Method of Controlling Corona Effects and Breakdown Voltage of Small Air Gaps Stressed by Impulse Voltages

This paper investigates the influence of a resistor on the dielectric behavior of an air gap. The resistor is connected in series with the air gap and the latter is stressed by impulse voltage. Air gap arrangements of different geometry with either the rod or the plate grounded are stressed with impulse voltages of both positive and negative polarity. The resistor is connected in series with the air gap in the return circuit connecting the gap with the impulse generator. The method followed involves the investigation of the graphs of the charging time concerning the air gaps capacitances, in connection to the value of the resistor, the geometry of the gap, the effect of grounding and the polarity effect. It is determined that the charging time of the air gap increases, as the value of the resistor increases. It is also determined that the peak voltage value of the fully charged air gap decreases as the value of the resistor increases. The results of the mathematical and simulation analysis are compared with the results of the oscillograms taken from experimental work. In addition and consequently to the above results it is concluded from the experimental work that the in series connection of the resistor in the circuit has significant influence on corona pulses (partial discharges) occurring in the gap and on the breakdown voltage of the gap. A new method of controlling the corona effects and consequently the breakdown voltage of small air gaps stressed by impulse voltage of short duration in connection to the ground effect and the polarity effect has arisen. Furthermore through mathematical analysis of the charging graphs obtained from simulation and experimental oscillograms there was a calculation of the values of the capacitance of the air gaps in relation to their geometry and the results were compared to the values calculated with mathematical analysis.Comment: 8 pages, 14 figure

Structure et spécificité de la thymidylate kinase du virus de la vaccine (vers une stratégie antipoxvirus)

La thymidylate kinase du virus de Vaccine (VaccTMPK) présente une spécificité de substrat plus étendue que celle de son homologue humain. Elle est capable de catalyser la phosphorylation de TMP, dUMP mais surtout du dGMP. Les paramètres cinétiques obtenus pour le TMP sont proches de ceux de la TMPK humaine (kcat = 2 s-1 ; KM = 20 M). Les données cristallographiques de l enzyme virale liés au TDP montre que VaccTMPK adopte le même repliement que l enzyme humaine avec une association orthogonale des sous-unités, probablement due à un défaut de compaction au niveau du domaine à NMP. Cette singularité permet à l enzyme de lier des susbtrats plus volumineux comme le dGMP et le 5-bromo-vinyl-dUMP et s accompagne d une stabilité moins grande comme l indiquent les expériences de microcalorimétrie. Dans le cadre de la recherche de nouveaux substrats antipoxvirus de VaccTMPK, une série de phosphonates analogues du dUMP, composés d une partie acyclique de 3, 4 ou 5 carbones à la place du désoxyribose, ont été testés pour leur réactivité avec les TMPK virale et humaine. De plus, un groupement méthyle-, halogène- ou aryl- est ajouté en position C5 de la base. Les dérivés methylés ou halogénés, des séries allyl- et pentenyl-, sont substrats des TMPKs alors que les dérivés substitués par un aryl- ne le sont pas. D autre part, une série d analogues alkylés et oxydés de dGMP a été testés pour leur réactivité avec VaccTMPK et la GMPK humaine. Ils sont tous substrats des deux enzymes sauf le O6-Me-dGMP qui est spécifiquement phosphorylé par VaccTMPKPARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Tenofovir activating kinases may impact the outcome of HIV treatment and prevention

publisher: Elsevier articletitle: Tenofovir Activating Kinases May Impact the Outcome of HIV Treatment and Prevention journaltitle: EBioMedicine articlelink: http://dx.doi.org/10.1016/j.ebiom.2015.07.042 associatedlink: http://dx.doi.org/10.1016/j.ebiom.2015.07.008 content_type: simple-article copyright: Copyright © 2015 Published by Elsevier B.V.status: publishe

Résistance des virus herpes simplex aux antiviraux

International audienceHerpes simplex virus (HSV) infections remain an important cause of morbidity among immunocompromised patients, such as transplant recipients and human immunodeficiency virus [HIV]-infected individuals. Only few antiviral drugs are available to treat HSV infections: (val)acyclovir, foscarnet, and cidofovir. Prophylactic and curative antiviral treatments administered during prolonged periods among patients with altered T-cell immunity may lead to the emergence of HSV resistance to antivirals, contributing to a challenging therapeutic management of viral infection. The persistence of herpetic lesions after 10 days of well-conducted antiviral therapy is suggestive of viral resistance. Resistance to antivirals can be detected using genotypic methods (identifications of antiviral resistance-associated mutations by sequencing genes encoding viral proteins involved in the mechanism of action of antivirals) or phenotypic methods (measure of antiviral drug concentration inhibiting 50% of viral replication in cell culture). The prevalence of HSV resistance to acyclovir is below 1% in immunocompetent individuals, except those with herpetic keratitis for whom prevalence can reach 7%, and varies from 3.5% to 11% in immunocompromised patients. Adverse effects and the absence of eradication of viral latent infection constitute other limits to the use of antiviral drugs. New antiviral compounds undergoing clinical trials and novel potential viral targets seem very promising to enlarge the panel of efficient compounds to treat HSV infections.Les infections par les virus herpes simplex (HSV) constituent une cause majeure de morbidité chez les patients immunodéprimés tels que les receveurs de greffe ou les individus infectés par le virus de l’immunodéficience humaine (HIV). Les molécules antivirales utilisées pour le traitement de ces infections sont actuellement peu nombreuses : (val)aciclovir, foscarnet et cidofovir. L’instauration de traitements antiviraux préventifs ou curatifs, souvent durant des périodes prolongées, chez des patients dont l’immunité cellulaire est altérée, peut conduire à l’émergence de résistance des HSV aux antiviraux, compliquant alors la prise en charge thérapeutique de l’infection virale. La persistance de lésions herpétiques après 10 jours de traitement antiviral bien conduit doit faire suspecter une résistance virologique. Il est possible de détecter cette résistance par des méthodes génotypiques (identification de mutations associées à la résistance aux antiviraux par séquençage des gènes codant les protéines virales directement impliquées dans le mécanisme d’action des antiviraux) ou par des méthodes phénotypiques (mesure de la concentration d’un antiviral inhibant 50 % de la multiplication virale en culture de cellules). La prévalence de la résistance des HSV à l’aciclovir est inférieure à 1 % chez les individus immunocompétents, hormis ceux souffrant de kératite herpétique pour qui elle est de l’ordre de 7 %, et elle varie de 2,5 % à 11 % chez les individus immunodéprimés. De plus, il existe d’autres limitations à l’utilisation de ces antiviraux, comme leurs effets indésirables ou l’impossibilité d’éradiquer les infections virales latentes. À ce jour, de nouveaux composés en cours d’essais cliniques et de nouvelles cibles virales potentielles semblent très prometteuses pour agrandir le panel de molécules efficaces pour traiter les infections dues aux HSV

The anti-HIV drug tenofovir, a reverse transcriptase inhibitor, also targets the herpes simplex virus (HSV) DNA polymerase

Genital herpes is an important cofactor for acquisition of HIV infection and effective prophylaxis is a helpful strategy to halt both HIV and HSV transmission. The antiretroviral agent tenofovir, formulated as a vaginal microbicide gel, was shown to reduce the risk of HIV and HSV-2 acquisition.status: publishe

Distribution and effects of amino acid changes in drug-resistant α and β herpesviruses DNA polymerase

Emergence of drug-resistance to all FDA-approved antiherpesvirus agents is an increasing concern in immunocompromised patients. Herpesvirus DNA polymerase (DNApol) is currently the target of nucleos(t)ide analogue-based therapy. Mutations in DNApol that confer resistance arose in immunocompromised patients infected with herpes simplex virus 1 (HSV-1) and human cytomegalovirus (HCMV), and to lesser extent in herpes simplex virus 2 (HSV-2), varicella zoster virus (VZV) and human herpesvirus 6 (HHV-6). In this review, we present distinct drug-resistant mutational profiles of herpesvirus DNApol. The impact of specific DNApol amino acid changes on drug-resistance is discussed. The pattern of genetic variability related to drug-resistance differs among the herpesviruses. Two mutational profiles appeared: one favoring amino acid changes in the Palm and Finger domains of DNApol (in α-herpesviruses HSV-1, HSV-2 and VZV), and another with mutations preferentially in the 3'-5' exonuclease domain (in β-herpesvirus HCMV and HHV-6). The mutational profile was also related to the class of compound to which drug-resistance emerged.status: publishe

Thymidine kinase and protein kinase in drug-resistant herpesviruses: heads of a Lernaean hydra

Herpesviruses thymidine kinase (TK) and protein kinase (PK) allow the activation of nucleoside analogues used in anti-herpesvirus treatments. Mutations emerging in these two genes often lead to emergence of drug-resistant strains responsible for life-threatening diseases in immunocompromised populations. In this review, we analyze the binding of different nucleoside analogues to the TK active site of the three α-herpesviruses [Herpes Simplex Virus 1 and 2 (HSV-1 and HSV-2) and Varicella-Zoster Virus (VZV)] and present the impact of known mutations on the structure of the viral TKs. Furthermore, models of β-herpesviruses [Human cytomegalovirus (HCMV) and human herpesvirus-6 (HHV-6)] PKs allow to link amino acid changes with resistance to ganciclovir and/or maribavir, an investigational chemotherapeutic used in patients with multidrug-resistant HCMV. Finally, we set the basis for the understanding of drug-resistance in γ-herpesviruses [Epstein-Barr virus (EBV) and Kaposi's sarcoma associated herpesvirus (KSHV)] TK and PK through the use of animal surrogate models.status: publishe

Insights into the mechanism of action of cidofovir and other acyclic nucleoside phosphonates against polyoma- and papillomaviruses and non-viral induced neoplasia

Acyclic nucleoside phosphonates (ANPs) are well-known for their antiviral properties, three of them being approved for the treatment of human immunodeficiency virus infection (tenofovir), chronic hepatitis B (tenofovir and adefovir) or human cytomegalovirus retinitis (cidofovir). In addition, cidofovir is mostly used off-label for the treatment of infections caused by several DNA viruses other than cytomegalovirus, including papilloma- and polyomaviruses, which do not encode their own DNA polymerases. There is considerable interest in understanding why cidofovir is effective against these small DNA tumor viruses. Considering that papilloma- and polyomaviruses cause diseases associated either with productive infection (characterized by high production of infectious virus) or transformation (where only a limited number of viral proteins are expressed without synthesis of viral particles), it can be envisaged that cidofovir may act as antiviral and/or antiproliferative agent. The aim of this review is to discuss the advances in recent years in understanding the mode of action of ANPs as antiproliferative agents, given the fact that current data suggest that their use can be extended to the treatment of non-viral related malignancies.publisher: Elsevier articletitle: Insights into the mechanism of action of cidofovir and other acyclic nucleoside phosphonates against polyoma- and papillomaviruses and non-viral induced neoplasia journaltitle: Antiviral Research articlelink: http://dx.doi.org/10.1016/j.antiviral.2014.10.012 content_type: article copyright: Copyright © 2014 Elsevier B.V. All rights reserved.status: publishe

Spectrum of activity and mechanisms of resistance of various nucleoside derivatives against gammaherpesviruses

The susceptibilities of gammaherpesviruses, including Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and animal rhadinoviruses, to various nucleoside analogs was investigated in this work. Besides examining the antiviral activities and modes of action of antivirals currently marketed for the treatment of alpha- and/or betaherpesvirus infections (including acyclovir, ganciclovir, penciclovir, foscarnet, and brivudin), we also investigated the structure-activity relationship of various 5-substituted uridine and cytidine molecules. The antiviral efficacy of nucleoside derivatives bearing substitutions at the 5 position was decreased if the bromovinyl was replaced by chlorovinyl. 1-β-d-Arabinofuranosyl-(E)-5-(2-bromovinyl)uracil (BVaraU), a nucleoside with an arabinose configuration of the sugar ring, exhibited no inhibitory effect against rhadinoviruses but was active against EBV. On the other hand, the fluoroarabinose cytidine analog 2'-fluoro-5-iodo-aracytosine (FIAC) showed high selectivity indices against gammaherpesviruses that were comparable to those of brivudin. Additionally, we selected brivudin- and acyclovir-resistant rhadinoviruses in vitro and characterized them by phenotypic and genotypic (i.e., sequencing of the viral thymidine kinase, protein kinase, and DNA polymerase) analysis. Here, we reveal key amino acids in these enzymes that play an important role in substrate recognition. Our data on drug susceptibility profiles of the different animal gammaherpesvirus mutants highlighted cross-resistance patterns and indicated that pyrimidine nucleoside derivatives are phosphorylated by the viral thymidine kinase and purine nucleosides are preferentially activated by the gammaherpesvirus protein kinase.status: publishe

Viral fitness of MHV-68 viruses harboring drug resistance mutations in the protein kinase or thymidine kinase

Murine γ-herpesvirus-68 (MHV-68), genetically and biologically related to human γ-herpesviruses Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus, can be easily propagated in vitro allowing drug resistance studies. Previously, we described specific changes in MHV-68 protein kinase (PK) or thymidine kinase (TK) associated with resistance to various purine or pyrimidine nucleoside analogues, respectively. To investigate how specific TK and PK mutations affect viral replication capacity, we performed dual infection competition assays in which wild-type and drug-resistant virus compete in absence or presence of antivirals in Vero cells. The composition of the mixed viral population was analyzed using next-generation sequencing and relative fitness of seven MHV-68 PK or TK mutants was calculated based on the frequency of viral variants at the time of infection and after 5-days growth. A MHV-68 mutant losing the PK function due to a 2-nucleotide deletion was less fit than the wild-type virus in absence of antivirals, consistent with the essential role of viral PKs during lytic replication, but overgrew the wild-type virus under pressure of purine nucleosides. TK mutant viruses, with frameshift or missense mutations, grew equal to wild-type virus in absence of antivirals, in accordance with the viral TK function only being essential in non-replicating or in TK-deficient cells, but were more fit when treated with pyrimidine nucleosides. Moreover, TK missense mutant viruses also increased fitness under pressure of antivirals other than pyrimidine nucleosides, indicating that MHV-68 TK mutations might influence viral fitness by acting on cellular and/or viral functions that are unrelated to nucleoside activation.status: publishe