RESUMO
Cheetahs (Acinonyx jubatus) are particularly susceptible to feline herpesvirus-1 (FHV-1). Recommendations for preventive health care in cheetahs include vaccination against FHV-1 using killed and modified live virus (MLV) vaccines. Although MLV vaccines tend to induce a more robust immune response than killed vaccines, they can induce disease. This case series details an FHV-1 outbreak in four adult cheetahs following the use of MLV vaccine in one of them. All four cheetahs developed severe FHV-1 clinical signs and were euthanized. Clinical signs included depression, anorexia, nasal discharge, ocular discharge, sneezing, and ulcerative dermatitis. Herpesvirus infection was diagnosed using history, clinical signs, polymerase chain reaction, and histologic evaluation. The timeline of events suggests the MLV vaccine was the inciting cause, although this was not conclusively proven. Outcome of this case suggests that when considering MLV vaccines for cheetahs, careful risk and benefit discussions are merited.
Assuntos
Acinonyx , Infecções por Herpesviridae/veterinária , Vacinação/veterinária , Vacinas Atenuadas/efeitos adversos , Varicellovirus/fisiologia , Animais , Animais de Zoológico , Feminino , Infecções por Herpesviridae/diagnóstico , Infecções por Herpesviridae/etiologia , Infecções por Herpesviridae/prevenção & controle , Masculino , Resultado do Tratamento , Vacinação/efeitos adversos , Varicellovirus/efeitos dos fármacosRESUMO
Alphaherpesvirus-associated ocular infections in humans caused by human alphaherpesvirus 1 (HHV-1) remain challenging to treat due to the frequency of drug application required and the potential for the selection of drug-resistant viruses. Repurposing on-the-market drugs is a viable strategy to accelerate the pace of drug development. It has been reported that the human immunodeficiency virus (HIV) integrase inhibitor raltegravir inhibits HHV-1 replication by targeting the DNA polymerase accessory factor and limits terminase-mediated genome cleavage of human betaherpesvirus 5 (HHV-5). We have previously shown, both in vitro and in vivo, that raltegravir can also inhibit the replication of felid alphaherpesvirus 1 (FeHV-1), a common ocular pathogen of cats with a pathogenesis similar to that of HHV-1 ocular disease. In contrast to what was reported for HHV-1, we were unable to select for a raltegravir-resistant FeHV-1 strain in order to define any basis for drug action. A candidate-based approach to explore the mode of action of raltegravir against FeHV-1 showed that raltegravir did not impact FeHV-1 terminase function, as described for HHV-5. Instead, raltegravir inhibited DNA replication, similarly to HHV-1, but by targeting the initiation of viral DNA replication rather than elongation. In addition, we found that raltegravir specifically repressed late gene expression independently of DNA replication, and both activities are consistent with inhibition of ICP8. Taken together, these results suggest that raltegravir could be a valuable therapeutic agent against herpesviruses.IMPORTANCE The rise of drug-resistant herpesviruses is a longstanding concern, particularly among immunocompromised patients. Therefore, therapies targeting viral proteins other than the DNA polymerase that may be less likely to lead to drug-resistant viruses are urgently needed. Using FeHV-1, an alphaherpesvirus closely related to HHV-1 that similarly causes ocular herpes in its natural host, we found that the HIV integrase inhibitor raltegravir targets different stages of the virus life cycle beyond DNA replication and that it does so without developing drug resistance under the conditions tested. This shows that the drug could provide a viable strategy for the treatment of herpesvirus infections.
Assuntos
Inibidores de Integrase de HIV/farmacologia , Raltegravir Potássico/farmacologia , Varicellovirus/fisiologia , Replicação Viral/efeitos dos fármacos , Animais , Gatos , Linhagem Celular , DNA Viral/metabolismo , Proteínas de Ligação a DNA/metabolismo , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Varicellovirus/efeitos dos fármacos , Proteínas Virais/metabolismoRESUMO
Guanine-rich sequences in the genomes of herpesviruses can fold into G-quadruplexes. Compared with the widely-studied G3-quadruplexes, the dynamic G2-quadruplexes are more sensitive to the cell microenvironment, but they attract less attention. Pseudorabies virus (PRV) is the model species for the study of the latency and reactivation of herpesvirus in the nervous system. A total of 1722 G2-PQSs and 205 G3-PQSs without overlap were identified in the PRV genome. Twelve G2-PQSs from the CDS region exhibited high conservation in the genomes of the Varicellovirus genus. Eleven G2-PQSs were 100% conserved in the repeated region of the annotated PRV genomes. There were 212 non-redundant G2-PQSs in the 3' UTR and 19 non-redundant G2-PQSs in the 5' UTR, which would mediate gene expression in the post-transcription and translation processes. The majority of examined G2-PQSs formed parallel structures and exhibited different sensitivities to cations and small molecules in vitro. Two G2-PQSs, respectively, from 3' UTR of UL5 (encoding helicase motif) and UL9 (encoding sequence-specific ori-binding protein) exhibited diverse regulatory activities with/without specific ligands in vivo. The G-quadruplex ligand, NMM, exhibited a potential for reducing the virulence of the PRV Ea strain. The systematic analysis of the distribution of G2-PQSs in the PRV genomes could guide further studies of the G-quadruplexes' functions in the life cycle of herpesviruses.
Assuntos
DNA Viral/química , Quadruplex G/efeitos dos fármacos , Regulação Viral da Expressão Gênica , Genoma Viral , Herpesvirus Suídeo 1/genética , Regiões 3' não Traduzidas/efeitos dos fármacos , Regiões 5' não Traduzidas/efeitos dos fármacos , Acridinas/química , Acridinas/farmacologia , Aminoquinolinas/química , Aminoquinolinas/farmacologia , Animais , Bovinos , Linhagem Celular , Biologia Computacional/métodos , DNA Helicases/genética , DNA Helicases/metabolismo , DNA Primase/genética , DNA Primase/metabolismo , DNA Viral/genética , DNA Viral/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Células HEK293 , Herpesvirus Suídeo 1/efeitos dos fármacos , Herpesvirus Suídeo 1/metabolismo , Humanos , Ligantes , Mesoporfirinas/química , Mesoporfirinas/farmacologia , Ácidos Picolínicos/química , Ácidos Picolínicos/farmacologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Suínos , Varicellovirus/efeitos dos fármacos , Varicellovirus/genética , Varicellovirus/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo , Ativação Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
Anti-microbial compounds typically exert their action by directly interfering with one or more stages of the pathogen's life cycle. However, some compounds also have secondary effects on the host that aid in pathogen clearance. Raltegravir is a human immunodeficiency virus (HIV)-integrase inhibitor that has been shown to alter the host immune response to HIV in addition to its direct antiviral effect. Interestingly, raltegravir can also directly inhibit the replication of various herpesviruses. However, the host-targeted effects of this drug in the context of a herpesvirus infection have not been explored. Here, we used felid alphaherpesvirus 1 (FHV-1), a close relative of human alphaherpesvirus 1 (HHV-1) that similarly causes ocular herpes, to characterize the host-targeted effects of raltegravir on corneal epithelial cells during an alphaherpesvirus infection. Using RNA deep sequencing, we found that raltegravir specifically boosts the expression of anti-angiogenic factors and promotes metabolic homeostasis in FHV-1-infected cells. In contrast, few changes in host gene transcription were found in uninfected cells. Importantly, we were able to demonstrate that these effects were specific to raltegravir and independent of the direct-acting antiviral effect of the drug, since treatment with the DNA polymerase inhibitor phosphonoacetic acid did not induce these host-targeted effects. Taken together, these results indicate that raltegravir has profound and specific effects on the host transcription profile of herpesvirus-infected cells that may contribute to the overall antiviral activity of the drug and could provide therapeutic benefits in vivo. Furthermore, this study provides a framework for future efforts evaluating the host-targeted effects of anti-microbial compounds.
Assuntos
Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Inibidores de Integrase de HIV/farmacologia , Raltegravir Potássico/farmacologia , Transcriptoma/efeitos dos fármacos , Varicellovirus/efeitos dos fármacos , Animais , Gatos , Células Cultivadas , Epitélio Corneano/citologia , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Amplificação de Ácido Nucleico , Reprodutibilidade dos Testes , Replicação de Sequência Autossustentável , Organismos Livres de Patógenos Específicos , Varicellovirus/fisiologiaRESUMO
Feline herpesvirus type-1 (FHV-1) is the most common viral cause of ocular surface disease in cats. Many antiviral drugs are used to treat FHV-1, but require frequent topical application and most lack well-controlled in vivo studies to justify their clinical use. Therefore, better validation of current and novel treatment options are urgently needed. Here, we report on the development of a feline whole corneal explant model that supports FHV-1 replication and thus can be used as a novel model system to evaluate the efficacy of antiviral drugs. The anti-herpes nucleoside analogues cidofovir and acyclovir, which are used clinically to treat ocular herpesvirus infection in cats and have previously been evaluated in traditional two-dimensional feline cell cultures in vitro, were evaluated in this explant model. Both drugs suppressed FHV-1 replication when given every 12 h, with cidofovir showing greater efficacy. In addition, the potential efficacy of the retroviral integrase inhibitor raltegravir against FHV-1 was evaluated in cell culture as well as in the explant model. Raltegravir was not toxic to feline cells or corneas, and most significantly, inhibited FHV-1 replication at 500 µM in both systems. Importantly, this drug was effective when given only once every 24 h. Taken together, our data indicate that the feline whole corneal explant model is a useful tool for the evaluation of antiviral drugs and, furthermore, that raltegravir appears a promising novel antiviral drug to treat ocular herpesvirus infection in cats.
Assuntos
Antivirais/farmacologia , Córnea/virologia , Avaliação Pré-Clínica de Medicamentos/métodos , Técnicas de Cultura de Órgãos/métodos , Varicellovirus/efeitos dos fármacos , Cultura de Vírus/métodos , Aciclovir/farmacologia , Animais , Gatos , Cidofovir , Citosina/análogos & derivados , Citosina/farmacologia , Organofosfonatos/farmacologiaRESUMO
Feline herpesvirus type 1 (FHV-1) is a common and important cause of ocular surface disease, dermatitis, respiratory disease, and potentially intraocular disease in cats. Many antiviral drugs developed for the treatment of humans infected with herpesviruses have been used to treat cats infected with FHV-1. Translational use of drugs in this manner ideally requires methodical investigation of their in vitro efficacy against FHV-1 followed by pharmacokinetic and safety trials in normal cats. Subsequently, placebo-controlled efficacy studies in experimentally inoculated animals should be performed followed, finally, by carefully designed and monitored clinical trials in client-owned animals. This review is intended to provide a concise overview of the available literature regarding the efficacy of antiviral drugs and other compounds with proven or putative activity against FHV-1, as well as a discussion of their safety in cats.
Assuntos
Antivirais/farmacologia , Varicellovirus/efeitos dos fármacos , Animais , Doenças do Gato/tratamento farmacológico , Doenças do Gato/virologia , Gatos , Infecções por Herpesviridae/tratamento farmacológico , Infecções por Herpesviridae/veterinária , HumanosRESUMO
In this study we examined the effects of non-myeloablative total body irradiation (TBI) in combination with immunosuppressive chemotherapy on immune homeostasis in rhesus macaques. Our results show that the administration of cyclosporin A or tacrolimus without radiotherapy did not result in lymphopenia. The addition of TBI to the regimen resulted in lymphopenia as well as alterations in the memory/naive ratio following reconstitution of lymphocyte populations. Dendritic cell (DC) numbers in whole blood were largely unaffected, while the monocyte population was altered by immunosuppressive treatment. Irradiation also resulted in increased levels of circulating cytokines and chemokines that correlated with T cell proliferative bursts and with the shift towards memory T cells. We also report that anti-thymocyte globulin (ATG) treatment and CD3 immunotoxin administration resulted in a selective and rapid depletion of naive CD4 and CD8 T cells and increased frequency of memory T cells. We also examined the impact of these treatments on reactivation of latent simian varicella virus (SVV) infection as a model of varicella zoster virus (VZV) infection of humans. None of the treatments resulted in overt SVV reactivation; however, select animals had transient increases in SVV-specific T cell responses following immunosuppression, suggestive of subclinical reactivation. Overall, we provide detailed observations into immune modulation by TBI and chemotherapeutic agents in rhesus macaques, an important research model of human disease.
Assuntos
Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/efeitos da radiação , Imunossupressores/farmacologia , Irradiação Corporal Total/métodos , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Ciclosporina/farmacologia , Citocinas/sangue , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Células Dendríticas/efeitos da radiação , Ensaio de Imunoadsorção Enzimática , Feminino , Homeostase/efeitos dos fármacos , Homeostase/efeitos da radiação , Sistema Imunitário/citologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Leucócitos/efeitos da radiação , Contagem de Linfócitos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Linfócitos/efeitos da radiação , Macaca mulatta/virologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Monócitos/efeitos da radiação , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/efeitos da radiação , Tacrolimo/farmacologia , Varicellovirus/efeitos dos fármacos , Varicellovirus/crescimento & desenvolvimento , Varicellovirus/efeitos da radiação , Carga Viral/efeitos dos fármacos , Carga Viral/efeitos da radiação , Ativação Viral/efeitos dos fármacos , Ativação Viral/efeitos da radiaçãoRESUMO
BACKGROUND: Herpesviruses are ubiquitous pathogens that infect and cause recurrent disease in multiple animal species. Feline herpesvirus-1 (FHV-1), a member of the alphaherpesvirus family, causes respiratory illness and conjunctivitis, and approximately 80% of domestic cats are latently infected. Oral administration of famciclovir or topical application of cidofovir has been shown in masked, placebo-controlled prospective trials to reduce clinical signs and viral shedding in experimentally inoculated cats. However, to the authors' knowledge, other drugs have not been similarly assessed or were not safe or effective. Likewise, to our knowledge, no drugs have been assessed in a placebo-controlled manner in cats with recrudescent herpetic disease. Controlled-release devices would permit long-term administration of these drugs and enhance compliance. METHODS: We therefore engineered implantable cylindrical devices made from silicone (MED-4750) impregnated with penciclovir, for long-term, steady-state delivery of this drug. RESULTS: Our data show that these devices release penciclovir with a burst of drug delivery until the tenth day of release, then at an average rate of 5.063 ± 1.704 µg per day through the next 50 days with near zero-order kinetics (in comparison to MED-4750-acyclovir devices, which show the same burst kinetics and average 2.236 ± 0.625 µg/day thereafter). Furthermore, these devices suppress primary infection of FHV-1 in a cell culture system. CONCLUSIONS: The clinical deployment of these silicone-penciclovir devices may allow long-term treatment of FHV-1 infection with a single intervention that could last the life of the host cat.
Assuntos
Aciclovir/análogos & derivados , Antivirais/metabolismo , Sistemas de Liberação de Medicamentos , Varicellovirus/efeitos dos fármacos , Aciclovir/metabolismo , Animais , Gatos , Células Cultivadas , Guanina , Polímeros , SiliconesRESUMO
BACKGROUND: Feline herpesvirus 1 (FHV-1) is a common cause of ocular and upper respiratory disease in cats and kittens, and a potential cause of eosinophilic dermatitis. HYPOTHESIS: The systemic anti-herpes drug, famciclovir (Famvir; Novartis), would be effective in the clinical management of disease attributable to FHV-1, including conjunctivitis, keratitis, corneal sequestra, rhinosinusitis and FHV-1 associated dermatitis. CLINICAL OUTCOME: Oral famciclovir was used to treat signs considered referable to FHV-1 in 10 cats: four had primary ocular disease, two had rhinosinusitis and four had FHV-1 associated dermatitis. Patients treated in Australia (five cats) and Europe (one cat) were given 62.5 mg of famciclovir once or twice daily. Four cats treated in the USA were given 125 mg three times daily. Famciclovir was uniformly well tolerated and, in all cases, had a positive impact on the patient's condition. The apparent improvement in lesions was superior to what had been achieved previously using other therapeutic strategies. One cat with severe destructive rhinosinusitis was significantly improved by a 4-month course of famciclovir in combination with antibacterials. Corneal sequestra detached in two out of three cats treated; cats with ocular signs were qualitatively more comfortable, with reduced clinical signs and an improved appearance of the eyes. Critically, oral famciclovir therapy was considered more convenient than topical ocular therapy. All four cats with FHV-1 associated dermatitis improved substantially, although relapse occurred subsequently in three patients. A further cat with presumptive FHV-1 associated dermatitis responded to topical aciclovir cream before famciclovir could be sourced. CONCLUSIONS: Famciclovir appears to be a promising systemic drug for treating diseases associated with FHV-1 infection. More rigorous clinical trials are required to optimise the dosing regimen for safe and effective specific anti-herpes treatment in feline clinical medicine.
Assuntos
2-Aminopurina/análogos & derivados , Antivirais/administração & dosagem , Doenças do Gato/tratamento farmacológico , Infecções por Herpesviridae/veterinária , Varicellovirus , 2-Aminopurina/administração & dosagem , Animais , Austrália , Doenças do Gato/virologia , Gatos , Conjuntivite Viral/tratamento farmacológico , Conjuntivite Viral/etiologia , Conjuntivite Viral/veterinária , Úlcera da Córnea/tratamento farmacológico , Úlcera da Córnea/etiologia , Úlcera da Córnea/veterinária , Úlcera da Córnea/virologia , Dermatite/tratamento farmacológico , Dermatite/veterinária , Dermatite/virologia , Famciclovir , Feminino , Infecções por Herpesviridae/tratamento farmacológico , Masculino , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/veterinária , Infecções Respiratórias/virologia , Resultado do Tratamento , Varicellovirus/efeitos dos fármacosRESUMO
Caprine alphaherpesvirus 1 (CpHV-1) induces genital lesions in its natural host similar to those caused by Human alphaherpesvirus 2 (HHV-2), commonly named herpes simplex virus 2 (HSV-2) in human patients. CpHV-1 infection in goats could represent a useful homologous animal model for the study of HSV-2 infection, chiefly for the assessment of antiviral drugs in in vivo studies. PHA767491 is a potent inhibitor of HSV-1 and HSV-2, being able to limit replication of HHVs both in vitro and in the mouse model. In the present study the antiviral efficacy of PHA767491 against CpHV-1 was evaluated in vitro in MDBK cells. PHA767491 inhibited significantly CpHV-1 replication in a dose-dependent fashion by up to 2.50 log10 TCID50/50⯵l and was able to decrease viral DNA by nearly 8 log10. These findings confirm that PHA767491 is highly effective not only against simplexviruses (HSV-1 and HSV-2), but also against the varicellovirus CpHV-1. Experiments will be necessary to assess whether PHA767491 is suitable for treatment of vaginal lesions in CpHV-1-goat model. This could provide hints for the therapy of genital alphaherpesvirus infections in humans.
Assuntos
Antivirais/farmacologia , Piperidonas/farmacologia , Pirróis/farmacologia , Varicellovirus/efeitos dos fármacos , Animais , Linhagem Celular , DNA Viral , Cães , Replicação Viral/efeitos dos fármacosRESUMO
The emergence of alphaherpesvirus strains resistant to commonly used antiviral drugs has prompted the research for alternative, biologically active anti-herpetic agents. Essential oils (EOs) have shown anti-infective properties against human herpes simplex viruses (HSV-1 and -2). Caprine alphaherpesvirus 1 (CpHV-1) induces genital lesions in its natural host and it is regarded as a useful homologous animal model for the study of HSV-2 infection, chiefly for the assessment of antiviral drugs in in vivo studies. In the present study we evaluated the activity in vitro of ginger EO (GEO) against CpHV-1. GEO was found to be effective as virucide on cell-free virus, inactivating CpHV-1 up to 100%. The virucidal activity of GEO is likely accounted for by disruption of herpesvirus envelope and its associated structures which are necessary for virus adsorption and entry into host cells. On the opposite, GEO was not able to inhibit virus adsorption and/or replication, as treatment of cells before and after infection did not abolish virus infectivity. GEO could be suggested for topical applications in in vivo experiments using CpHV-1/goat model, since the lipophilic nature of EOs favours their adsorption through the cutaneous/mucosal barrier, either alone or in conjunction with other molecules. These findings open several perspectives in terms of therapeutic possibilities for a number of human and animal alphaherpesviruses.
Assuntos
Antivirais/farmacologia , Doenças das Cabras/virologia , Óleos Voláteis/farmacologia , Varicellovirus/efeitos dos fármacos , Zingiber officinale/química , Administração Tópica , Animais , Bovinos , Linhagem Celular , Células Epiteliais/virologia , Cabras , Infecções por Herpesviridae/tratamento farmacológico , Infecções por Herpesviridae/veterinária , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
Feline herpesvirus type 1 (FHV-1) and feline calicivirus (FCV) are considered as main causes of feline upper respiratory tract disease and the most common clinical manifestations include rhinotracheitis, conjunctivitis, and nasal/facial ulcerations. While the primary infection is relatively mild, secondary infections pose a threat to young or immunocompromised cats and may result in a fatal outcome. In this study, we made an effort to evaluate antiviral potency of poly(sodium 4-styrenesulfonates) (PSSNa) as potent FHV-1 and FCV inhibitors for topical use. Mechanistic studies showed that PSSNa exhibits a different mechanism of action depending on target species. While PSSNa acts directly on FHV-1 particles blocking their interaction with the host's cell and preventing the infection, the antiviral potency against FCV is based on inhibition at late stages of the viral replication cycle. Altogether, PSSNa polymers are promising drug candidates to be used in the treatment and prevention of the viral upper respiratory tract disease (URTD), regardless of the cause.
Assuntos
Antivirais/farmacologia , Infecções por Caliciviridae/veterinária , Calicivirus Felino/efeitos dos fármacos , Doenças do Gato/virologia , Infecções por Herpesviridae/veterinária , Infecções Respiratórias/veterinária , Varicellovirus/efeitos dos fármacos , Animais , Infecções por Caliciviridae/tratamento farmacológico , Doenças do Gato/tratamento farmacológico , Gatos , Linhagem Celular , Sinergismo Farmacológico , Infecções por Herpesviridae/tratamento farmacológico , Polímeros/farmacologia , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/virologia , Replicação Viral/efeitos dos fármacosRESUMO
Feline herpesvirus type 1 (FHV-1) causes a potentially fatal disease in cats. Through the use of virus inhibition and cytotoxicity assays, sinefungin, a nucleoside antibiotic, was assessed for its potential to inhibit the growth of FHV-1. Sinefungin inhibited in vitro growth of FHV-1 most significantly over other animal viruses, such as feline infectious peritonitis virus, equine herpesvirus, pseudorabies virus and feline calicivirus. Our results revealed that sinefungin specifically suppressed the replication of FHV-1 after its adsorption to the host feline kidney cells in a dose-dependent manner without obvious cytotoxicity to the host cells. This antibiotic can potentially offer a highly effective treatment for animals infected with FHV-1, providing alternative medication to currently available antiviral therapies.
Assuntos
Adenosina/análogos & derivados , Antivirais/farmacologia , Varicellovirus/efeitos dos fármacos , Adenosina/farmacologia , Adenosina/toxicidade , Animais , Antivirais/toxicidade , Calicivirus Felino/efeitos dos fármacos , Doenças do Gato/tratamento farmacológico , Gatos , Linhagem Celular , Coronavirus Felino/efeitos dos fármacos , Relação Dose-Resposta a Droga , Infecções por Herpesviridae/tratamento farmacológico , Infecções por Herpesviridae/veterinária , Herpesvirus Equídeo 1/efeitos dos fármacos , Herpesvirus Suídeo 1/efeitos dos fármacos , Cavalos , Rim/citologia , Rim/virologia , Testes de ToxicidadeRESUMO
Caprine herpesvirus 1 (CpHV-1) infection in goats induces genital vesicular-ulcerative lesions that strictly resemble those produced by human herpesvirus 2 in humans. In previous studies, the potent inhibition of CpHV-1 by cidofovir was demonstrated. Cidofovir antiherpetic activity was evaluated in goats infected experimentally by the vaginal route with CpHV-1 and then treated locally at different times after infection. The administration of 1% cidofovir cream onto vaginal mucosa was able to prevent the onset of genital lesions and to decrease significantly the titers of the virus shed by the infected animals, notably in the groups treated shortly after infection (24 and 48 h). The efficacy of cidofovir against caprine herpesvirus infection was higher when the treatment was started shortly after infection than when lesions were already present and advanced. Herpesvirus genital infection of goats is a useful animal model to study the activity of antiviral drugs against human herpesvirus infections.
Assuntos
Antivirais/uso terapêutico , Citosina/análogos & derivados , Doenças dos Genitais Femininos/veterinária , Doenças das Cabras/tratamento farmacológico , Infecções por Herpesviridae/veterinária , Organofosfonatos/uso terapêutico , Varicellovirus , Animais , Antivirais/administração & dosagem , Sequência de Bases , Cidofovir , Citosina/administração & dosagem , Citosina/uso terapêutico , Primers do DNA/genética , DNA Viral/genética , Modelos Animais de Doenças , Feminino , Doenças dos Genitais Femininos/tratamento farmacológico , Doenças das Cabras/virologia , Cabras , Herpes Genital/tratamento farmacológico , Infecções por Herpesviridae/tratamento farmacológico , Infecções por Herpesviridae/virologia , Humanos , Organofosfonatos/administração & dosagem , Especificidade da Espécie , Cremes, Espumas e Géis Vaginais , Varicellovirus/efeitos dos fármacos , Varicellovirus/genética , Varicellovirus/isolamento & purificaçãoRESUMO
Feline herpesvirus-1 (FHV-1) is considered as the most common viral infection of domestic cats worldwide. It causes a disease characterized by upper respiratory and ocular clinical signs. Several attempts are currently underway to develop antiviral chemotherapy for treating FHV-1 infections. The availability of a rapid quantitative method for detecting FHV-1 would greatly facilitate prompt therapy, and hence enhance the success of any antiviral regime. In this study, a TaqMan real-time PCR assay was established for measuring FHV-1 DNA levels in culture supernatants. This assay was shown to be highly specific, reproducible and allows quantitation over a range of 2 to 2 x 10(8) copies per reaction. The assay was then applied to measure the reduction of FHV-1 DNA levels in the presence of increasing concentrations of acyclovir (ACV), penciclovir (PCV) and cidofovir (CDV). The 50% inhibitory concentrations (IC(50s)) obtained with the B927 laboratory strain of FHV-1 were 15.8 microM for ACV, 7.93 microM for CDV and 1.2 microM for PCV. The assay described here is sensitive, time-saving and does not involve prior titration of virus stocks or monitoring virus-induced cytopathic effects. Therefore, it is suitable for routine anti-FHV-1 drug susceptibility testing in veterinary clinics.
Assuntos
Aciclovir/análogos & derivados , Aciclovir/farmacologia , Antivirais/farmacologia , Testes de Sensibilidade Microbiana/métodos , Reação em Cadeia da Polimerase/métodos , Varicellovirus/efeitos dos fármacos , Animais , Gatos , Linhagem Celular , Concentração Inibidora 50 , Cinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Varicellovirus/genética , Replicação Viral/efeitos dos fármacosRESUMO
BACKGROUND: Like human herpesvirus 2 (HHV-2) in humans, infection by caprine herpesvirus 1 in goats is associated with genital lesions, and this provides a unique model to study the efficacy and effects of anti-herpetic drugs. METHODS: The antiviral activity of cidofovir was assessed in goats infected experimentally, using various therapeutic protocols. RESULTS: Topic administration of cidofovir 1% cream prevented the onset of virus-induced genital lesions and drastically reduced virus shedding. CONCLUSION: Cidofovir appears to be a very efficient drug for the prevention of genital lesions caused by an alphaherpesvirus.
Assuntos
Antivirais/uso terapêutico , Citosina/análogos & derivados , Herpes Genital/tratamento farmacológico , Infecções por Herpesviridae/tratamento farmacológico , Organofosfonatos/uso terapêutico , Varicellovirus/efeitos dos fármacos , Animais , Cidofovir , Citosina/uso terapêutico , Cabras , Herpes Genital/virologia , Infecções por Herpesviridae/virologiaRESUMO
Caprine herpesvirus 1 (CpHV-1) is a virus able to cause genital infection leading to vulvovaginitis or balanoposthitis in adult goats. CpHV-1 shares several biological similarities with herpes simplex type 2 (HSV-2) infection in man, such as genital tropism, type and site of typical lesions and it might provide an animal model for studies on antiviral drugs for HSV-2 infection in man. In this view the efficacy of cidofovir (CDV) drug was tested in six goats intravaginally infected with BA.1 strain of CpHV-1. Three goats received an intravaginal application of 3 ml of a 1% CDV preparation at 4h post infection and then every 12 h for five consecutive days. Three goats were kept as untreated controls. The goats were daily examined for clinical evidence of the infection and viral shedding. CDV was able to protect against disease progression and inhibited the onset of the local lesions due to the CpHV-1 replication. Treated animals shed virus for a shorter period (3 days less) and at lower titres than the control animals. CpHV-1 infection in goats may represent an excellent animal model for the study of novel strategies for the treatment of primary genital HSV-2 infection in man.
Assuntos
Citosina/análogos & derivados , Infecções por Herpesviridae/tratamento farmacológico , Organofosfonatos/uso terapêutico , Varicellovirus/efeitos dos fármacos , Animais , Cidofovir , Citosina/administração & dosagem , Citosina/uso terapêutico , Modelos Animais de Doenças , Cabras , Infecções por Herpesviridae/virologia , Organofosfonatos/administração & dosagem , Varicellovirus/isolamento & purificação , Eliminação de Partículas Virais/efeitos dos fármacosRESUMO
Caprine herpesvirus 1 (CpHV-1) infection in goats is responsible for genital lesions resembling the lesions induced by herpesvirus 2 in humans (HHV-2). The immunosuppressive drug Mizoribine (MIZ) is able to increase the antiviral activity of Acyclovir (ACV) against herpesvirus infections, raising interesting perspectives on new combined therapeutic strategies. In this study the anti-CpHV-1 activity in vitro of ACV alone or in combination with MIZ was evaluated. ACV (100µg/ml) displayed an antiviral effect on CpHV-1 replication. This inhibitory effect was higher when ACV (100µg/ml) was used in association with MIZ (20µg/ml). Other combinations of ACV and MIZ in various concentrations were not as effective as ACV 100µg/ml/MIZ 20µg/ml. These findings suggest that the association of ACV and MIZ is potentially useful for treatment of genital infection by herpesviruses.
Assuntos
Aciclovir/farmacologia , Antivirais/farmacologia , Doenças das Cabras/tratamento farmacológico , Infecções por Herpesviridae/veterinária , Imunossupressores/farmacologia , Ribonucleosídeos/farmacologia , Varicellovirus/efeitos dos fármacos , Animais , Bovinos , Linhagem Celular , Doenças das Cabras/virologia , Cabras , Infecções por Herpesviridae/tratamento farmacológico , Infecções por Herpesviridae/virologiaRESUMO
Caprine herpesvirus 1 (CpHV-1) infection in goats induces genital vesicular-ulcerative lesions that strictly resemble the lesions induced by herpesvirus 2 in the human host. The immunosuppressive drug Mizoribine (MIZ) was found to increase the antiviral activity of Acyclovir (ACV) against herpesvirus infections, raising interesting perspectives on new combined therapeutic strategies. In this study the anti-CpHV-1 activity in vitro of ACV alone or in combination with MIZ was characterized. When applied alone at non-toxic concentrations, ACV had a slight effect on CpHV-1 replication while in combination with MIZ a dose-dependent inhibition of the virus yield was observed with an IC50 of ACV of 28.5 µM. These findings suggest that combined therapy of ACV and MIZ is potentially exploitable in the treatment of genital infection by herpesviruses.
Assuntos
Aciclovir/farmacologia , Antivirais/farmacologia , Infecções por Herpesviridae/veterinária , Ribonucleosídeos/farmacologia , Varicellovirus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Aciclovir/uso terapêutico , Animais , Antivirais/uso terapêutico , Bovinos , Células Cultivadas , Infecções por Herpesviridae/tratamento farmacológico , Infecções por Herpesviridae/virologia , Ribonucleosídeos/uso terapêutico , Varicellovirus/crescimento & desenvolvimentoRESUMO
Although famciclovir is efficacious in feline herpesvirus type 1 (FHV-1)-infected cats, effects of a single dose early in disease course have not been reported. In this two part, randomized, masked, placebo controlled study, cats received a single dose of 125 mg famciclovir (n = 43) or placebo (n = 43; pilot study), or 500 mg famciclovir (n = 41) or placebo (n = 40; clinical trial) on entering a shelter. FHV-1 PCR testing was performed, bodyweight and food intake were recorded, and signs of respiratory disease were scored prior to and 7 days following treatment. FHV-1 DNA was detected in 40% of cats in both parts at study entry. In the pilot study, ocular and nasal discharge scores increased from days 1 to 7 in famciclovir and placebo treated cats. Sneezing scores increased and bodyweight decreased in famciclovir-treated cats. The proportion of cats in which FHV-1 DNA was detected increased over time in all cats in the pilot study. In the clinical trial, food intake and median clinical disease scores for nasal discharge and sneezing increased from days 1 to 7 in both groups and demeanor scores worsened in famciclovir-treated cats. The proportion of cats shedding FHV-1 DNA was greater on day 7 than on day 1 in cats receiving 500 mg famciclovir. A single dose of famciclovir (125 or 500 mg) administered at shelter intake was not efficacious in a feline population in which 40% were already shedding FHV-1.