this molecule as a multi-target drug in cancer therapy.
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MADEJ, JANUSZ A. "Influence of selected genes on neogenesis at the molecular level." Medycyna Weterynaryjna 75, no. 05 (2019): 6259–2019. http://dx.doi.org/10.21521/mw.6259.
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The paper describes the influence of selected genes on neogenesis, including their expression, RNA transformation, translation and transcription. The role of adhesive molecules, extracellular matrix, cytoskeleton and signal conduction in neoplastic induction is described. External stimuli, internal factors and disturbances in DNA repair can cause cell mutations (fig. 1). An accumulation of various factors in different gene classes, together with their amplification, leads to tumour formation. Neoplastic cells undergo a dominant mutation, thereby gaining a new function, or cumulate recessive mutations which cause the loss of a function. This is particularly true in genetic anomalies associated with the cadherin system, e.g. the loss of E-cadherin expression in mammary cancer. The loss of E-cadherin or catenin expression causes the loss of cell connections, which facilitates metastasizing. Cells in metastases often show genetic disorders, a more malignant phenotype and increased drug resistance, which worsens clinical prognosis. The search for new anti-neoplastic drugs for humans is based on molecular studies and mice experimental models. The animals in these models show a phenotype corresponding with specific human diseases, e.g. Pax gene mutation in sarcomas and carcinomas, antisense DNA therapy (in Burkitt’s lymphoma or chronic leukaemia) or induction of retroviral vectors (thymidine kinase gene) in herpes virus (HS-th) in proliferating cells in multiform glioblastoma.
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Wang, Y., S. M. Camp, M. Niwano, X. Shen, J. C. Bakowska, X. O. Breakefield, and P. D. Allen. "Herpes Simplex Virus Type 1/Adeno-Associated Virus rep+ Hybrid Amplicon Vector Improves the Stability of Transgene Expression in Human Cells by Site-Specific Integration." Journal of Virology 76, no. 14 (July 15, 2002): 7150–62. http://dx.doi.org/10.1128/jvi.76.14.7150-7162.2002.
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ABSTRACT Herpes simplex virus type 1 (HSV-1) amplicon vectors are promising gene delivery tools, but their utility in gene therapy has been impeded to some extent by their inability to achieve stable transgene expression. In this study, we examined the possibility of improving transduction stability in cultured human cells via site-specific genomic integration mediated by adeno-associated virus (AAV) Rep and inverted terminal repeats (ITRs). A rep − HSV/AAV hybrid amplicon vector was made by inserting a transgene cassette flanked with AAV ITRs into an HSV-1 amplicon backbone, and a rep + HSV/AAV hybrid amplicon was made by inserting rep68/78 outside the rep − vector 3′ AAV ITR sequence. Both vectors also had a pair of loxP sites flanking the ITRs. The resulting hybrid amplicon vectors were successfully packaged and compared to a standard amplicon vector for stable transduction frequency (STF) in human 293 and Gli36 cell lines and primary myoblasts. The rep +, but not the rep −, hybrid vector improved STF in all three types of cells; 84% of Gli36 and 40% of 293 stable clones transduced by the rep + hybrid vector integrated the transgene into the AAVS1 site. Due to the difficulty in expanding primary myoblasts, we did not assess site-specific integration in these cells. A strategy to attempt further improvement of STF by “deconcatenating” the hybrid amplicon DNA via Cre-loxP recombination was tested, but it did not increase STF. These data demonstrate that introducing the integrating elements of AAV into HSV-1 amplicon vectors can significantly improve their ability to achieve stable gene transduction by conferring the AAV-like capability of site-specific genomic integration in dividing cells.
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Egorova, Anna, Alexander Selutin, Marianna Maretina, Sergei Selkov, Vladislav Baranov, and Anton Kiselev. "Characterization of iRGD-Ligand Modified Arginine-Histidine-Rich Peptides for Nucleic Acid Therapeutics Delivery to αvβ3 Integrin-Expressing Cancer Cells." Pharmaceuticals 13, no. 10 (October 10, 2020): 300. http://dx.doi.org/10.3390/ph13100300.
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Efficient and specific delivery of nucleic acid (NA) therapeutics to tumor cells is extremely important for cancer gene therapy. Various therapeutic strategies include delivery of DNA-therapeutics such as immunostimulatory or suicide genes and delivery of siRNA-therapeutics able to silence expression of cancer-related genes. Peptides are a promising class of non-viral vehicles which are biodegradable and can efficiently condense, protect and specifically deliver NA to the cells. Here we designed arginine-histidine-rich peptide carriers consisting of an iRGD ligand to target αvβ3 integrins and studied them as vehicles for DNA and siRNA delivery to cancer cells. Combination of iRGD-modified and unmodified arginine–histidine-rich peptides during NA complexation resulted in carriers with different ligand contents. The NA-binding and protecting properties in vitro transfection efficiency and cytotoxicity of the DNA- and siRNA-polyplexes were studied and the most efficient carrier RGD1 was determined. The ability of the peptides to mediate specific intracellular uptake was confirmed inhuman cervical carcinoma (HeLa), human kidney (293T) and human pancreatic (PANC-1) cell lines with different αvβ3 integrins surface expression. By means of RGD1 carrier, efficient delivery of the herpes simplex virus (HSV-1) thymidine kinase gene to PANC-1 cells was demonstrated. Subsequent ganciclovir treatment led to a reduction of PANC-1 cells’ viability by up to 54%. Efficient RNAi-mediated down-regulation of GFP and VEGFA gene expression was achieved in MDA-MB-231-GFP+ breast cancer and EA.hy926 endothelial cells, respectively, by means of RGD1/siRNA polyplexes. Here we demonstrated that the peptide carrier RGD1 can be considered as promising candidate for development of NA therapeutics delivery systems useful in cancer gene therapy.
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Bayraktar, Ulas D., Roberto Ochoa, Soley Bayraktar, Maria Matsangou, and Juan Carlos Ramos. "High-Dose Methotrexate and Azidothymidine in Combination with Alternating DA-EPOCH Is An Effective Regimen for the Treatment of EBV-Related Plasmablastic Lymphoma." Blood 114, no. 22 (November 20, 2009): 4753. http://dx.doi.org/10.1182/blood.v114.22.4753.4753.
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Abstract Abstract 4753 Introduction Plasmablastic lymphoma (PBL) is an aggressive and generally fatal, rare type of B-cell non-Hodgkin's lymphoma (NHL) with predilection to sino-oral mucosa. PBL is usually associated with human immunodeficiency virus (HIV) and displays an unusual phenotype lacking the expression of B-cell surface antigens. PBLs are infected by Epstein Barr virus (EBV) in approximately 80% of cases and exhibit a restricted pattern of EBV gene expression as they do not typically express latent membrane proteins (LMPs), which enforce viral latency. Azidothymidine (AZT), a thymidine analogue, is an excellent substrate for EBV thymidine kinase, and is capable of inducing EBV lytic gene expression and apoptosis in primary Type I latency EBV+ Burkitt lymphoma (BL) cell lines. AZT was initially developed as an antineoplastic agent but was found to have low efficacy due to poor affinity to human DNA polymerase and low incorporation into DNA. The chemotherapy drug methotrexate (MTX), which also induces gamma-herpes virus lytic induction, inhibits thymidylate synthase thus blocking de novo synthesis of dTMP increasing the likelihood of AZT incorporation into DNA. Indeed, the combination of high-dose MTX and AZT was found to be clinically efficacious in HIV-infected patients with aggressive relapsed NHL. Similarly, at the University of Miami, we have found this drug combination to be highly effective when used in patients with aggressive gamma-herpes virus lymphomas including EBV+ BL and human herpes virus 8 (HHV-8) related primary effusion lymphoma (solid PEL). We report here the role of high dose MTX plus intravenous AZT with alternating infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and adriamycin) in the treatment of HIV associated EBV+ plasmablastic lymphoma. Methods Three HIV+ patients with biopsy proven, EBV-encoded RNA (EBER)+ PBL in sino-oral mucosa were treated with high dose methotrexate (4.5 g/m2 IV on day 1) and AZT 1.5 g IV infusion q12 hours (days 1-3) alternating with dose-adjusted (DA) EPOCH chemotherapy for 6-8 cycles as first line therapy. Patients were started/kept on HAART and were administered prophylactic intrathecal MTX±cytarabine. Responses were evaluated by oral exam and CT scans. Results Selected characteristics of patients are demonstrated in Table. Only Patient 2 was on HAART at the time of diagnosis. Patient 1 had intracranial extension of the large left maxillary lesion through sphenoid sinus with negative CSF cytology. All patients treated with HD-MTX/AZT and alternating EPOCH as above achieved a complete remission (CR). Patient 1 achieved CR after the 3rd cycle. However, 19 days after the 4th cycle he was found to have local recurrence, which was thought to be secondary to poor chemotherapy penetration to necrotic oral palate tissue, and was administered a total of 4620 cGy intensity-modulated radiotherapy to head and neck region followed by consolidation with the same chemotherapy regimen for 4 more cycles. He remains alive and free of disease after 14 months. Patient 2 and 3 received a total of 6 cycles of chemotherapy and remain disease-free after 12 and 13 months, respectively. No grade ≥3 toxicities were encountered during the treatment. Conclusion The combination of high dose MTX and AZT plus alternating DA-EPOCH chemotherapy is a tolerable and effective treatment for HIV related EBV+ plasmablastic lymphomas. The combination of MTX and AZT is a highly active, EBV lytic inducing and targeted regimen which deserves further investigation in the treatment of gamma-herpes virus associated malignancies. Disclosures: No relevant conflicts of interest to declare.
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Erlandsson, AC, LG Bladh, P. Stierna, T. Yucel-Lindberg, O. Hammarsten, T. Modeer, J. Harmenberg, and AC Wikstrom. "Herpes simplex virus type 1 infection and glucocorticoid treatment regulate viral yield, glucocorticoid receptor and NF-kappaB levels." Journal of Endocrinology 175, no. 1 (October 1, 2002): 165–76. http://dx.doi.org/10.1677/joe.0.1750165.
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The interplay between the endocrine and immune systems has come into focus in recent years with the insight that endocrine parameters may affect susceptibility to both auto-immune and infectious diseases. Our interest in immunoendocrine regulation led us to investigate the effects of glucocorticoids on Herpes simplex virus type 1 (HSV-1) infections. Glucocorticoids used to treat inflammatory conditions are not yet recommended for HSV-1 therapy, since they have been reported to prolong viral shedding both in vivo and in vitro. Here we report that glucocorticoids did not alter the viral yield in human gingival fibroblast (HGF) cell culture when glucocorticoid treatment and viral infection occured simultaneously, but the viral yield increased when cells were treated with the glucocorticoid dexamethasone (dex) prior to viral infection. We found that viral infection in our primary cell system increased NF-kappaB levels and DNA binding. In addition, the amount of glucocorticoid receptor (GR) increased following viral infection, and HSV-1 infection as such could induce glucocorticoid-driven transcription of a reporter gene in human embryo kidney (HEK) 293 cells stably transfected with GR. Dex treatment did not affect HSV-1-induced binding of p65 to an NF-kappaB element in an electrophoretic mobility shift assay, and acyclovir was still efficient as an anti-viral drug in the presence of dex. Further studies of the observed effects of HSV-1 infection and glucocorticoid treatment on GR and NF-kappaB regulation could give insights into the immunoendocrine mechanisms important for defence and therapy against viral infections.
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Converse, Andrea D., Lalitha R. Belur, Jennifer L. Gori, Geyi Liu, Felipe Amaya, Estuardo Aguilar-Cordova, Perry B. Hackett, and R. Scott McIvor. "Counterselection and Co-Delivery of Transposon and Transposase Functions for Sleeping Beauty-Mediated Transposition in Cultured Mammalian Cells." Bioscience Reports 24, no. 6 (December 1, 2004): 577–94. http://dx.doi.org/10.1007/s10540-005-2793-9.
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Sleeping Beauty (SB) is a gene-insertion system reconstructed from transposon sequences found in teleost fish and is capable of mediating the transposition of DNA sequences from transfected plasmids into the chromosomes of vertebrate cell populations. The SB system consists of a transposon, made up of a gene of interest flanked by transposon inverted repeats, and a source of transposase. Here we carried out a series of studies to further characterize SB-mediated transposition as a tool for gene transfer to chromosomes and ultimately for human gene therapy. Transfection of mouse 3T3 cells, HeLa cells, and human A549 lung carcinoma cells with a transposon containing the neomycin phosphotransferase (NEO) gene resulted in a several-fold increase in drug-resistant colony formation when co-transfected with a plasmid expressing the SB transposase. A transposon containing a methotrexate-resistant dihydrofolate reductase gene was also found to confer an increased frequency of methotrexate-resistant colony formation when co-transfected with SB transposase-encoding plasmid. A plasmid containing a herpes simplex virus thymidine kinase gene as well as a transposon containing a NEO gene was used for counterselection against random recombinants (NEO+TK+) in medium containing G418 plus ganciclovir. Effective counterselection required a recovery period of 5 days after transfection before shifting into medium containing ganciclovir to allow time for transiently expressed thymidine kinase activity to subside in cells not stably transfected. Southern analysis of clonal isolates indicated a shift from random recombination events toward transposition events when clones were isolated in medium containing ganciclovir as well as G418. We found that including both transposon and transposase functions on the same plasmid substantially increased the stable gene transfer frequency in Huh7 human hepatoma cells. The results from these experiments contribute technical and conceptual insight into the process of transposition in mammalian cells, and into the optimal provision of transposon and transposase functions that may be applicable to gene therapy studies.
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Broberg, Eeva K., Jutta Peltoniemi, Michaela Nygårdas, Tero Vahlberg, Matias Röyttä, and Veijo Hukkanen. "Spread and Replication of and Immune Response to γ134.5-Negative Herpes Simplex Virus Type 1 Vectors in BALB/c Mice." Journal of Virology 78, no. 23 (December 1, 2004): 13139–52. http://dx.doi.org/10.1128/jvi.78.23.13139-13152.2004.
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ABSTRACT We have previously shown that intracranial infection of herpes simplex virus type 1 (HSV-1) vector R8306 expressing interleukin-4 (IL-4) can abolish symptoms of experimental autoimmune encephalomyelitis, which is used as a model for human multiple sclerosis (Broberg et al., Gene Ther. 8:769-777, 2001). The aim of the current study was to search for means other than intracranial injection to deliver HSV-derived vectors to the central nervous system of mice. We also aimed to study the replication efficiency of these vectors in nervous system tissues and to elucidate the effects of the viruses on the immune response. We studied the spread and replication of the following viruses with deletions in neurovirulence gene γ134.5: R3616, R849 (lacZ transgene), R3659 (alpha-tk), R8306 (murine IL-4 transgene), and R8308 (murine IL-10 transgene). The samples were taken from trigeminal ganglia and brains of BALB/c mice after corneal, intralabial, and intranasal infection, and the viral load was examined by viral culture, HSV DNA PCR, and VP16 reverse transcription (RT)-PCR. The results show that (i) intranasal infection was the most efficient means of spread to the central nervous system (CNS) besides intracranial injection; (ii) the viruses did not grow in the culture from the brain samples, but the viral DNA persisted even until day 21 postinfection; (iii) viral replication, as observed by VP16 mRNA RT-PCR, occurred mainly on days 4 and 7 postinfection in trigeminal ganglia and to a low extent in brain; (iv) R3659, R8306, and R8308 showed reactivation from the trigeminal ganglia in explant cultures; (v) in the brain, the vectors spread to the midbrain more efficiently than to other brain areas; and (vi) the deletions in the R3659 genome significantly limited the ability of this virus to replicate in the nervous system. The immunological studies show that (i) the only recombinant to induce IL-4 mRNA expression in the brain was R8306, the gamma interferon response was very low in the brain for R3659 and R8306, and the IL-23p19 response to R8306 decreased by day 21 postinfection, unlike for the other viruses; (ii) Δγ134.5 HSV vectors modulated the subsets of the splenocytes differently depending on the transgene; (iii) R3659 infection of the nervous system induces expression and production of cytokines from the stimulated splenocytes; and (iv) HSV vectors expressing IL-4 or IL-10 induce expression and production of both of the Th2-type cytokines from splenocytes. We conclude that the intranasal route of infection is a possible means of delivery of Δγ134.5 HSV vectors to the CNS in addition to intracranial infection, although replication in the CNS remains minimal. The DNA of the HSV vectors is able to reside in the brain for at least 3 weeks. The features of the immune response to the vectors must be considered and may be exploited in gene therapy experiments with these vectors.
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Borenstein, Ronen, Oded Singer, Adi Moseri, and Niza Frenkel. "Use of Amplicon-6 Vectors Derived from Human Herpesvirus 6 for Efficient Expression of Membrane-Associated and -Secreted Proteins in T Cells." Journal of Virology 78, no. 9 (May 1, 2004): 4730–43. http://dx.doi.org/10.1128/jvi.78.9.4730-4743.2004.
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ABSTRACT The composite amplicon-6 vectors, which are derived from human herpesvirus 6 (HHV-6), can target hematopoietic cells. In the presence of the respective helper viruses, the amplicons are replicated by the rolling circle mechanism, yielding defective genomes of overall size 135 to 150 kb, composed of multiple repeats of units, containing the viral DNA replication origin, packaging signals, and the selected transgene(s). We report the use of amplicon-6 vectors designed for transgene expression in T cells. The selected transgenes included the green fluorescent protein marker, the herpes simplex virus type 1 glycoprotein D (gD), and the gD gene deleted in the transmembrane region (gDsec). The vectors were tested after electroporation and passage in T cells with or without helper HHV-6A superinfections. The results were as follows. (i)The vectors could be passaged both as cell-associated and as cell-free secreted virions infectious to new cells. (ii)The intact gD accumulated at the cell surface, whereas the gDsec was dispersed at internal locations of the cells or was secreted into the medium. (iii)Analyses of amplicon-6-gD expression by flow cytometry have shown significant expression in cultures with reiterated amplicons and helper viruses. The vector has spread to >60% of the cells, and the efficiency of expression per cell increased 15-fold, most likely due to the presence of concatemeric amplicon repeats. Current studies are designed to test whether amplicon-6 vectors can be used for gene therapy in lymphocytes and whether amplicon-6 vectors expressed in T cells and dendritic cells can induce strong cellular and humoral immune responses.
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Markowicz-Piasecka, Magdalena, Johanna Huttunen, Ahmed Montaser, Santosh Kumar Adla, Seppo Auriola, Marko Lehtonen, and Kristiina M. Huttunen. "Ganciclovir and Its Hemocompatible More Lipophilic Derivative Can Enhance the Apoptotic Effects of Methotrexate by Inhibiting Breast Cancer Resistance Protein (BCRP)." International Journal of Molecular Sciences 22, no. 14 (July 20, 2021): 7727. http://dx.doi.org/10.3390/ijms22147727.
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Efflux transporters, namely ATP-binding cassette (ABC), are one of the primary reasons for cancer chemoresistance and the clinical failure of chemotherapy. Ganciclovir (GCV) is an antiviral agent used in herpes simplex virus thymidine kinase (HSV-TK) gene therapy. In this therapy, HSV-TK gene is delivered together with GCV into cancer cells to activate the phosphorylation process of GCV to active GCV-triphosphate, a DNA polymerase inhibitor. However, GCV interacts with efflux transporters that are responsible for the resistance of HSV-TK/GCV therapy. In the present study, it was explored whether GCV and its more lipophilic derivative (1) could inhibit effluxing of another chemotherapeutic, methotrexate (MTX), out of the human breast cancer cells. Firstly, it was found that the combination of GCV and MTX was more hemocompatible than the corresponding combination with compound 1. Secondly, both GCV and compound 1 enhanced the cellular accumulation of MTX in MCF-7 cells, the MTX exposure being 13–21 times greater compared to the MTX uptake alone. Subsequently, this also reduced the number of viable cells (41–56%) and increased the number of late apoptotic cells (46–55%). Moreover, both GCV and compound 1 were found to interact with breast cancer resistant protein (BCRP) more effectively than multidrug-resistant proteins (MRPs) in these cells. Since the expression of BCRP was higher in MCF-7 cells than in MDA-MB-231 cells, and the cellular uptake of GCV and compound 1 was smaller but increased in the presence of BCRP-selective inhibitor (Fumitremorgin C) in MCF-7 cells, we concluded that the improved apoptotic effects of higher MTX exposure were raised mainly from the inhibition of BCRP-mediated efflux of MTX. However, the effects of GCV and its derivatives on MTX metabolism and the quantitative expression of MTX metabolizing enzymes in various cancer cells need to be studied more thoroughly in the future.
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Sakharnov, N. A., O. V. Utkin, E. N. Filatova, D. I. Knyazev, E. A. Kulova, and N. B. Presnyakova. "Expression analysis of apoptotic and survival genes in blood leukocytes of children with various forms of HHV-6 infection." Russian Journal of Infection and Immunity 10, no. 2 (May 22, 2020): 315–28. http://dx.doi.org/10.15789/2220-7619-eao-1335.
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Despite that human herpes virus type 6 (HHV-6) is extremely spread worldwide, molecular mechanisms of behind HHV-6 infection pathogenesis remain largely unexplored. No molecular markers were found linked to unfavorable course of HHV-6 infection which could allow to ease up selecting proper therapy and preventing development of complications. The aim of the study was to analyze expression of apoptosis and survival-related genes in blood leukocytes from 7–17-year-old children upon various forms of HHV-6 infection. The analysis was carried out by using DNA microarrays developed by us allowing to assess changes in expression level both of individual mRNAs and total gene set (-Σ). It was shown that during the acute phase of HHV-6 infection mRNA level was shifted toward pro-apoptotic factors. In the convalescence phase, most altered mRNA levels returned to normal. We have identified a set of mRNAs and genes whose expression level was significantly changed in acute disease phase. According to available data, these factors play an important role in regulation of studied signaling pathways. In order to search for HHV-6-associated factors, which markedly affect disease pattern of severe herpesvirus mixed infection, we analyzed significant changes of mRNA and genes expression levels in patients with severe HHV-6+EBV+CMV mixed infection and EBV+CMV mixed infection of moderate severity compared with healthy donors. The levels of 5 mRNAs (FAF1-NM_007051, DAPK2-NM_014326, CASP8AP2-NM_001137667, CASP8-NM_033356, BTK-NM_001287345) and 3 genes (FAS-Σ, Puma/BBC3-Σ, ITCH-Σ) were significantly increased in severe mixed infection comorbid with HHV-6 (EBV+CMV+HHV-6) but without HHV-6 (EBV+CMV) compared with healthy donors. Most of detected factors belong to Fas-mediated apoptosis pathway, and may be considered as candidate prognostic development factors of severe herpes virus infection involving HHV-6. This study profoundly extends existing understanding on molecular pathogenesis of HHV-6 infection involving apoptosis and pro-survival signaling pathways. Marked changes of mRNA and gene levels most likely contributed to the pathogenesis of HHV-6 as well as severe HHV-6+EBV+CMV mixed infection.
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Glorioso, J. C., N. A. DeLuca, and D. J. Fink. "Development and Application of Herpes Simplex Virus Vectors for Human Gene Therapy." Annual Review of Microbiology 49, no. 1 (October 1995): 675–710. http://dx.doi.org/10.1146/annurev.mi.49.100195.003331.
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Wang, Jing, Xiao-Xuan Lu, Dao-Zhen Chen, Shu-Feng Li, and Li-Shan Zhang. "Herpes simplex virus thymidine kinase and ganciclovir suicide gene therapy for human pancreatic cancer." World Journal of Gastroenterology 10, no. 3 (2004): 400. http://dx.doi.org/10.3748/wjg.v10.i3.400.
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Kunishige, Ichiro, Yoshihiro Samejima, Yasuhiko Shiki, Akihiro Moriyama, Daniel Meruelo, Fumitaka Saji, and Yuji Murata. "Suicide Gene Therapy for Human Uterine Adenocarcinoma Cells Using Herpes Simplex Virus Thymidine Kinase." Gynecologic Oncology 72, no. 1 (January 1999): 16–25. http://dx.doi.org/10.1006/gyno.1998.5224.
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Jovanović, Marina. "Genital Herpes / Genitalni herpes." Serbian Journal of Dermatology and Venerology 3, no. 1 (January 1, 2011): 7–22. http://dx.doi.org/10.2478/v10249-011-0033-9.
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Abstract Genital herpes is a chronic, nearly always active herpes simplex virus (HSV) infection of sacral ganglia, that may appear bilaterally and in more ganglia than previously thought. It represents one of the most prevalent sexually transmitted infections, and the most frequent cause of genital ulcer disease in the general populations of developed countries. It is caused by HSV type-2 (HSV-2) in 60-80% of cases, with HSV-1 infections causing the remainder. Genital herpes caused by HSV-1 is on the rise. Since genital HSV-1 infections have higher risk for transmission from mother to infant during delivery than HSV-2, they account for 30% of all cases of neonatal herpes. Serological studies have found prevalence of HSV-2 in the general population of developed contries to be up to 25%. Thirty years ago, herpes was defined as “Today’s Scarlet Letter”in the absence of reliable serological tests and highly effective medications, for diagnosis and treatment of genital herpes. In 2000, apart from virus isolation in cell culture (70% sensitivity), that has long been regarded as the diagnostic gold standard, type specific serological tests and higly effective antiviral agents have evolved. However, the following questions were raised: should serological testing be routinely recommended in asymptomatic patients; can antiviral therapy reduce asymptomatic shedding of the virus; can antiviral therapy reduce sexual transmission of infection; can antiviral therapy reduce acquisitation of viral copathogens, such as human immunodeficiency virus (HIV)? Now, ten years later, we know the answers. Type specific HSV DNA detection by real-time PCR assays (100% sensitivity) are tests of choice for every person with recurrent genital ulcers lasting more than 4 days, and must be available in those laboratories currently performing a significant number of PCR tests for different purposes. Type specific IgG serology assays are indicated in all asymptomatic persons who are at increased risk for HSV infection. In sexually active patients experiencing ≥ 6 recurrences per year, daily supressive dose of acyclovir, valacyclovir or famciclovir should be discontinued after a maximum of a year of continuous antiviral therapy in order to reassess recurrence frequency. If necessary, the therapy should be restarted after at least two recurrences. With such expansive diagnostic possibilities and more aggressive therapeutic approaches, we can define genital herpes not as a “Scarlet Letter”, but as a “widespread untoward consequence of human sexuality”.
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Wittekindt, Boris, Annemarie Berger, Luciana Porto, Stefan Vlaho, Hans Peter Grüttner, Martina Becker, and Thomas Lehrnbecher. "Human herpes virus-6 DNA in cerebrospinal fluid of children undergoing therapy for acute leukaemia." British Journal of Haematology 145, no. 4 (May 2009): 542–45. http://dx.doi.org/10.1111/j.1365-2141.2009.07641.x.
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WIDEN, B. F., J. P. LOWINGS, S. BELAK, and M. BANKS. "Development of a PCR system for porcine cytomegalovirus detection and determination of the putative partial sequence of its DNA polymerase gene." Epidemiology and Infection 123, no. 1 (August 1999): 177–80. http://dx.doi.org/10.1017/s0950268899002599.
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After PCR amplification with conservative cytomegalovirus primers, a 520 nucleotide putative partial sequence of the DNA polymerase gene of porcine cytomegalovirus (PCMV) was determined. Sequence comparison revealed homology to DNA polymerase genes from various beta herpes viruses and a dendrogram was constructed depicting the relationship of PCMV to other members of the Herpesviridae family. The dendrogram indicates that PCMV is indeed a beta herpes virus that is more closely related to human herpes virus types 6 and 7 than to type 5.To address the difficulties encountered during conventional PCMV detection and characterization a set of nested PCR primers were constructed which generated DNA fragments of 415 and 257 bp from the DNA polymerase gene. The nested PCR system proved specific for PCMV and provided a novel means for the detection of this poorly characterized herpes virus in pig populations, vaccines and in organs used in xenotransplantation.
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Moretz, R. C., and James J. Crute. "High resolution rotary shadowing of herpes simplex virus helicase proteins." Proceedings, annual meeting, Electron Microscopy Society of America 54 (August 11, 1996): 64–65. http://dx.doi.org/10.1017/s0424820100162788.
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Herpes viruses cause numerous human diseases. Herpes Simplex viruses (HSV1 and HSV2), varicella zoster virus (VSV),cytomegalovirus (CMV), and Epstein-Barr Virus (EBV) cause conditions ranging from peripheral sores (HSV, VSV), generalized viremia (CMV) and recurrent malaise (EBV). The common targets for HSV are neurons in the CNS, peripheral nerve cells or plexuses of sensory ganglia in highly innervated epithelium (e.g. lips, genitals).Interfering with the mechanisms of infection and virus production depends on the ability to target specific stages of viral reproduction. Helicases are enzymes that are essential for the duplication of viral DNA. The origin binding protein (OBP) helicase (encoded by the DNA replication gene UL9) binds to sequences in DNA at the three replication origins. These origins are points within the HSV chromosome where DNA replication initiates. The protein is a 83kDa polypeptide which exists as a dimer. Although the role of the UL9 helicase in HSV DNA replication has not been exactly determined, by analogy to other eukaryotic origin binding replication proteins, the binding and enzymatic action of the UL9 helicase to the origin sequences may initiate the assembly of a multiprotein replication complex. Helicase-primase (the product of the DNA replication genes UL5. UL8 and UL52) acts to unwind double-stranded DNA at growing replication forks. The helicaseprimase activity is expressed by a 213kDa heterodimer consisting of the 99kDa UL5 and 114kDA UL52 subunits. ICP8 (SSB—UL29 gene product) is a single-stranded binding protein of 122kDa that complexes with OBP (two SSB/OBP dimer). Each of these gene products has been expressed in insect cells with a recombinant baculovirus and purified to near homogeneity. Assays have been established for the screening of compounds that could inhibit the helicase activity of HSV 1 helicases. Analysis of helicase/DNA substrate complexes under different conditions will be facilitated by a better understanding of the structure of the individual proteins.
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Gao, Zhenqiang, Zhiping Gao, Tao Zhang, and Xifu Liu. "Selective gene therapy for human lung adenocarcinoma by tumor-specific expression of herpes simplex virus thymidine kinase gene." Science in China Series C: Life Sciences 40, no. 4 (August 1997): 430–36. http://dx.doi.org/10.1007/bf02881738.
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Arvin, A. M. "Varicella-zoster virus." Clinical Microbiology Reviews 9, no. 3 (July 1996): 361–81. http://dx.doi.org/10.1128/cmr.9.3.361.
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Varicella-zoster virus (VZV) is a ubiquitous human alphaherpesvirus that causes varicella (chicken pox) and herpes zoster (shingles). Varicella is a common childhood illness, characterized by fever, viremia, and scattered vesicular lesions of the skin. As is characteristic of the alphaherpesviruses, VZV establishes latency in cells of the dorsal root ganglia. Herpes zoster, caused by VZV reactivation, is a localized, painful, vesicular rash involving one or adjacent dermatomes. The incidence of herpes zoster increases with age or immunosuppression. The VZV virion consists of a nucleocapsid surrounding a core that contains the linear, double-stranded DNA genome; a protein tegument separates the capsid from the lipid envelope, which incorporates the major viral glycoproteins. VZV is found in a worldwide geographic distribution but is more prevalent in temperate climates. Primary VZV infection elicits immunoglobulin G (IgG), IgM, and IgA antibodies, which bind to many classes of viral proteins. Virus-specific cellular immunity is critical for controlling viral replication in healthy and immunocompromised patients with primary or recurrent VZV infections. Rapid laboratory confirmation of the diagnosis of varicella or herpes zoster, which can be accomplished by detecting viral proteins or DNA, is important to determine the need for antiviral therapy. Acyclovir is licensed for treatment of varicella and herpes zoster, and acyclovir, valacyclovir, and famciclovir are approved for herpes zoster. Passive antibody prophylaxis with varicella-zoster immune globulin is indicated for susceptible high-risk patients exposed to varicella. A live attenuated varicella vaccine (Oka/Merck strain) is now recommended for routine childhood immunization.
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Hirano, Makoto, Shin Nakamura, Maki Okada, Masahiro Ueda, and Ryozaburo Mukai. "Rapid Discrimination of Monkey B Virus from Human Herpes Simplex Viruses by PCR in the Presence of Betaine." Journal of Clinical Microbiology 38, no. 3 (2000): 1255–57. http://dx.doi.org/10.1128/jcm.38.3.1255-1257.2000.
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A PCR method to amplify DNA segments of the glycoprotein G gene of monkey B virus (BV) was achieved by adding betaine to the PCR mixture, in spite of the high G+C content of this gene. No product was obtained when DNA of human herpes simplex viruses (HSVs) was used as the template under the same conditions. Thus, this PCR method is useful in discriminating BV from HSVs.
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Fu, Xinping, Hua Wang, and Xiaoliu Zhang. "High-Frequency Intermolecular Homologous Recombination during Herpes Simplex Virus-Mediated Plasmid DNA Replication." Journal of Virology 76, no. 12 (June 15, 2002): 5866–74. http://dx.doi.org/10.1128/jvi.76.12.5866-5874.2002.
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ABSTRACT Homologous recombination is a prominent feature of herpes simplex virus (HSV) type 1 DNA replication. This has been demonstrated and traditionally studied in experimental settings where repeated sequences are present or are being introduced into a single molecule for subsequent genome isomerization. In the present study, we have designed a pair of unique HSV amplicon plasmids to examine in detail intermolecular homologous recombination (IM-HR) between these amplicon plasmids during HSV-mediated DNA replication. Our data show that IM-HR occurred at a very high frequency: up to 60% of the amplicon concatemers retrieved from virion particles underwent intermolecular homologous recombination. Such a high frequency of IM-HR required that both plasmids be replicated by HSV-mediated replication, as IM-HR events were not detected when either one or both plasmids were replicated by simian virus 40-mediated DNA replication, even with the presence of HSV infection. In addition, the majority of the homologous recombination events resulted in sequence replacement or targeted gene repair, while the minority resulted in sequence insertion. These findings imply that frequent intermolecular homologous recombination may contribute directly to HSV genome isomerization. In addition, HSV-mediated amplicon replication may be an attractive model for studying intermolecular homologous recombination mechanisms in general in a mammalian system. In this regard, the knowledge obtained from such a study may facilitate the development of better strategies for targeted gene correction for gene therapy purposes.
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Loimas, Sami, Marjo-Riitta Toppinen, Tapio Visakorpi, Juhani Jänne, and Jarmo Wahlfors. "Human prostate carcinoma cells as targets for herpes simplex virus thymidine kinase–mediated suicide gene therapy." Cancer Gene Therapy 8, no. 2 (February 2001): 137–44. http://dx.doi.org/10.1038/sj.cgt.7700286.
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Sato, Takeya, Anton Neschadim, Vanessa I. Rasaiah, Manfred Konrad, Daniel H. Fowler, Arnon Lavie, and Jeffrey A. Medin. "Improved Suicide Gene Therapy: Lentiviral Gene Transfer of Equine Herpes Virus Type 4 Thymidine Kinase into Target Cells." Blood 106, no. 11 (November 16, 2005): 5251. http://dx.doi.org/10.1182/blood.v106.11.5251.5251.
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Abstract Herpes virus type 1 thymidine kinase (HSV1-TK) with ganciclovir (GCV) prodrug treatment is the most widely used approach for suicide gene therapy. This ‘suicide’ strategy allows direct reduction of tumors and clearance of donor cells should graft-versus-host disease (GvHD) arise after bone marrow transplantation. Given recent clinical outcomes, this suicide approach may also provide a key safety component for therapeutic gene transfer vectors that integrate. Although suicide gene therapy using HSV1-TK-encoding oncoretroviral vectors has been evaluated in the clinic, the success of this approach has been relatively modest. Reasons for this include: low gene transfer efficacy, reduced expression of the suicide gene, and insufficient conversion of substrate. Our goal is to overcome these limitations by using a novel lentiviral vector (LV) encoding an alternative kinase/prodrug combination. The rational for our innovative suicide gene therapy strategy is two-fold: 1) Lentiviral vectors can efficiently transduce not only dividing cells but also non-dividing cells. 2) Applying a faster viral enzyme like equine herpes virus type 4 thymidine kinase (EHV4-TK) could be advantageous as it has been shown to be kinetically superior to HSV1-TK at GCV phosphorylation. The aim of this study is to evaluate whether LV-mediated gene modification of target cells with EHV4-TK can lead to efficient killing following GCV treatment. We first constructed a LV expression system carrying the wild-type EHV4-TK cDNA with an IRES element followed by a truncated form of human CD19 (hCD19Δ). Human CD19 was chosen as a cell surface marker to allow functional titering of virus and for immuno-enrichment of transduced cells prior to infusion since it is not expressed in the T cell lineage. The truncated form lacks the intracellular domain and therefore does not signal. Use of an IRES element can abrogate some variegated expression seen with vectors having dual promoters. The LV was pseudotyped with VSV-g and concentrated by ultracentrifugation. After one infection, Jurkat cells (human T cell leukemia) showed a more than 80% functional and stable transduction efficiency (MOI = 10). Using hCD19Δ as a selective marker, transduced Jurkat cells were enriched to over 95% positive by immuno-affinity sorting. EHV4-TK-transduced Jurkat cells exhibited increased cell killing in response to GCV treatment (the apoptotic cell indexes with or without GCV were 69.4 ± 1.5 % and 18.8 ± 1.7 %, respectively; n=3). Highly efficient transduction (more than 60%) of primary human T cells was accomplished by a three time exposure to virus over 36 hours at MOI of 20. Next, we found that GCV efficiently killed transduced primary human T cells in a dose dependent manner. We are now comparing the efficiency of GCV conversion by HSV1-TK and EHV4-TK using LV-transduced cells that express the similar protein levels. We are also evaluating intracellular levels of GCV metabolites by HPLC. These results demonstrate that our novel suicide gene therapy strategy has significant potential for many clinical applications.
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Pisani, S., D. Fioriti, M. P. Conte, F. Chiarini, L. Seganti, and A. M. Degener. "Involvement of Herpes Simplex Virus Type 2 in Modulation of Gene Expression of Human Papillomavirus Type 18." International Journal of Immunopathology and Pharmacology 15, no. 1 (January 2002): 59–63. http://dx.doi.org/10.1177/039463200201500108.
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Human papillomaviruses (HPVs) and herpes simplex virus type 2 (HSV-2) can establish latent or persistent infections in the host, and are involved in the aetiology of benign and/or malignant lesions of the urogenital tract. To investigate the putative interaction between these DNA viruses when a double infection occurs, we have studied the effect of HSV-2 infection in HeLa 229 cells containing 10–50 copies of HPV type 18 genomic DNA. Twenty hours post HSV-2 infection, the analysis of mRNA transcripts from El, E2, E6 early and L1 late HPV18 genes was performed in HeLa cells by a semi-quantitative RT-PCR assay. A modulation of HPV18 E1 and E6 early genes was observed, resulting in a 9-fold and 3-fold increased transcription respectively.
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OBARU, KENSHI, SHINICHIRO FUJII, SHUZO MATSUSHITA, TAKASHI SHIMADA, and KIYOSHI TAKATSUKI. "Gene Therapy for Adult T Cell Leukemia Using Human Immunodeficiency Virus Vector Carrying the Thymidine Kinase Gene of Herpes Simplex Virus Type 1." Human Gene Therapy 7, no. 18 (December 1996): 2203–8. http://dx.doi.org/10.1089/hum.1996.7.18-2203.
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Yao, Feng, Nao Murakami, Oliver Bleiziffer, Pengwei Zhang, Natali V. Akhrameyeva, Ximing Xu, and Richard Brans. "Development of a Regulatable Oncolytic Herpes Simplex Virus Type 1 Recombinant Virus for Tumor Therapy." Journal of Virology 84, no. 16 (June 2, 2010): 8163–71. http://dx.doi.org/10.1128/jvi.00059-10.
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ABSTRACT Oncolytic viruses are genetically modified viruses that preferentially replicate in host cancer cells, leading to the production of new viruses and, ultimately, cell death. Currently, no oncolytic viruses that are able to kill only tumor cells while leaving normal cells intact are available. Using T-REx (Invitrogen, Carlsbad, CA) gene switch technology and a self-cleaving ribozyme, we have constructed a novel oncolytic HSV-1 recombinant, KTR27, whose replication can be tightly controlled and regulated by tetracycline in a dose-dependent manner. Infection of normal replicating cells as well as multiple human cancer cell types with KTR27 in the presence of tetracycline led to 1,000- to 250,000-fold-higher progeny virus production than in the absence of tetracycline, while little viral replication and virus-associated cytotoxicity was observed in infected growth-arrested normal human cells. We show that intratumoral inoculation with KTR27 markedly inhibits tumor growth in a xenograft model of human non-small-cell lung cancer in nude mice. It is shown further that replication of KTR27 in the inoculated tumors can be efficiently controlled by local codelivery of tetracycline to the target tumors at the time of KTR27 inoculation. Collectively, KTR27 possesses a unique pharmacological feature that can limit its replication to the targeted tumor microenvironment with localized tetracycline delivery, thus minimizing unwanted viral replication in distant tissues following local virotherapy. This regulatory mechanism would also allow the replication of the virus to be quickly shut down should adverse effects be detected.
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Jia, William W. G., Jiren Tan, Gary J. Redekop, and James H. Goldie. "Toxicity studies in thymidine kinase—deficient herpes simplex virus therapy for malignant astrocytoma." Journal of Neurosurgery 85, no. 4 (October 1996): 662–66. http://dx.doi.org/10.3171/jns.1996.85.4.0662.
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✓ Previous studies have shown that genetically engineered thymidine kinase (tk)—defective herpes simplex virus type 1 (HSV-1) can effectively and selectively destroy gliomas in animal models. The consequences of viral infection and tumor regression must be characterized before this therapy can be applied in human trials. To study the potential for long-term toxicity, immunocompetent rats harboring 9L gliosarcomas were injected intratumorally with a tk—defective HSV-1, KOS-SB, at titers that previously have been demonstrated to cause tumor regression. In animals surviving 3 months or longer following viral treatment, there was no evidence of persistent infection or inflammation in peritumoral brain tissue or in remote systemic organs studied with routine histological and immunocytochemical analyses. Polymerase chain reaction using primers specific for HSV-1 detected HSV-1 DNA in peritumoral tissue only in animals sacrificed within 3 months of viral injection. There was no evidence of HSV-1 DNA in systemic tissues at any time after treatment. We conclude that stereotactic intratumoral injection of tk—deficient HSV can be attempted for the treatment of brain tumors without risk of systemic infection or significant toxicity to normal brain or remote proliferating tissues.
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Manisha. B. Shinde, Dr. Archana D. Kajale, Dr. Madhuri A. Channawar, and Dr. Shilpa R. Gawande. "Vector-mediated cancer gene therapy: A review." GSC Biological and Pharmaceutical Sciences 13, no. 2 (November 30, 2020): 152–65. http://dx.doi.org/10.30574/gscbps.2020.13.2.0368.
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Gene therapy is the transfer of genetic material to cure a disease or at least to improve the clinical status of a patient. One of the basic concepts of gene therapy is to transform viruses into genetic shuttles, which will deliver the gene of interest into the target cells. Safe methods have been devised to do this, using several viral and non-viral vectors. Two main approaches emerged: in vivo modification and ex vivo modification. Retrovirus, adenovirus, adenoassociated virus are suitable for gene therapeutic approaches which are based on permanent expression of the therapeutic gene. Non-viral vectors are far less efficient than viral vectors, but they have advantages due to their low immunogenicity and their large capacity for therapeutic DNA. The most commonly used DNA virus vectors are based on adenoviruses and adeno-associated viruses. An example of gene-knockout mediated gene therapy is the knockout of the human CCR5 gene in T-cells in order to control HIV infection. To improve the function of non-viral vectors, the addition of viral functions such as receptor mediated uptake and nuclear translocation of DNA may finally lead to the development of an artificial virus. Gene transfer protocols have been approved for human use in inherited diseases, cancers and acquired disorders. Although the available vector systems are able to deliver genes in vivo into cells, the ideal delivery vehicle has not been found. Thus, the present viral vectors should be used only with great caution in human beings and further progress in vector development is necessary.
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Tolstano, Axel A., José Luis Villarreal C, Franklin E. Torres J, Edward Lozano H., Nelys P. Movilla P, and Lina M. Barroso M. "DIAGNÓSTICO MOLECULAR DE INFECCIÓN POR VIRUS HERPES SIMPLEX TIPO 1 EN TEJIDO ATEROSCLERÓTICO HUMANO." Biociencias 13, no. 2 (December 5, 2018): 97–110. http://dx.doi.org/10.18041/2390-0512/biociencias.2.5001.
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Introducción: Las enfermedades del sistema circulatorio representan uno de los mayores problemas de salud pública a nivel mundial, nacional y regional. El mecanismo patogénico que subyace esta patología es la aterosclerosis. Existen varios factores que favorecen la etiopatogenia de la lesión aterosclerótica. Las infecciones, juegan un papel importante. La infección por el Virus del Herpes Simplex se ha considerado como un factor de riesgo emergente. Objetivo: Realizar diagnóstico molecular de infección por Virus Herpes Simplex tipo 1 y tipo 2 en tejido aterosclerótico humano. Método: Se realizó extracción de ADN viral a partir de ateromas usando el kit comercial PureGenomeTM Tissue DNA Extraction. La amplificación del material genético viral se realizó por PCR en tiempo real (qPCR) con el kit comercial “Human Herpes Virus 2 (Herpes simplex type 2) UL36 region genesig Standard Kit y Human Herpes Virus 1 (Herpes simplex type 1) Capsid assembly and DNA maturation gene. Genesig Standard Kit”. Resultados: En total se obtuvieron 102 muestras de ateromas, extraídas de diferentes fuentes anatómicas. Tres muestras resultaron positivas para VHS tipo 1 (3/102). Ninguna muestra evidenció material genético para VHS tipo 2 (0/102). Conclusión: La etiopatogenia de la aterosclerosis es un proceso altamente complejo. Los virus juegan un papel importante, en especial la infección por Virus del herpes simplex tipo 1. La infección por este virus genera cambios a nivel de las células vasculares y no vasculares, favoreciendo el acumulo de lipoproteínas de baja densidad químicamente oxidadas, importantes para la aterogénesis.
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Kanai, F., Y. Shiratori, Y. Yoshida, H. Wakimoto, H. Hamada, Y. Kanegae, I. Saito, et al. "Gene therapy for ?-fetoprotein-producing human hepatoma cells by adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene." Hepatology 23, no. 6 (June 1996): 1359–68. http://dx.doi.org/10.1002/hep.510230611.
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Selden, R. F., K. B. Howie, M. E. Rowe, H. M. Goodman, and D. D. Moore. "Human growth hormone as a reporter gene in regulation studies employing transient gene expression." Molecular and Cellular Biology 6, no. 9 (September 1986): 3173–79. http://dx.doi.org/10.1128/mcb.6.9.3173.
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The human growth hormone (hGH) transient assay system described here is based on the expression of hGH directed by cells transfected with hGH fusion genes. Levels of secreted hGH in the medium, measured by a simple radioimmunoassay, are proportional to both levels of cytoplasmic hGH mRNA and the amount of transfected DNA. The system is extremely sensitive, easy to perform, and is qualitatively different from other transient expression systems in that the medium is assayed and the cells themselves are not destroyed. The hGH transient assay system is appropriate for analyses of regulation of gene expression and was utilized here to investigate the effect of the simian virus 40 enhancer on the herpes simplex virus thymidine kinase promoter and the effect of zinc on the mouse metallothionein-I promoter. The expression of hGH can also be used as an internal control to monitor transfection efficiency along with any other transient expression system. All cell types tested thus far (including AtT-20, CV-1, GC, GH4, JEG, L, and primary pituitary cells) were able to secrete hGH into the medium.
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Selden, R. F., K. B. Howie, M. E. Rowe, H. M. Goodman, and D. D. Moore. "Human growth hormone as a reporter gene in regulation studies employing transient gene expression." Molecular and Cellular Biology 6, no. 9 (September 1986): 3173–79. http://dx.doi.org/10.1128/mcb.6.9.3173-3179.1986.
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The human growth hormone (hGH) transient assay system described here is based on the expression of hGH directed by cells transfected with hGH fusion genes. Levels of secreted hGH in the medium, measured by a simple radioimmunoassay, are proportional to both levels of cytoplasmic hGH mRNA and the amount of transfected DNA. The system is extremely sensitive, easy to perform, and is qualitatively different from other transient expression systems in that the medium is assayed and the cells themselves are not destroyed. The hGH transient assay system is appropriate for analyses of regulation of gene expression and was utilized here to investigate the effect of the simian virus 40 enhancer on the herpes simplex virus thymidine kinase promoter and the effect of zinc on the mouse metallothionein-I promoter. The expression of hGH can also be used as an internal control to monitor transfection efficiency along with any other transient expression system. All cell types tested thus far (including AtT-20, CV-1, GC, GH4, JEG, L, and primary pituitary cells) were able to secrete hGH into the medium.
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Saadi, Hogir. "Gene Therapy Approaches." Qubahan Academic Journal 1, no. 1 (March 28, 2021): 52–56. http://dx.doi.org/10.48161/qaj.v1n1a35.
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Gene therapy can be described broadly as the transfer of genetic material to control a disease or at least to enhance a patient's clinical status. The transformation of viruses into genetic shuttles is one of the core principles of gene therapy, which will introduce the gene of interest into the target tissue and cells. To do this, safe strategies have been invented, using many viral and non-viral vector delivery. Two major methods have emerged: modification in vivo and modification ex vivo. For gene therapeutic approaches which are focused on lifelong expression of the therapeutic gene, retrovirus, adenovirus, adeno-associated viruses are acceptable. Non-viral vectors are much less successful than viral vectors, but because of their low immune responses and their broad therapeutic DNA ability, they have advantages. The addition of viral functions such as receptor-mediated uptake and nuclear translocation of DNA may eventually lead to the development of an artificial virus in order to improve the role of non-viral vectors. For human use in genetic conditions, cancers and acquired illnesses, gene transfer techniques have been allowed. The ideal delivery vehicle has not been identified, although the accessible vector systems are capable of transporting genes in vivo into cells. Therefore, only with great caution can the present viral vectors be used in human beings and further progress in the production of vectors is required. Current progresses in our understanding of gene therapy approaches and their delivery technology, as well as the victors used to deliver therapeutic genes, are the primary goals of this review. For that reason, a literature search on PubMed and Google Scholar was carried out using different keywords.
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Sadelain, Michel, and Ronald G. Blasberg. "Imaging Transgene Expression for Gene Therapy." Journal of Pharmacy Practice 14, no. 5 (October 2001): 376–82. http://dx.doi.org/10.1106/wklk-n777-76cv-p88n.
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Imaging transgene activity is of great interest to the development and implementation of genetically based therapies. Gene transfer in human cells and in humans is performed using either viral or nonviral vectors. Vectors are the vehicles used to transduce cells that are either cultured and destined to be transfused or implanted in patients (ex vivo gene transfer) or cells residing in the body (in vivo gene transfer). To illustrate the principles involved in imaging transgene expression, focus was given to the herpes simplex virus thymidine kinase gene (HSV1-tk) and the HSV1-tk ganciclovir “drug sensitivity” cancer treatment protocol. The imaging paradigm is based on an enzymatic radiotracer assay in which the market substrate, radiolabeled 2′-fluoro-1-β-D-arabinofuranosyl-5-iodo-uracil (FIAU), is selectively phosphorylated by HSV1-thymidine kinase and “trapped” in transduced cells. Information is presented that shows that the images of FIAU-derived radioactivity obtained using quantitative autoradiography, single photon emission computed tomography, and positron emission tomography imaging techniques reflect the level of HSV1-tk gene expression.
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Vandenbroeck, K., I. Alloza, B. Swaminathan, A. Antigüedad, D. Otaegui, J. Olascoaga, M. G. Barcina, et al. "Validation of IRF5 as multiple sclerosis risk gene: putative role in interferon beta therapy and human herpes virus-6 infection." Genes & Immunity 12, no. 1 (September 23, 2010): 40–45. http://dx.doi.org/10.1038/gene.2010.46.
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Roller, Richard J., Yuping Zhou, Renee Schnetzer, John Ferguson, and Diana DeSalvo. "Herpes Simplex Virus Type 1 UL34 Gene Product Is Required for Viral Envelopment." Journal of Virology 74, no. 1 (January 1, 2000): 117–29. http://dx.doi.org/10.1128/jvi.74.1.117-129.2000.
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ABSTRACT The herpes simplex virus type 1 UL34 gene encodes a protein that is conserved in all human herpesviruses. The association of the UL34 protein with membranes in the infected cell and its expression as a gamma-1 gene suggest a role in maturation or egress of the virus particle from the cell. To determine the function of this gene product, we have constructed a recombinant virus that fails to express the UL34 protein. This recombinant virus, in which the UL34 protein coding sequence has been replaced by green fluorescent protein, forms minute plaques and replicates in single-step growth experiments to titers 3 to 5 log orders of magnitude lower than wild-type or repair viruses. On Vero cells, the deletion virus synthesizes proteins of all kinetic classes in normal amounts. Electron microscopic and biochemical analyses show that morphogenesis of the deletion virus proceeds normally to the point of formation of DNA-containing nuclear capsids, but electron micrographs show no enveloped virus particles in the cytoplasm or at the surface of infected cells, suggesting that the UL34 protein is essential for efficient envelopment of capsids.
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Pietropaolo, Valeria, Carla Prezioso, and Ugo Moens. "Role of Virus-Induced Host Cell Epigenetic Changes in Cancer." International Journal of Molecular Sciences 22, no. 15 (August 3, 2021): 8346. http://dx.doi.org/10.3390/ijms22158346.
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The tumor viruses human T-lymphotropic virus 1 (HTLV-1), hepatitis C virus (HCV), Merkel cell polyomavirus (MCPyV), high-risk human papillomaviruses (HR-HPVs), Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpes virus (KSHV) and hepatitis B virus (HBV) account for approximately 15% of all human cancers. Although the oncoproteins of these tumor viruses display no sequence similarity to one another, they use the same mechanisms to convey cancer hallmarks on the infected cell. Perturbed gene expression is one of the underlying mechanisms to induce cancer hallmarks. Epigenetic processes, including DNA methylation, histone modification and chromatin remodeling, microRNA, long noncoding RNA, and circular RNA affect gene expression without introducing changes in the DNA sequence. Increasing evidence demonstrates that oncoviruses cause epigenetic modifications, which play a pivotal role in carcinogenesis. In this review, recent advances in the role of host cell epigenetic changes in virus-induced cancers are summarized.
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Tang, Y., J. Li, S. Zhao, and J. Liu. "Killing Effect of the Herpes Simplex Virus Thymidine Kinase/Ganciclovir Enzyme/Prodrug System on Human Nasopharyngeal Carcinoma Cells." Journal of International Medical Research 35, no. 4 (July 2007): 433–41. http://dx.doi.org/10.1177/147323000703500401.
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A promising new approach for the gene therapy of cancer is the introduction of the herpes simplex virus thymidine kinase (HSV tk) gene into tumour cells, where the HSV tk gene product converts the non-toxic prodrug ganciclovir (GCV) into its cytotoxic metabolite. We constructed a recombinant plasmid containing the HSV tk gene using standard molecular biology techniques in order to investigate whether the HSV tk/GCV enzyme/prodrug system could kill the human nasopharyngeal carcinoma cell line HNE-1. The recombinant plasmid pcDNA3.1(–) CMV.TK was transfected into the HNE-1 cells by electroporation. The expression of HSV tk by the transfected HNE-1/TK cells was confirmed by mRNA amplification and Western blotting. The growth of HNE-1/TK cells was inhibited by GCV in a dose-dependent manner. The HSV tk/GCV system also demonstrated a considerable bystander effect on co-cultured wild type HNE-1 cells. We conclude that the HSV tk/GCV system could be used as gene therapy for nasopharyngeal carcinoma.
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Cohrs, Randall J., Jessica Randall, John Smith, Donald H. Gilden, Christine Dabrowski, Harjeet van der Keyl, and Ruth Tal-Singer. "Analysis of Individual Human Trigeminal Ganglia for Latent Herpes Simplex Virus Type 1 and Varicella-Zoster Virus Nucleic Acids Using Real-Time PCR." Journal of Virology 74, no. 24 (December 15, 2000): 11464–71. http://dx.doi.org/10.1128/jvi.74.24.11464-11471.2000.
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ABSTRACT Herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) establish latent infections in the peripheral nervous system following primary infection. During latency both virus genomes exhibit limited transcription, with the HSV-1 LATs and at least four VZV transcripts consistently detected in latently infected human ganglia. In this study we used real-time PCR quantitation to determine the viral DNA copy number in individual trigeminal ganglia (TG) from 17 subjects. The number of HSV-1 genomes was not significantly different between the left and right TG from the same individual and varied per subject from 42.9 to 677.9 copies per 100 ng of DNA. The number of VZV genomes was also not significantly different between left and right TG from the same individual and varied per subject from 37.0 to 3,560.5 copies per 100 ng of DNA. HSV-1 LAT transcripts were consistently detected in ganglia containing latent HSV-1 and varied in relative expression by >500-fold. Of the three VZV transcripts analyzed, only transcripts mapping to gene 63 were consistently detected in latently infected ganglia and varied in relative expression by >2,000-fold. Thus, it appears that, similar to LAT transcription in HSV-1 latently infected ganglia, VZV gene 63 transcription is a hallmark of VZV latency.
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Chang, Jean, and Don Ganem. "On the control of late gene expression in Kaposi’s sarcoma-associated herpesvirus (human herpesvirus-8)." Journal of General Virology 81, no. 8 (August 1, 2000): 2039–47. http://dx.doi.org/10.1099/0022-1317-81-8-2039.
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Herpesvirus late genes require viral DNA replication for maximal expression. Although late gene expression appears to require DNA replication in cis in alphaherpesviruses, studies in Epstein–Barr virus (EBV) suggest that this cis-requirement might not pertain to the gammaherpesviruses. Based on these findings, a system was created to investigate the elements required for the regulation of Kaposi’s sarcoma-associated herpesvirus (KSHV; human herpesvirus-8) late gene expression. The transcript of a classic late gene encoding the viral assembly protein was characterized and reporter genes driven by the assembly protein promoter region were constructed. Unlike the EBV case, expression of a reporter gene under the control of the assembly protein promoter did not display authentic regulation when removed from the context of the viral genome. Although reporter expression rose in cells displaying lytic replication, this expression was not diminished by specific inhibitors of viral DNA synthesis. Minimal core promoters were similarly unable to reproduce late gene regulation. These results suggest that proper KSHV late gene expression is likely to be dependent upon virus lytic replication in cis and indicate that the regulation of KSHV late genes more closely resembles that observed in herpes simplex virus than that described for EBV.
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Iwasawa, Chizuru, Ryota Tamura, Yuki Sugiura, Sadafumi Suzuki, Naoko Kuzumaki, Minoru Narita, Makoto Suematsu, et al. "Increased Cytotoxicity of Herpes Simplex Virus Thymidine Kinase Expression in Human Induced Pluripotent Stem Cells." International Journal of Molecular Sciences 20, no. 4 (February 14, 2019): 810. http://dx.doi.org/10.3390/ijms20040810.
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Human induced pluripotent stem cells (iPSCs) hold enormous promise for regenerative medicine. The major safety concern is the tumorigenicity of transplanted cells derived from iPSCs. A potential solution would be to introduce a suicide gene into iPSCs as a safety switch. The herpes simplex virus type 1 thymidine kinase (HSV-TK) gene, in combination with ganciclovir, is the most widely used enzyme/prodrug suicide system from basic research to clinical applications. In the present study, we attempted to establish human iPSCs that stably expressed HSV-TK with either lentiviral vectors or CRISPR/Cas9-mediated genome editing. However, this task was difficult to achieve, because high-level and/or constitutive expression of HSV-TK resulted in the induction of cell death or silencing of HSV-TK expression. A nucleotide metabolism analysis suggested that excessive accumulation of thymidine triphosphate, caused by HSV-TK expression, resulted in an imbalance in the dNTP pools. This unbalanced state led to DNA synthesis inhibition and cell death in a process similar to a “thymidine block”, but more severe. We also demonstrated that the Tet-inducible system was a feasible solution for overcoming the cytotoxicity of HSV-TK expression. Our results provided a warning against using the HSV-TK gene in human iPSCs, particularly in clinical applications.
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Kanai, F. "Gene therapy for alpha-fetoprotein-producing human hepatoma cells by adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene." Hepatology 23, no. 6 (June 1996): 1359–68. http://dx.doi.org/10.1053/jhep.1996.v23.pm0008675152.
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Eastham, James A., Shu-Hsai Chen, Inder Sehgal, Guang Yang, Terry L. Timme, Simon J. Hall, Savio L. C. Woo, and Timothy C. Thompson. "Prostate Cancer Gene Therapy: Herpes Simplex Virus Thymidine Kinase Gene Transduction Followed by Ganciclovir in Mouse and Human Prostate Cancer Models." Human Gene Therapy 7, no. 4 (March 1996): 515–23. http://dx.doi.org/10.1089/hum.1996.7.4-515.
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Aubert, Martine, Jennifer O’Toole, and John A. Blaho. "Induction and Prevention of Apoptosis in Human HEp-2 Cells by Herpes Simplex Virus Type 1." Journal of Virology 73, no. 12 (December 1, 1999): 10359–70. http://dx.doi.org/10.1128/jvi.73.12.10359-10370.1999.
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ABSTRACT Cultured human epithelial cells infected with an ICP27 deletion strain of herpes simplex virus type 1 (HSV-1) show characteristic features of apoptotic cells including cell shrinkage, nuclear condensation, and DNA fragmentation. These cells do not show such apoptotic features when infected with a wild-type virus unless the infections are performed in the presence of a protein synthesis inhibitor. Thus, both types of virus induce apoptosis, but the ICP27-null virus is unable to prevent this process from killing the cells. In this report, we show that this ICP27-deficient virus induced apoptosis in human HEp-2 cells through a pathway which involved the activation of caspase-3 and the processing of the death substrates DNA fragmentation factor and poly(ADP-ribose) polymerase. The induction of apoptosis by wild-type HSV-1 occurred prior to 6 h postinfection (hpi), and de novo viral protein synthesis was not required to induce the process. The ability of the virus to inhibit apoptosis was shown to be effective between 3 to 6 hpi. Wild-type HSV-1 infection was also able to block the apoptosis induced in cells by the addition of cycloheximide, staurosporine, and sorbitol. While US3- and ICP22-deficient viruses showed a partial prevention of apoptosis, deletion of either the UL13 or vhs gene products did not affect the ability of HSV-1 to prevent apoptosis in infected cells. Finally, we demonstrate that in UV-inactivated viruses, viral binding and entry were not sufficient to induce apoptosis. Taken together, these results suggest that either gene expression or another RNA metabolic event likely plays a role in the induction of apoptosis in HSV-1-infected human cells.
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Jones, C. "Cervical cancer: is herpes simplex virus type II a cofactor?" Clinical Microbiology Reviews 8, no. 4 (October 1995): 549–56. http://dx.doi.org/10.1128/cmr.8.4.549.
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In many ways, cervical cancer behaves as a sexually transmitted disease. The major risk factors are multiple sexual partners and early onset of sexual activity. Although high-risk types of human papillomaviruses (HPV) play an important role in the development of nearly all cases of cervical cancer, other sexually transmitted infectious agents may be cofactors. Herpes simplex virus type 2 (HSV-2) is transmitted primarily by sexual contact and therefore has been implicated as a risk factor. Several independent studies suggest that HSV-2 infections correlate with a higher than normal incidence of cervical cancer. In contrast, other epidemiological studies have concluded that infection with HSV-2 is not a major risk factor. Two separate transforming domains have been identified within the HSV-2 genome, but continued viral gene expression apparently is not necessary for neoplastic transformation. HSV infections lead to unscheduled cellular DNA synthesis, chromosomal amplifications, and mutations. These observations suggest that HSV-2 is not a typical DNA tumor virus. It is hypothesized that persistent or abortive infections induce permanent genetic alterations that interfere with differentiation of cervical epithelium and subsequently induce abnormal proliferation. Thus, HSV-2 may be a cofactor in some but not all cases of cervical cancer.