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Signs herpes outbreak is coming

Des souches cliniques de virus herpes simplex (VHS) isolees de patients atteints du SIDA et recevant une therapie au foscarnet ont ete evaluees pour leur sensibilite envers l’adefovir.
Sequential herpes simplex virus (HSV) isolates from AIDS patients receiving foscarnet therapy were evaluated for their susceptibility to adefovir. Foscarnet, a pyrophosphate analogue that inhibits directly the herpes simplex virus (HSV) DNA polymerase (pol), is the primary alternative treatment for immunocompromised patients with suspected or confirmed acyclovir-resistant HSV infections [Safrin et al., 1991]. We identified previously DNA pol mutations that were associated with resistance to foscarnet in clinical HSV isolates recovered from HIV-infected subjects [Schmit and Boivin, 1999].
For the first five patients (1 to 5), sequential isolates (pre- and post-foscarnet therapy) were available. ANP compounds are characterized by their long intracellular half-life allowing infrequent dosing and by their large spectrum of antiviral activity [Naesens et al., 1997]. Each foscarnet-resistant virus from this study contained one or two nucleotide substitutions within the conserved regions II, III, VI, and between regions I and VII of the HSV DNA pol gene [Schmit and Boivin, 1999].
Finally, this study did not allow the identification of mutations associated with a significant decrease in susceptibility to cidofovir.
To our knowledge, this is the first report in which clinical HSV 1 and 2 isolates resistant to foscarnet were evaluated for their susceptibility to adefovir. Lalezari JP, Drew WL, Glutzer E, Miner D, Safrin S, Owen WF, Jr., Davidson JM, Fisher PE, Jaffe HS.
Lalezari J, Schacker T, Feinberg J, Gathe J, Lee S, Cheung T, Kramer F, Kessler H, Corey L, Drew WL, Boggs J, McGuire B, Jaffe HS, Safrin S. Safrin S, Crumpacker C, Chatis P, Davis R, Hafner R, Rush J, Kessler HA, Landry B, Mills J. Snoeck R, Andrei G, Gerard M, Silverman A, Hedderman A, Balzarini J, Sadzot-Delvaux C, Tricot G, Clumeck N, De Clercq E.
La resistance des virus herpes simplex (VHS) a l’acyclovir (ACV) est principalement conferee par des mutations dans le gene de la thymidine kinase (TK) virale. Clinical resistance of Herpes simplex virus (HSV) type 1 and 2 to acyclovir (ACV) is usually caused by the presence of point mutations within the coding region of the viral thymidine kinase (TK) gene.
Acyclovir (ACV)-resistant Herpes simplex viruses (HSV) infections are relatively frequent and can be associated with significant morbidity among immunocompromised patients [14, 15, 17, 37, 38].
Changes in the TK gene can result in viruses producing no or partial amounts of TK or with an altered substrate specificity [4, 23]. Characterization of the TK gene from ACV-susceptible isolates frequently reveals the presence of non-silent mutations outside the active sites of the TK gene reflecting a certain degree of viral polymorphism [21, 24, 25]. ACV-resistant HSV viruses are recovered relatively frequently from immunocompromised subjects receiving this drug for a prolonged period of time [8]. In the clinic, HSV resistance to nucleoside analogues is usually confirmed by determination of IC50 values using the time-consuming and subjective PRA.
IC50 value for GCV of 6391 µM) although additional experiments are needed to appreciate the overall contribution of the DNA pol mutation in the ACV-resistant phenotype. It is particularly important to assess the role of viral substitutions in the case where a high degree of gene polymorphism is present and no pre-therapy isolates are available. The HSV TK and the phosphotransferase neomycine (NEO) genes are under the control of the intergenic region (IR) of the Leishmania enrietti α-tubulin gene [22] represented by the grey boxes.
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Chapitre 32 Herpesviridae Les virus herpes simplex (type 1 et 2) (HSV) Les virus de la varicelle et du Zona (VZV) Le cytomegalovirus (CMV) Le virus dEpstein-Barr(EBV) Lherpesvirus humain 6 et 7 Le virus B du singe memingo-encephalite mortelle. Les virus herpes simplexe(HSV) Morphologie et Structure virus 150-200nm spheriques, icosaedriques enveloppes, ADN bicatenaire acide nucleique deux segments lies de facon covalente.
Les virus de la varicelle et du Zona le meme virus un type antigenique reservoir de virus humain. Zona persister des annees dans les ganglions des racines rachidiennes posterieures reactivation: le virus se propage le long des fibres nerveuses sensitives juaqua la peau, reaction inflammatoire de cette racine rachidienne et des vesicules cutanees sur la zone dinnervation de cette racine. Le virus dEpstein-Barr (Virus EB) agent de la mononucleose infectieuse (MI) lymphome de Burkitt carcinome du rhinopharynx.
Suite la lyse cellulaire nintervient que tres rarement, lorsque le cycle de replication du virus aboutit a la production de virion. Infection a herpes virus de l’enfant et de l’adulte : §herpes cutaneomuqueux §varicelle §zona. Chapitre 26 Les virus de la voie respiratoire maladies respiratoiresdes infections generalisees. HEPATITES Hepatites virales Hepatites medicamenteuses Hepatites alcooliques Hepatites toxiques. L'herpes est un virus qui peut entrainer des cloques et des plaies qui apparaissent sur les muqueuses.
Le virus de l'herpes simplex provoque des lesions douloureuses et inesthetiques sur la bouche ou les organes genitaux. Les infections de l'herpes simplex se caracterisent par l'apparition de petites vesicules rouges, individuellement ou en groupes, sur la bouche, des levres, les parties genitales ou dans les yeux.
Environ une personne sur six Americains ages de 14 a 49 ans ont l'herpes de type 2, selon les Centers for Disease Control and Prevention. Les deux virus herpes simplex, HSV-1 ou HSV-2, sont a l'origine de l'herpes oraux et genitaux. Garder les poussees d'herpes a distance peut etre aussi simple que la negociation dans le melange de sentiers pendant l'heure du gouter. L'herpes est une famille de virus qui provoque une serie de maladies, a partir d'un bouton de fievre sur les levres a des maladies dangereuses telles que la mononucleose.
L'herpes simplex virus de type 1, le HSV-1, est l'un des deux infections a herpes simplex qui peuvent infecter l'homme. L'herpes est causee par le virus de l'herpes simplex, qui peut infecter les muqueuses de la bouche et de l'appareil genital.
Vue d'ensemble L'herpes genital (virus de l'herpes simplex ou HSV) peuvent etre difficiles a diagnostiquer parce que les symptomes sont similaires a ceux d'autres maladies sexuellement transmissibles, ou ils peuvent etre trop doux a remarquer.
Parmi les souches d'herpes 25 ou plus connus, huit peut infecter les etres humains, selon les manuels de Merck. L'herpes est une maladie commune qui affecte les regions buccales et genitales chez les hommes.
L'herpes genital est causee par le virus de l'herpes simplex et peut affecter les hommes et les femmes. Une mauvaise experience avec un medecin peut varier de, une attitude brutale insensible a la negligence pure et simple qui pourrait causer des dommages physiques ou meme la mort. Jeans viennent dans beaucoup de coupes et de styles; mais parfois il peut etre difficile a essayer de comprendre ce qui est bon pour vous.
Cancer du ganglion lymphatique, communement appele le lymphome, le cancer qui se produit dans les cellules des ganglions lymphatiques.
Lorsque vous essayez de maintenir une peau saine, il est utile de manger certains aliments sains qui sont riches en nutriments specifiques. Une machine jambe-extension isole et renforce les muscles sur le devant de la jambe superieure, vos quadriceps. Il est difficile de battre le sentiment de monter dans un lit qui est deja chaud, surtout en hiver quand il fait froid dehors. Herpes simplex virus (HSV) DNA polymerase (pol) mutations can confer resistance to all currently-available anti-herpetic drugs. Two categories of antivirals are available for the management of herpes simplex virus (HSV) infections. Resistance to ACV, the most widely-used anti-HSV agent, is mainly due to mutations in the viral thymidine kinase (TK) gene which impairs the initial drug phosphorylation (24). The putative catalytic domain of the HSV DNA pol enzyme contains eight conserved regions designated I to VII along with δ-region C (9, 28, 48). The set of five overlapping DNA cosmids containing the entire genome of strain 17 was kindly donated by Dr Charles Cunningham, Institute of Virology, United Kingdom (17). Mutagenesis was performed using the QuickChangeTM Site-Directed mutagenesis kit (Stratagene), according to the manufacturer’s instructions.
Susceptibility to ACV, FOS, CDV (gift from Gilead), and ADV (gift from Gilead) was determined by a plaque reduction assay (PRA) on Vero cells (42). Cotransfection into Vero cells of digested cosmids and plasmids generated infectious recombinant viruses with typical cytopathic effects usually observed within 3 days. A total of twenty DNA pol mutants were evaluated in this study by generating two independent recombinants for each specific mutation. When not lethal, some of the previously-reported HSV mutations in δ-region C have been associated with resistance to pyrophosphate analogues (23, 30, 34), whereas other mutations within the same region of the HCMV DNA pol have been associated with resistance to ganciclovir (GCV) and CDV (13, 21, 31, 45). Mutations located in conserved region II of the HSV DNA pol gene are frequently associated with resistance to ACV and pyrophosphate analogues (2, 23, 35, 43).
Only a few mutations have been described in conserved region VI of the DNA pol gene of HSV (7, 44), or HCMV (5, 13, 45, 47), and all were identified in clinical isolates. Onlya few mutations located between conserved regions of the HSV DNA pol gene have been reported in drug-resistant viruses (2, 7, 23, 44). Although HSV resistance to ACV is mostly due to alterations within the TK gene (24), mutations within the viral DNA pol gene can be more problematic as the latter protein is the target of all anti-herpetic agents. The main advantage of our method consists of the lack of a drug selection step, since only homogenous progeny of mutant virus is generated from the overlapping viral fragments.
Our results demonstrate that mutations in all conserved regions of the enzyme could be associated with ACV resistance. Mutations associated with FOS resistance were found to be mostly located within conserved regions II, VI, and I.
ADV resistance was associated with several DNA pol mutations mainly in regions II, VI, I, and VII, as previously reported in laboratory-derived (2) and clinical (7) HSV isolates. The viral pol is an essential enzyme part of a complex of seven proteins involved in the viral DNA replication cycle. In summary, we showed that the structure-function relationship of the HSV DNA pol catalytic domain was more complex than what could be assumed based on HCMV recombinants studies (13). The authors would like to thank Dominic Gagne for technical support and helpful discussions.
However, a significant level of toxicity may occur following prolonged intravenous foscarnet therapy.
In contrast to acyclovir but similar to foscarnet, ANP derivatives do not require a virally-dependent phosphorylation step [Merta et al., 1990] with the potential to inhibit most acyclovir-resistant isolates containing thymidine kinase (TK) mutations. We now report on susceptibility patterns to adefovir induced by viral DNA pol mutations from the same clinical isolates.
Viral susceptibility of those isolates to acyclovir, foscarnet and cidofovir has been previously reported by our group [Schmit and Boivin, 1999]. Such features are particularly interesting when treating immunocompromised patients with several concomitant opportunistic viral infections. Mutations in regions II, VI, and between I and VII were also associated with a valuable decrease in adefovir susceptibility.
The post-foscarnet isolate of patient 1 had a moderate (2.7-fold) increase in cidofovir IC50 value when compared to the pre-foscarnet strain.
Our results demonstrate that most foscarnet-resistant clinical HSV isolates are also associated with a remarkable decrease in adefovir susceptibility. Cidofovir-resistant HSV isolates were not selected in our patients receiving prolonged therapy with acyclovir and foscarnet. Il est difficile avec les methodes actuelles (transfection et recombinaison homologue) de faire la distinction entre les mutations virales impliquees dans la resistance et celles faisant simplement partie du polymorphisme genetique. The distinction between viral TK mutations involved in ACV resistance or part of viral polymorphism can be difficult to evaluate with current methodologies based on transfection and homologous recombination. Resistance to ACV can be the result of point mutations within the viral thymidine kinase (TK) gene, the enzyme responsible for the initial phosphorylation of ACV into ACV-monophosphate or, more rarely, mutations within the viral DNA polymerase (pol) gene [4, 10]. Recent studies by our group [16] and others [25] have demonstrated that about 50% of the clinical ACV-resistant strains contain an insertion or a deletion of 1 or 2 nucleotides in homopolymer runs of Gs and Cs, whereas the other half presents single-base substitutions in conserved or non-conserved regions of the TK gene.
At this time, identification of TK mutations conferring resistance to nucleoside analogues is fastidious and requires transfection of the mutated TK gene in a wild-type virus by a rare homologous recombination event followed by selection of the recombinant strain with an antiviral drug. Susceptibility to ACV was determined by a plaque reduction assay (PRA) performed on Vero cells [39].
Eighteen HSV clinical isolates were recovered from 12 patients, including 10 HIV-infected subjects (1-3, 5-10, 12), one solid organ transplant recipient (4), and one subject with undefined underlying illness (11). When compared to pre-therapy ACV-susceptible clinical isolates, ACV-resistant isolates from patients 1-5 contained at least one distinct mutation within the coding region of the TK gene (Table 1).
Rapid genotypic characterization of drug-resistant mutants directly from clinical biological fluids requires a good knowledge of viral mutations associated with resistance and those associated with viral polymorphism [21, 24, 25]. DNA sequencing of the open reading frame of the TK gene can further confirm the resistance phenotype of an isolate by identifying mutations most likely responsible for ACV resistance. Mutations occurring within the catalytic domains or conserved regions of the enzyme are presumed to be responsible for ACV resistance. Moreover, a similar strategy can be used to evaluate the activity of the TK enzyme or its analogue in other herpesviridae (for example varicella zoster virus [40]) and the impact of TK mutations detected in such viruses. Vous vous interdisez d'y diffuser des messages dont les propos sont contraires a la loi (lire l'article 4 des CGU) ou dont le contenu reproduirait sans autorisation une oeuvre protegee par la propriete intellectuelle (tels qu'articles de presse, message d'un tiers). La primo-infection a HSV-1 transmission entre 1 et 3 ans, contact direct avec le liquide vesiculaire ou la salive. SOUS FAMILLE Espece Alpha-herpesvirinae Herpes simplex type 1 HSV-1 Herpes simplex type 2 HSV-2 Varicelle-zona VZV Beta-herpesvirinae. DEFINITION: Maladie infectieuse generalement benigne due a une primo-infection par le virus EPSTEIN BARR appartenant.
Les virus sont des micro-organismes a parasitisme intracellulaire obligatoire, dotes dun seul type dacide nucleique, ADN ou ARN. Introduction Homme seul reservoir Virus tres fragile Transmis par contact cutaneomuqueux direct Diffuse par propagation le.
Les modes et les voies de transmission Transmission horizontale dun individu a un autre Les voies muqueuses. Generalites (1) Appartient a la sous famille des Paramyxoviridae, genre Rubulavirus Virus a tropisme glandulaire. Le VIH Recepteur viral – Gp120 Recepteur cellulaire – CD4 Cellules Ta, monocytes et macrophages Ninfecte pas.
Le VHS est la cause de multiples infections qui peuvent A?tre, dans certains cas, mortelles.
La condition tend a se reproduire dans le temps et peut varier d'une plaie sur la paupiere a la cicatrisation de la cornee et eventuellement perte de vision.
Dans chaque cas, les symptomes sont similaires: des plaques rouges qui demangent ou picotement, puis un jour ou deux de cloques qui durent quelques jours puis se ouvrent. Les deux virus entrent par les surfaces humides, telles que la bouche, l'anus ou le vagin, ou a travers de petites fissures dans la peau.
Certains aliments, en particulier ceux riches en arginine d'acide amine, peuvent declencher la croissance virale. L'herpes oral est causee par de l'herpes simplex virus de type 1 tandis que l'herpes genital est causee par le virus de l'herpes simplex de type 2. Jusqu'a 90 pour cent des adultes aux Etats-Unis ont ete exposes a HSV-1, selon l'Universite du Maryland Medical Center en 2007. Il est le plus souvent transmise sexuellement et peut causer de la douleur, des demangeaisons et une sensation de brulure dans la region genitale.
Bonne et due forme, le poids et la technique sont necessaires pour eviter les blessures sur cette machine. D’un autre cote, la distinction entre les mutations responsables de la resistance aux antiviraux de celles faisant simplement partie du polymorphisme viral est difficile a evaluer avec les methodes actuelles.
However, discrimination between mutations responsible for drug resistance and those part of viral polymorphism can be difficult with current methodologies. These regions share significant amino acid sequence homology with all other herpesvirus DNA pol enzymes.
Vero cells were maintained in Eagle’s minimum essential medium supplemented with 10% fetal calf serum and antibiotics.
All enzymes were inactivated and the seven overlapping DNA fragments were cotransfected in 6-well plates containing Vero cells using LipofectamineTM 2000 (Life technologies) according to the manufacturer’s instructions.
Viral DNA was then transferred onto Hybond-N+ membranes (Amersham) and probed with the various cosmids labelled by the ECL direct nucleic acid labelling system (Amersham) according to the manufacturer’s instructions. The mean 50% inhibitory concentration (IC50) value for each mutant virus was determined by testing in duplicate each of two independently-generated recombinants.
Those mutations were selected on the basis of their presence within clinical HSV isolates reported by our group (7, 44) and others (28), or within laboratory-derived HSV strains (2, 23, 29, 30, 33, 35, 37). Two (A719T and S724N) of the four mutations located within this region conferred a similar phenotype and were also associated with ADV resistance. Mutation D907V was identified in a clinical HSV-2 isolate that also contained a TK mutation (44).


Mutations within this gene can thus alter the replicative capacity of herpesviruses (6, 14, 25, 29, 34, 37). Mutants F891C and Y941H were so severely impaired in their ability to propagate in cell culture that sufficient titers could not be obtained to perform replication kinetic experiments (Figure 3).
In this study, we designed a novel approach to elucidate the role of specific DNA pol mutations by using a set of overlapping viral plasmids and cosmids.
Although the chosen resistance definition for our recombinants was somewhat arbitrary (2-fold increase in IC50 value over wt), we were able to corroborate most previously-reported ACV resistance phenotypes associated with DNA pol mutations in laboratory-derived (2, 23, 33, 35, 37) and clinical (28, 40) HSV isolates. Mutation D907V, which is located in a non conserved region, was also associated with resistance to FOS.
We found that a few DNA pol mutants within regions II, VI, and III exhibited decreased susceptibility towards this antiviral.
Moreover, consistent with the previous HSV studies (2, 7) and with those of HCMV recombinants (13), an almost perfect cross-resistance pattern was seen between FOS and ADV in our HSV recombinants.
As such, it is not unexpected that some DNA pol mutations could affect the efficiency of viral growth (6, 14, 25, 29, 34, 37). Also, our results confirm that resistance to a single drug such as ACV can be mapped to numerous conserved regions as well as non-conserved regions of the DNA pol which will limit rapid genotyping analysis based on discriminative PCR or RFLP analysis.
Genotypic characterization of the DNA polymerase of a clinical herpes simplex virus type 1 (HSV-1) isolate with a unique phenotype, abstr.V-921m o,436. Resistance of herpes simplex virus type 1 against different phosphonylmethoxyalkyl derivatives of purines and pyrimidines due to specific mutations in the viral DNA polymerase gene. Differential susceptibility of several drug-resistant strains of herpes simplex virus type 2 to various antiviral compounds.
Four dually resistant human cytomegalovirus strains from AIDS patients: single mutations in UL97 and UL54 open reading frames are responsible for ganciclovir- and foscarnet-specific resistance, respectively. Single amino acid changes in the DNA polymerase confer foscarnet resistance and slow-growth phenotype, while mutations in the UL97-encoded phosphotransferase confer ganciclovir resistance in three double-resistant human cytomegalovirus strains recovered from patients with AIDS.
Herpes simplex virus isolates with reduced adefovir susceptibility selected in vivo by foscarnet therapy. Highly reliable heterologous system for evaluating resistance of clinical herpes simplex virus isolates to nucleoside analogues. Novel mutations in the thymidine kinase and DNA polymerase genes of acyclovir and foscarnet resistant herpes simplex viruses infecting an immunocompromised patient. Interstrain variation in the human cytomegalovirus DNA polymerase sequence and its effect on genotypic diagnosis of antiviral drug resistance. Characterization of drug resistance-associated mutations in the human cytomegalovirus DNA polymerase gene by using recombinant mutant viruses generated from overlapping DNA fragments. A point mutation in the human cytomegalovirus DNA polymerase gene selected in vitro by cidofovir confers a slow replication phenotype in cell culture. Characterization of a DNA polymerase mutant of herpes simplex virus from a severely immunocompromised patient receiving acyclovir.
Site-specific mutagenesis of a highly conserved region of the herpes simplex virus type 1 DNA polymerase gene. Resistance to antiviral inhibitors caused by the mutation S889A in the highly-conserved 885-GDTDS motif of the herpes simplex virus type 1 DNA polymerase. Assessing the contribution of the herpes simplex virus DNA polymerase to spontaneous mutations.
Drug-resistant human cytomegalovirus infection in children after allogeneic stem cell transplantation may have different clinical outcomes.
Identification of amino acids in herpes simplex virus DNA polymerase involved in substrate and drug recognition. Mutations within conserved motifs in the 3'-5' exonuclease domain of herpes simplex virus DNA polymerase. Aphidicolin resistance in herpes simplex virus type I reveals features of the DNA polymerase dNTP binding site. The enzymological basis for resistance of herpesvirus DNA polymerase mutants to acyclovir: relationship to the structure of alpha-like DNA polymerases. A point mutation within a distinct conserved region of the herpes simplex virus DNA polymerase gene confers drug resistance. Effects of mutations in the Exo III motif of the herpes simplex virus DNA polymerase gene on enzyme activities, viral replication, and replication fidelity. Mutations in the Exo III motif of the herpes simplex virus DNA polymerase gene can confer altered drug sensitivities. Mutations conferring ganciclovir resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. Restoration of wild-type pathogenicity to an attenuated DNA polymerase mutant of herpes simplex virus type 1. Engineered herpes simplex virus DNA polymerase point mutants: the most highly conserved region shared among alpha-like DNA polymerases is involved in substrate recognition. The structure and function of the HSV DNA replication proteins: defining novel antiviral targets. Bacteriophage T4 DNA polymerase mutations that confer sensitivity to the PPi analog phosphonoacetic acid. A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome. Bone marrow transplantation in a child with Wiskott-Aldrich syndrome latently infected with acyclovir-resistant (ACVr) herpes simplex virus type 1: Emergence of foscarnet-resistant virus originating from the ACVr virus. Characterization of the DNA polymerase and thymidine kinase genes of herpes simplex virus isolates from AIDS patients in whom acyclovir and foscarnet therapy sequentially failed. High-level resistance of cytomegalovirus to ganciclovir is associated with alterations in both the UL97 and DNA polymerase genes. Crystal structure of a pol alpha family replication DNA polymerase from bacteriophage RB69.
Mutations conferring foscarnet resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. Primary structure of the catalytic subunit of calf thymus DNA polymerase delta: sequence similarities with other DNA polymerases.
Schematic representation of viral cosmids and plasmids used to generate HSV-1 recombinants. Southern blot analysis of some recombinant HSV-1 wild type (wt) and mutant viruses along with the parental laboratory strain HSV 17 using some of the viral cosmids (cos 24, 51, and 71) as probes.
Plaque morphology of some recombinant HSV-1 wild-type (wt) and mutant viruses in 24-well plates containing Vero cells. Influence of DNA polymerase mutations on HSV replication capacity in single-step growth kinetics. Susceptibility testing for the latter drugs and adefovir were evaluated using a plaque reduction assay [Safrin et al., 1994]. Clinical histories of the patients as well as genotypic characterization of the HSV strains have been previously reported [Schmit and Boivin, 1999]. Moreover, an oral prodrug of adefovir (adefovir dipivoxil) has been developed and is currently in phase III trial for hepatitis B virus infections [Naesens et al., 1997]. However, since this pre-foscarnet isolate also contained a TK mutation, the relevance of this observation is difficult to interpret. Similarly, most DNA pol mutations arising from foscarnet therapy in this study did not confer resistance to acyclovir with the possible exception of DNA pol mutations located in conserved region II. Susceptibilities of several drug-resistant herpes simplex virus type 1 strains to alternative antiviral compounds. Herpes simplex virus-specified DNA polymerase is the target for the antiviral action of 9-(2-phosphonylmethoxyethyl)adenine.
Treatment with intravenous (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]-cytosine of acyclovir-resistant mucocutaneous infection with herpes simplex virus in a patient with AIDS.
A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. Successful treatment of an acyclovir- and foscarnet-resistant herpes simplex virus type 1 lesion with intravenous cidofovir. Biochemical basis for increased susceptibility to cidofovir of herpes simplex viruses with altered or deficient thymidine kinase activity. Phosphorylation of acyclic nucleotide analogs HPMPA and PMEA in L1210 mouse leukemia cell extracts. HPMPC (cidofovir), PMEA (adefovir) and related acyclic nucleoside phosphonate analogues: a review of their pharmacology and clinical potential in the treatment of viral infections. A controlled trial comparing foscarnet with vidarabine for acyclovir- resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome. Successful treatment of progressive mucocutaneous infection due to acyclovir- and foscarnet-resistant herpes simplex virus with (S)-1-(3- hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC). Properties of a 9-(2-phosphonylmethoxyethyl)adenine (PMEA)-resistant herpes simplex virus type 1 virus mutant.
The former mechanism is most frequently seen in the clinic [8, 16, 17, 29], probably because TK is not essential for viral replication in most tissues and culture cells [36]. Resistance to ACV was defined by a 50% inhibitory drug concentration (IC50) value ≥ 8,8 µM [7, 14, 39].
Briefly, parasites expressing the HSV TK gene were grown in the presence of various concentrations of ganciclovir (5-10000 µM).
The first two resistant strains (1b and 2b) had an additional G within a stretch of 7 Gs (nt 433-439) when compared to their pre-therapy counterpart.
Two distinct mutations Asp55Asn and Arg222His were present in the proposed ATP-binding site and in conserved region 5 [3], respectively, of isolate 5b but not in the susceptible virus (5a) isolated from the same patient.
However, two additional amino-acid changes at codons 78 and 140 were also detected in those TK genes. Such distinction is particularly important in the case of point substitutions and when pre-therapy isolates are unavailable.
In some cases, the role of the identified mutation in conferring ACV resistance is highly probable.
However, confirmation of their role in the ACV resistance phenotype may contribute to identify more precisely the importance of specific amino-acid residues part of these domains. Thus, one obvious consequence of our study was to confirm and expand TK gene polymorphisms associated with HSV type 1 and 2 [21, 24, 25] (Table 3).
Un nouveau systeme base sur la transfection de cosmides et de plasmides permettant de generer rapidement des VHS recombinants de type 1 (VHS-1) et qui comportent des mutations dans le gene de l’ADN pol a ete mis au point. A new system is reported for rapid generation of recombinant HSV type 1 (HSV-1) DNA pol mutants based on transfection of a set of overlapping viral cosmids and plasmids.
Acyclovir (ACV) and penciclovir with their respective pro-drugs, valacyclovir and famciclovir, are representative agents of this class and are considered the standard therapy for HSV infections.
HSV DNA pol mutations leading to CDV resistance have also been found in laboratory-derived strains (2, 3), although not yet identified in clinical isolates from patients failing therapy. Drug resistance mutations have been found mainly within such conserved regions of the HSV DNA pol gene with regions II and III containing the greatest clusters of mutations (reviewed in (24)). Although not specifically designed for site-directed mutagenesis experiments in the DNA pol gene, a similar system has been reported for HSV-1 by Cunningham et al. Briefly, a viral fragment corresponding to nt 61377 to 67549 encompassing the entire HSV DNA pol gene (UL30; nt 62807 to 66514) was cloned into the pBluescript II vector (Stratagene) to generate pPol6.
Each mutation was introduced by using a specific pair of mutagenic primers ranging in length from 28 to 40 bp. A 2-fold difference in IC50 values compared to the wt recombinant virus was considered significant as previously reported (13). Overall, Southern blot analysis of the recombinants revealed no structural differences compared to the genome of the parental HSV-1 strain 17.
Furthermore, a few HSV-1 DNA pol mutants were generated based on similar mutations within the HCMV DNA pol gene (5, 6, 13, 32, 45). The former mutants were susceptible to all antivirals, although a slight increase in ACV IC50 values was observed for mutant V573M (mean increase: 1,90-fold). Moreover, mutants L778M and L782I showed some reduction in CDV susceptibility (mean IC50 increase: 2,04- and 1,76-fold, respectively). In contrast to previous results (28, 40), the mutant Y941H (region VII) was not associated with a significant increase in FOS IC50 values although a marked decrease in ACV susceptibility (mean IC50 increase: 9,39-fold) was noted as reported.
Our results confirm the role of this DNA pol mutation in conferring resistance to ACV, FOS, and ADV.
For instance, we were unable, despite many attempts, to generate two mutants (K552E and Y577H) located within δ-region C. The extracellular yield of the other recombinant mutants were determined over a period of 144 h post-infection and compared to the wt (Figure 4). Twenty DNA pol recombinant mutants were generated and tested for their drug susceptibility patterns.
The HSV DNA pol is a multi-functional enzyme that shows several similarities with α-like DNA pols (9). Of interest, mutation F891C, within conserved region I, was shown to confer the highest level of resistance to ACV in our study. While some mutations part of conserved region III have been associated with resistance to pyrophosphate analogues (7, 23, 26, 44), the three mutants tested in this study remained susceptible to FOS.
Only one of these HSV-1 mutants (K805Q) had the same drug resistance phenotype as described for HCMV (13). Importantly, we found that some HSV DNA pol mutations (including ones previously-reported in clinical isolates) are associated with a resistance phenotype to all currently-available anti-herpetic agents emphasizing the need to develop new drugs with different mechanisms of action. Extracellular viruses were collected at different times (up to 144 h post infection) and titrated. Thus, development of new anti-HSV agents with different mechanisms of action is of high interest. Ten wild type (wt) (five HSV 1 and five HSV 2) isolates from untreated immunocompetent subjects, and two control strains (MS2 and KOS) were also tested for their susceptibility to the different antivirals.
Table I summarizes the mean IC50 values (from three different experiments) to acyclovir, foscarnet, cidofovir, and adefovir for all isolates.
However, further experiments using recombinant viruses are needed to confirm this observation. Indeed, HSV mutants with deficient or altered TK activity have been reported to be more susceptible to cidofovir in tissue culture than parental strains, probably due to a decreased dCTP pool in infected cells [Mendel et al., 1995]. In conclusion, adefovir would not constitute a valuable alternative treatment for immunocompromised patients developing HSV infections resistant to foscarnet therapy. However, several reports have demonstrated that TK activity facilitates HSV reactivation from latency in neural ganglia [11, 13, 44, 46]. Reference laboratory HSV strains KOS (HSV type 1) and MS2 (HSV type 2) were used as susceptible controls. Results were compared with known TK sequences from KOS (type 1) or 333 (type 2) reference strains and to sensitive pre-therapy isolates from patients when available. After 72 h of incubation, the growth of the parasites was assessed by measuring the absorbance of culture medium at 600 nm and the IC50 value was determined.
Isolate 3b had a single base substitution at nt 1007 which resulted in a Cys to Tyr amino-acid change at codon 336. Both are located in non-conserved regions of HSV TK and have been reported in ACV-susceptible isolates described in this study (Table 1) and elsewere [20, 24, 31].
Homologous recombination of a mutated TK gene in a wild-type virus following transfection is the method currently in use to confirm the role of specific point mutations. For instance, nucleotide deletion or addition in G and C homopolymer runs have been commonly reported in ACV-resistant isolates [16, 41, 42]. Such knowledge could be used to rapidly ascertain the role of specific viral mutations in isolates or directly in clinical samples when some of them have been already associated with gene polymorphism. Les sites majeurs da€™une infection latente sont les neurones sensitifs, plus particuliA?rement au niveau des corps ganglionnaires (Figure 4). Using this approach, twenty HSV-1 recombinants with single or dual mutations within the DNA pol gene were successfully generated and subsequently evaluated for their susceptibility to acyclovir (ACV), foscarnet (FOS), cidofovir (CDV), and adefovir (ADV).
Although not indicated for the treatment of HSV infections, cidofovir (HPMPC, CDV) and adefovir (PMEA, ADV) are acyclic nucleoside phosphonate (ANP) derivatives that, once activated, are also alternative substrates for the viral DNA pol. Moreover, our group has previously reported the emergence of HSV DNA pol mutations associated with a reduction in both FOS and ADV susceptibility in patients receiving FOS therapy (7). The correct nucelotide sequence of the catalytic domain of the DNA pol gene from each mutated plasmid was verified by sequence analysis and compared to reference strain 17.
The catalytic domain of the DNA pol gene from each recombinant was amplified and verified by DNA sequencing.
Each recombinant was tested at least twice for its susceptibility to four antivirals (ACV, FOS, CDV, and ADV) by using the PRA (Table 1). Recombinant P561S demonstrated a marked increase in ADV susceptibility compared to the wt virus (mean IC50 decrease: 4,76-fold). Mutation V715M led to significant and almost significant (1,8-fold) decreased levels of susceptibility to ACV and ADV, respectively, whereas it was associated with susceptibility to FOS and hypersusceptibility to CDV (mean IC50 decrease: 2,86-fold). The three recombinants containing mutations within conserved region III were associated with variable levels of resistance or hypersusceptibility towards the different antiviral agents.


Furthermore, this substitution was associated with a significant level of resistance to ADV but induced hypersusceptibility to CDV. Mutation P920S was also found in combination with mutation S724N (region II) in three clinical HSV-1 isolates from an HIV-infected patient (7, 44). Our results have revealed that alterations in a specific conserved region are not necessarily associated with a uniform drug resistance pattern. Although no direct crystallographic data are available to place specific HSV DNA pol mutations in a three-dimensional context, the structural significance of some mutations may be deduced based on similarity with pol regions from other members of this family (22, 27, 46).
It has been previously suggested that this mutation could alter the conformation of this highly conserved region so that the polymerase is less able to incorporate ACV-TP (27).
As the authors did not sequence the entire DNA pol of those laboratory-derived strains, it is possible that additional mutations could be responsible for the CDV-resistant phenotype.
These results suggest the possibility that a unique DNA pol mutation can confer resistance to all available anti-herpetic agents.
Hwang et al., (29, 30) have found a drastic increase in the mutational rate of recombinant Y577H (exoIII motif) generated in a complementary cell line expressing a wt HSV-1 DNA pol (29). The development of efficient methods to generate recombinant viruses like the one reported here should facilitate the understanding of drug resistance mechanisms and the assessment of various viral gene functions. All TK mutations were confirmed by double-strand DNA sequencing from two different PCR products. This mutation has been previously reported in both laboratory-derived HSV-1 mutants [12, 19, 35] and HSV-2 clinical isolates [41] resulting in a TK-altered or TK–low producer phenotype.
Isolate 6b also contained a mutation in the DNA pol gene conferring resistance to foscarnet [42]. However, homologous recombination is a rare event and the need to apply a drug pressure to select for such mutant can lead to additional viral mutations.
As an example, the Asn to Asp change at position 78 that was found in both ACV-susceptible and –resistant strains from our study has been previously reported in an ACV-resistant isolate that also contained a mutation at residue 177 within the nucleoside binding site [20].
Evidence that the "active centre" of the herpes simplex virus thymidine kinase involves an interaction between three distinct regions of the polypeptide.
The other class of HSV inhibitors consists of pyrophosphate analogues such as foscarnet (FOS). When not lethal, some mutations within this region have been shown to confer resistance to pyrophosphate analogues (23, 30, 34, 35).
Herein, we report a modification of the previous cosmid-based recombination system aimed at generating specific HSV-1 DNA pol mutants.
On all occasions, the two generated recombinant viruses harboring the same mutation had similar IC50 values for all antivirals.
Mutation N961K within conserved region V only conferred resistance to ACV, as previously reported in laboratory-derived HSV-1 strains (23). The role of these two mutations was studied by generating three different recombinant viruses. Although codon 552 is not part of the critical exo motifs, the Lys at this position is highly conserved among all herpesviruses. Furthermore, we showed the importance of the central part of the enzyme’s catalytic domain (regions II and VI) as a multi-drug recognition site. The mutant L846I (region III) generated in this study was not associated with FOS resistance. Finally, we confirmed the role of the unique mutant (L778M) reported as CDV-resistant in our previous study (7).
Importantly, we previously reported that such mutations can be selected in vivo in patients who sequentially received ACV and FOS therapy only (7, 44). Thus, despite structural similarities among α-like DNA pols, functional differences regarding interactions with antivirals can be present among distinct viral members (39).
Characterization of drug-resistant viruses and determination of their patterns of cross-resistance may be useful to clarify the selective mechanism of action for new drugs and may facilitate the management of drug-resistant HSV infections in the clinic. All pre-foscarnet isolates from this study contained a TK mutation responsible for acyclovir resistance [Schmit and Boivin, 1999] and these isolates were indeed found to be slightly more susceptible to cidofovir than wt isolates by a factor of 1.8. Isolate 4b contained a nucleotide substitution (C→T) at position 664 that produced a change from Arg to Cys at codon 222. Isolate 7 contained a deleted A at nt 1065 and three other non-silent mutations of which two (Pro42Leu and Arg89Gln) have been found in other pre-therapy isolates from this study and elsewhere [21, 25] and thus presumably associated with gene polymorphism. Thus, based on our work, the functional role of the TK mutation at codon 78 can be definitively ruled out.
Analysis of the thymidine kinase gene from clinically isolated acyclovir-resistant herpes simplex viruses. An altered spectrum of herpes simplex virus mutations mediated by an antimutator DNA polymerase. A point mutation in the thymidine kinase gene is responsible for acyclovir-resistance in herpes simplex virus type 2 sequential isolates. Foscarnet therapy for acyclovir-resistant mucocutaneous herpes simplex virus infection in 26 AIDS patients: preliminary data. Le mutant F891C a ete associe au plus haut niveau de resistance a l’ACV et au FOS et les capacites replicatives de ce mutant furent fortement diminuees.
Mutant F891C was associated with the highest levels of resistance towards ACV and FOS, and was strongly impaired in its replication capacity.
Only a few drug-resistant mutations have been described within the other conserved regions or outside such regions (2, 7, 19, 23, 28, 37, 44). Such approach was used to evaluate the drug susceptibility phenotype and replicative capacities of several HSV-1 DNA pol mutants.
The susceptible mutant P920S had replication kinetics similar to those of the wt (data not shown).
This fact illustrates the difficulty of relying on a specific IC50 value for defining resistance in the absence of a pre-therapy isolate.
This mutation was located next to the corresponding HSV-1 (L845I) mutation reported by our group (7, 44). We also found the same phenotype for the mutant S724N otherwise reported as susceptible to CDV (7). Such differences in drug interaction could be explained by slight variance in the conserved regions of the different viruses combined with distinct conformations created by the diversity of non-conserved domains (38). Only the foscarnet-resistant isolate from patient 6 was definitively still susceptible to adefovir (1.2-fold adefovir IC50 increase) whereas the post-foscarnet isolate from patient 4 was associated with a modest decrease in adefovir susceptibility (2-fold IC50 increase). Moreover, foscarnet- and adefovir-resistant isolates were generally more susceptible to cidofovir than wt isolates by a factor of 2.2. Five HSV isolates recovered from patients either before ACV (n=2) or after foscarnet (n=3) therapy were susceptible to ACV (IC50 range: 2-4,4 µM) as measured by the PRA method. We were also able to confirm the role of an amino-acid substitution in a non-catalytic and non-conserved region of the TK gene (codon 131) in conferring resistance to ACV.
Herpesviral deoxythymidine kinases contain a site analogous to the phosphoryl-binding arginine-rich region of porcine adenylate kinase; comparison of secondary structure predictions and conservation. Polymorphisms of thymidine kinase gene in herpes simplex virus type 1: analysis of clinical isolates from herpetic keratitis patients and laboratory strains. Occurrence and characterization of acyclovir-resistant herpes simplex virus isolates: report on a two-year sensitivity screening survey. Changes in folate and pterin metabolism after disruption of the Leishmania H locus short chain dehydrogenase gene. Finalement, les Gammaherpesvirinae comptent dans leur groupe le virus Epstein-Barr (EBV ou HHV-4) et le HHV-8.
Les kinases cellulaires vont par la suite catalyser la€™ajout de deux autres phosphates pour finalement donner la forme biologique active, la€™ACV triphosphate (Figures 5 et 6). A single DNA pol mutation could thus confer resistance to more than one antiviral depending on the specific drug binding site on the enzyme.
Because of the reported viral polymorphism (12, 33), the role of any DNA pol mutation must be carefully assessed. Two mutations in the C-terminal part of the HSV DNA pol gene have been described in laboratory-derived strains selected with HPMP derivatives (2). Thus, the role of newly-observed mutations in drug resistance must be adequately confirmed even when located close to a known mutation associated with a specific drug phenotype. However, the use of a few wt isolates (not obtained from the same patient) to compare CDV IC50 values may explain such discrepancy. This unusual phenotype has also been reported occasionally for other clinical DNA pol mutants (L850I, N815S) (1, 7), suggesting that subtle differences do exist in the interaction of the two drugs on the enzyme. Along the same line, our V715M HSV-1 mutant had decreased replication capacity as reported for the corresponding HCMV mutant (6). Indeed, interaction of an antiviral with the polymerase requires the folding of several non-contiguous regions within the protein (27, 38). On the other hand, susceptibility of foscarnet-resistant isolates to cidofovir was generally unchanged although one isolate from patient 1 had a 2.7-fold increase in cidofovir IC50 value compared with its foscarnet-susceptible counterpart. The availability of wt TK-competent and post-treatment strains isolated from the same patients will thus be important to evaluate more precisely the patterns of resistance to cidofovir. Thirteen HSV isolates recovered either during or after ACV treatment were resistant to ACV (IC50 range: 9,9-966,1 µM). Such deletions resulted in the generation of a premature stop codon and, presumably, in a truncated TK protein.
Specific mutations could also be evaluated in our system using site-directed mutagenesis on PCR-amplified TK genes.
Phenotypic and genotypic characterization of acyclovir-resistant herpes simplex viruses from immunocompromised patients. In vitro and in vivo characterization of herpes simplex virus clinical isolates recovered from patients infected with human immunodeficiency virus.
Retroviral-mediated gene therapy for the treatment of hepatocellular carcinoma: an innovative approach for cancer therapy. Genetic characterization of thymidine kinase from acyclovir-resistant and -susceptible herpes simplex virus type 1isolated from bone marrow transplant recipients.
Herpes simplex virus isolates from an immunocompromised patient who failed to respond to acyclovir treatment express thymidine kinase with altered substrate specificity. A rapid phenotypic assay for detection of acyclovir-resistant varicella-zoster virus with mutations in the thymidine kinase open reading frame. Latency-associated transcript but not reactivatable virus is present in sensory ganglion neurons after inoculation of thymidine kinase-negative mutants of herpes simplex virus type 1.
The H circles of Leishmania tarentolae are a unique amplifiable system of oligomeric DNAs associated with drug resistance. Replication, latent infection, and reactivation in neuronal culture with a herpes simplex virus thymidine kinase-negative mutant. Marker-transfer experiments, in which a specific mutation is transferred to a wild-type (wt) virus background by homologous recombination, have been used to generate recombinant HSV DNA pol mutants (11, 28, 29, 36, 37, 40). When generated in our system, mutation L1007M conferred an almost significant increase in ACV IC50 values (mean IC50 increase: 1,84-fold) but susceptibility to CDV in contrast to previous data.
In the first case, we were able to confirm the role of mutation D907V located outside conserved regions in the resistance phenotype to ACV.
Most notably, our recombinant Y941H mutant was susceptible to FOS despite the fact that this exact mutation was found in a FOS-resistant HSV-1 clinical isolate (28, 40). Importantly, we did not find a correlation between ACV and CDV resistance in HSV mutants as reported between GCV and CDV in HCMV DNA pol mutants, suggesting that the binding sites of ACV and GCV may differ (4, 15) or that those sites may vary according to the virus. Interestingly, we were successful in generating mutant V573M which involves a non-conserved residue of the exoIII motif. Further experiments such as structural and conformational analysis of the different DNA pol proteins are therefore needed to clarify these observations. The specific point mutations within the viral DNA pol gene of foscarnet-resistant HSV isolates [Schmit and Boivin, 1999] and the resulting drug phenotypes are summarized in table I. For patients with both ACV-susceptible and ACV-resistant isolates, the mean change in IC50 values over time was 22,9 (range: 4,1-55,6). Isolates 8 and 9 also contained an amino-acid substitution (Glu39Gly and Asn78Asp, respectively) in a non-conserved region of the TK gene. However, since only the coding region of the TK gene is expressed in the parasite, any mutations occurring outside this region (i.e. Expression of a Tat-inducible herpes simplex virus-thymidine kinase gene protects acyclovir-treated CD4 cells from HIV-1 spread by conditional suicide and inhibition of reverse transcription.
Protection against Leishmania major challenge infection in mice vaccinated with live recombinant parasites expressing a cytotoxic gene.
Recombinants harboring mutations within conserved regions V (N961K) and VII (Y941H) were resistant to ACV but susceptible to FOS. In addition to being fastidious and inefficient, such methods rely on selection of recombinant mutants through drug pressure which may frequently lead to additional undesired mutations.
This finding, combined with our previous confirmation of the role of a TK mutation in the same clinical isolate (8), establishes the additive effect of mutations in two genes with respect to the final ACV resistance phenotype (7, 43). It is possible that additional DNA pol mutations (not part of the sequenced region) could have been present in the previous isolate.
However, this mutant had some impairment in replication as reported in our study and was also shown to be less neurovirulent in mice (2). The only isolate with high level resistance to acyclovir (patient 5) also contained a TK mutation [Schmit and Boivin, 1999].
The former substitution has been previously associated with a TK-deficient phenotype as determined by plaque autoradiography [41]. Finalement, les mutations dans la region conservee III ont ete associees a divers profils de sensibilite aux differents antiviraux.
Finally, mutations within conserved region III were associated with various susceptibility profiles. In the second case, our data now support a role for the S724N (region II) mutation but not for a concomitant DNA pol mutation (P920S) located outside conserved region in the ACV resistance phenotype. Alternatively, differences in the genetic background of the two HSV-1 strains could also possibly explain the discrepant phenotype. The recombinant F891C, which lies two amino acids next to the invariant YGDTDS motif of conserved region I (37), could also be generated in our study albeit with severe impairment in replication capacities. On the other hand, the amino-acid substitution (Asn78Asp) detected in isolate 9 was also present in one ACV-susceptible isolate from this study (1a).
Ce nouveau systeme permet une evaluation rapide et efficace du role fonctionnel de plusieurs mutations dans le gene de l’ADN pol du VHS, ce qui permettra certainement de faciliter le traitement des infections engendrees par des VHS resistants aux antiviraux.
This new system allows a rapid and accurate evaluation of the functional role of various DNA pol mutations, which should translate into improved management of drug-resistant HSV infections.
Of note, the acute HSV disease associated with this clinical DNA pol mutant was successfully managed with intravenous FOS therapy (40). Previous investigators have shown that most mutations in this highly-conserved motif inactivate pol elongation activity with a few notable exceptions such as the S889A mutant (18, 19).
Isolate 10 contained a nt substitution at codon 131 resulting in a threonine to proline change within a non-conserved region of the HSV TK gene.
Isolate 11 contained a substitution at nt 527 that resulted in an amino-acid substitution at codon 176 within the putative nucleoside binding site as well as two other changes (codon 42 and 89) associated with gene polymorphism [21, 25].
The amino-acid change (Arg176Glu) has been previously reported in a laboratory-derived HSV-1 mutant [12] and in ACV-resistant HSV-1 isolates [30]. A 3G for 3C substitution was observed in isolate 12 at positions 175-179 within the proposed ATP-binding site [42]. Acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome.
Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate. Long-term survival of rats harboring brain neoplasms treated with ganciclovir and a herpes simplex virus vector that retains an intact thymidine kinase gene. Role of genotypic analysis of the thymidine kinase gene of herpes simplex virus for determination of neurovirulence and resistance to acyclovir.
LAT empA?cherait aussi la€™apoptose des neurones sujets A  une infection latente par le VHS [99].
En effet, la€™ARN pol II de la cellule hA?te est responsable la transcription de tout les ARN messagers (m) viraux [27].
La€™ensemble des symptA?mes da€™une infection labiale primaire varie grandement da€™un individu A  la€™autre.
Ce type da€™infection comporte une production importante de virus pouvant persister jusqua€™A  3 semaines suite A  la€™infection. En effet, une valeur quantitative de la charge virale est un bon indicateur du pronostic de la maladie [165, 166]. La VDE est disponible en onguent (crA?me 3%) pour le traitement des infections oculaires A  VHS.



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