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1.
Life Sci ; 274: 119313, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33667511

RESUMO

AIMS: To design and evaluate a novel AWRK6 peptide-based long-acting GLP-1 receptor agonist (GLP-1RA) conjugated a recombinant polyethylene glycol mimetic (XTEN protein) with significant therapeutic potential on type 2 diabetes mellitus (T2DM) alone as well as Herpes simplex virus type 2 (HSV-2) infection in combination with double shRNA. MAIN METHODS: First, four AWRK6 analogs (termed XA-1 to XA-4) were designed and produced by solid phase synthesis strategy. Further surface plasmon resonance (SPR) measurement and in vitro cAMP accumulation assay were performed to detect the GLP-1R binding affinities and GLP-1R activation, respectively. The in vivo efficacy evaluation including pharmacokinetic test, oral glucose tolerance test (OGTT), hypoglycemic duration test and chronic pharmacodynamics study in rodent animals were all carefully performed. KEY FINDINGS: Four XA peptides were synthesized with purity >99%. High binding affinity as well as activation potency of XA-4 for GLP-1R were demonstrated by SPR and cell-based luciferase reporter assay, respectively. Additionally, XA-4 exhibited the long-lasting antidiabetic effects in the multiple OGTTs, hypoglycemic duration test and chronic study in mice. Furthermore, combined treatment of XA-4 and double shRNA (D-shRNA) achieved potent antiviral effects in HSV-2 infected HEK293 cells. SIGNIFICANCE: XA-4 exhibited promising pharmaceutical potential to be a therapeutic drug for treating T2D, and also held potential to against the HSV-2 infection, which is really an accidental discovery. The strategy of recombinant XTENylation can also be applied to other peptides or small molecules for the development of long-acting therapeutic drugs.


Assuntos
Diabetes Mellitus Experimental/terapia , Herpes Simples/terapia , Herpesvirus Humano 2/efeitos dos fármacos , Obesidade/complicações , Fragmentos de Peptídeos/farmacologia , Peptídeos/farmacologia , RNA Interferente Pequeno/administração & dosagem , Animais , Terapia Combinada , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica/efeitos adversos , Herpes Simples/genética , Herpes Simples/virologia , Herpesvirus Humano 2/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Fragmentos de Peptídeos/química , Peptídeos/química , RNA Interferente Pequeno/genética
2.
BMJ Case Rep ; 14(3)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33692072

RESUMO

Neonatal herpes simplex virus (HSV) infection is rare, with an estimated incidence of 3.58 per 100 000 live births in the UK and should be suspected in any newborn with fever and bacterial culture-negative sepsis. We describe a case of a previously well full-term male neonate who presented with persistent fever and elevated ferritin level that was carried out during the era of the COVID-19 pandemic as part of SARS-CoV-2 panel investigations. Despite the initial negative HSV serology, HSV-1 PCR from a scalp lesion returned positive. He made a full recovery after acyclovir therapy. This case highlights the importance of maintaining a high clinical index of suspicion of HSV infection in any febrile neonate even with absence of maternal history and negative serology, particularly if associated with hyperferritinaemia. We also address the challenge of interpreting inflammatory biomarkers' results for SARS-CoV-2 infection in neonates.


Assuntos
/epidemiologia , Ferritinas/sangue , Febre/etiologia , Herpes Simples/diagnóstico , Complicações Infecciosas na Gravidez/diagnóstico , Aciclovir/uso terapêutico , Antivirais/uso terapêutico , Feminino , Herpes Simples/complicações , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/isolamento & purificação , Humanos , Recém-Nascido , Masculino , Pandemias , Reação em Cadeia da Polimerase , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Resultado do Tratamento
3.
Viruses ; 13(2)2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546431

RESUMO

Nuclear domains 10 (ND10), a.k.a. promyelocytic leukemia nuclear bodies (PML-NBs), are membraneless subnuclear domains that are highly dynamic in their protein composition in response to cellular cues. They are known to be involved in many key cellular processes including DNA damage response, transcription regulation, apoptosis, oncogenesis, and antiviral defenses. The diversity and dynamics of ND10 residents enable them to play seemingly opposite roles under different physiological conditions. Although the molecular mechanisms are not completely clear, the pro- and anti-cancer effects of ND10 have been well established in tumorigenesis. However, in herpesvirus research, until the recently emerged evidence of pro-viral contributions, ND10 nuclear bodies have been generally recognized as part of the intrinsic antiviral defenses that converge to the incoming viral DNA to inhibit the viral gene expression. In this review, we evaluate the newly discovered pro-infection influences of ND10 in various human herpesviruses and analyze their molecular foundation along with the traditional antiviral functions of ND10. We hope to shed light on the explicit role of ND10 in both the lytic and latent cycles of herpesvirus infection, which is imperative to the delineation of herpes pathogenesis and the development of prophylactic/therapeutic treatments for herpetic diseases.


Assuntos
Herpes Simples/metabolismo , Herpesviridae/fisiologia , Proteínas Nucleares/metabolismo , Carcinogênese , Herpes Simples/virologia , Herpesviridae/classificação , Herpesviridae/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Proteínas Virais/metabolismo , Latência Viral , Replicação Viral
4.
Obstet Gynecol Clin North Am ; 48(1): 53-74, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33573790

RESUMO

Viral infections are common complications of pregnancy. Although some infections have maternal sequelae, many viral infections can be perinatally transmitted to cause congenital or chronic infection in fetuses or infants. Treatments of such infections are geared toward reducing maternal symptoms and complications and toward preventing maternal-to-child transmission of viruses. The authors review updates in the treatment of herpes simplex virus, cytomegalovirus, hepatitis B and C viruses, human immunodeficiency virus, and COVID-19 during pregnancy.


Assuntos
Transmissão Vertical de Doença Infecciosa , Complicações Infecciosas na Gravidez/terapia , Viroses/terapia , Viroses/transmissão , Adulto , Antivirais/uso terapêutico , /transmissão , Infecções por Citomegalovirus/terapia , Infecções por Citomegalovirus/transmissão , Feminino , Infecções por HIV/terapia , Infecções por HIV/transmissão , Hepatite B/terapia , Hepatite B/transmissão , Hepatite C/terapia , Hepatite C/transmissão , Herpes Simples/terapia , Herpes Simples/transmissão , Humanos , Lactente , Gravidez , Complicações Infecciosas na Gravidez/virologia
5.
Viruses ; 13(1)2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33435520

RESUMO

Herpes simplex virus type 1 (HSV-1) causes a lifelong latent infection with an estimated global prevalence of 66%. Primary and recurrent HSV infections are characterized by a tingling sensation, followed by an eruption of vesicles, which can cause painful erosions. Commonly used antiviral drugs against HSV infection are nucleoside analogues including acyclovir (ACV), famciclovir, and valacyclovir. Although these nucleoside analogues reduce morbidity and mortality in immunocompetent individuals, ACV-resistant HSV strains (ACVR-HSV) have been isolated from immunocompromised patients. Thus, ACVR-HSV infection poses a critical emerging public health concern. Recently, we reported that ginkgolic acid (GA) inhibits HSV-1 by disrupting viral structure, blocking fusion, and inhibiting viral protein synthesis. Additionally, we showed GA affords a broad spectrum of fusion inhibition of all three classes of fusion proteins, including those of HIV, Ebola, influenza A and Epstein Barr viruses. Here we report GA's antiviral activity against HSV-1 skin infection in BALB/cJ mice. GA-treated mice demonstrated a significantly reduced mortality rate and decreased infection scores compared to controls treated with dimethylsulfoxide (DMSO)-vehicle. Furthermore, GA efficiently inhibited ACVR-HSV-1 strain 17+ in vitro and in vivo. Since GA's mechanism of action includes virucidal activity and fusion inhibition, it is expected to work alone or synergistically with other anti-viral drugs, and we anticipate it to be effective against additional cutaneous and potentially systemic viral infections.


Assuntos
Antivirais/farmacologia , Dermatite/virologia , Herpes Simples/virologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/fisiologia , Salicilatos/farmacologia , Animais , Linhagem Celular , Chlorocebus aethiops , Dermatite/tratamento farmacológico , Modelos Animais de Doenças , Herpes Simples/tratamento farmacológico , Herpes Simples/transmissão , Camundongos , Células Vero , Ensaio de Placa Viral , Replicação Viral/efeitos dos fármacos
6.
BMJ Case Rep ; 14(1)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431534

RESUMO

A man in his late 30s presented with a several-day history of rectal pain, discharge and bleeding associated with systemic upset. Sexual history revealed receptive anal sex with several male partners in the 2 weeks preceding his clinic visit. Examination of the perianal area was unremarkable. Proctoscopy showed evidence of non-ulcerative proctitis. Microscopy for Gram stain showed pus cells plus extracellular Gram-negative diplococci. The patient was treated for presumptive gonorrhoea and chlamydial infection with ceftriaxone, azithromycin and doxycycline. The patient failed to improve with this treatment regimen. Rectal swab results at 48 hours confirmed the causative agent to be herpes simplex virus (HSV) type 2. The patient was recalled and treated successfully with valaciclovir. This case serves as a useful reminder to clinicians to consider HSV in the differential diagnosis of sexually transmitted proctitis, in the absence of perianal or anorectal ulceration.


Assuntos
Herpes Simples/diagnóstico , Herpesvirus Humano 2/isolamento & purificação , Proctite/diagnóstico , Doenças Sexualmente Transmissíveis/diagnóstico , Adulto , Antivirais/uso terapêutico , DNA Viral/isolamento & purificação , Diagnóstico Diferencial , Gonorreia/diagnóstico , Herpes Simples/tratamento farmacológico , Herpes Simples/transmissão , Herpes Simples/virologia , Herpesvirus Humano 2/genética , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Mucosa Intestinal/virologia , Masculino , Proctite/tratamento farmacológico , Proctite/virologia , Reto/virologia , Comportamento Sexual , Doenças Sexualmente Transmissíveis/tratamento farmacológico , Doenças Sexualmente Transmissíveis/transmissão , Doenças Sexualmente Transmissíveis/virologia , Valaciclovir/uso terapêutico
7.
Viruses ; 13(1)2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33419081

RESUMO

Herpes simplex virus type 2 (HSV-2) is the primary cause of genital herpes which results in significant morbidity and mortality, especially in women, worldwide. HSV-2 is transmitted primarily through infection of epithelial cells at skin and mucosal surfaces. Our earlier work to examine interactions between HSV-2 and vaginal epithelial cells demonstrated that infection of the human vaginal epithelial cell line (VK2) with HSV-2 resulted in increased expression of TRIM26, a negative regulator of the Type I interferon pathway. Given that upregulation of TRIM26 could negatively affect anti-viral pathways, we decided to further study the role of TRIM26 in HSV-2 infection and replication. To do this, we designed and generated two cell lines derived from VK2s with TRIM26 overexpressed (OE) and knocked out (KO). Both, along with wildtype (WT) VK2, were infected with HSV-2 and viral titres were measured in supernatants 24 h later. Our results showed significantly enhanced virus production by TRIM26 OE cells, but very little replication in TRIM26 KO cells. We next examined interferon-ß production and expression of two distinct interferon stimulated genes (ISGs), MX1 and ISG15, in all three cell lines, prior to and following HSV-2 infection. The absence of TRIM26 (KO) significantly upregulated interferon-ß production at baseline and even further after HSV-2 infection. TRIM26 KO cells also showed significant increase in the expression of MX1 and ISG15 before and after HSV-2 infection. Immunofluorescent staining indicated that overexpression of TRIM26 substantially decreased the nuclear localization of IRF3, the primary mediator of ISG activation, before and after HSV-2 infection. Taken together, our data indicate that HSV-2 utilizes host factor TRIM26 to evade anti-viral response and thereby increase its replication in vaginal epithelial cells.


Assuntos
Células Epiteliais/virologia , Herpes Simples/genética , Herpesvirus Humano 2/fisiologia , Fator Regulador 3 de Interferon/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Células Cultivadas , Citocinas/metabolismo , Regulação para Baixo , Células Epiteliais/metabolismo , Técnicas de Inativação de Genes , Células HEK293 , Herpesvirus Humano 2/genética , Humanos , Fator Regulador 3 de Interferon/genética , Proteínas de Resistência a Myxovirus/metabolismo , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinas/metabolismo , Replicação Viral
8.
Res Vet Sci ; 134: 78-85, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33338952

RESUMO

Bovine alphaherpesvirus 2 (BoHV-2) - the agent of bovine herpetic mamillitis (BHM) - is related to Human alphaherpesviruses 1 and 2 (HHV-1, HHV-2) and, as such, has been proposed as a model for vaccine and drug testing. We herein investigated the anti-viral activity in vitro against BoHV-2 of three anti-herpetic drugs: Cidofovir (CDV), Fanciclovir (FAM), Foscarnet (PFA), and diphenyl disselenide (Ph2Se2), a compound that has showed activity against HHV-2. Plaque reduction assays (PRA) revealed a significant reduction in viral plaques (p < 0.05) in cells treated with Ph2Se2 (79.7% reduction) or CDV (62.8%). FAM treatment resulted in a slight decrease in plaque number (22.9%, p < 0.05); PFA showed no activity. The effects of Ph2Se2 and CDV, alone or in combination, were investigated in ewes inoculated with BoHV-2 transdermally and submitted to daily topic treatment. Virus inoculated ewes developed lesions progressing through the stages of hyperemia, large papules or depressed dark areas, followed by scab formation. Treatment with Ph2Se2 resulted in reduction in clinical score from day 10 pi onwards (P < 0.05), shortening of clinical course and reduction in duration of virus shedding (P < 0.05) compared to untreated controls. Combined treatment (Ph2Se2 + CDV) and CDV alone, also led to clinical improvement (P < 0.05), yet less pronounced and delayed. These results are promising towards the use of Ph2Se2, alone or in combination with anti-herpetic drugs, in the treatment of udder and teat lesions produced by BoHV-2 in dairy cows.


Assuntos
Antivirais/farmacologia , Derivados de Benzeno/farmacologia , Cidofovir/farmacologia , Herpes Simples/veterinária , Herpesvirus Bovino 2/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Doenças dos Ovinos/tratamento farmacológico , Animais , Antivirais/uso terapêutico , Derivados de Benzeno/uso terapêutico , Cidofovir/uso terapêutico , Feminino , Herpes Simples/tratamento farmacológico , Glândulas Mamárias Animais/imunologia , Glândulas Mamárias Animais/virologia , Compostos Organosselênicos/uso terapêutico , Ovinos , Doenças dos Ovinos/virologia , Eliminação de Partículas Virais/efeitos dos fármacos
9.
Biochem J ; 478(1): 261-279, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33355669

RESUMO

Herpes simplex virus 1 (HSV-1) is a human DNA virus that causes cold sores, keratitis, meningitis, and encephalitis. Ubiquitination is a post-translational protein modification essential for regulation of cellular events, such as proteasomal degradation, signal transduction, and protein trafficking. The process is also involved in events for establishing viral infection and replication. The first step in ubiquitination involves ubiquitin (Ub) binding with Ub-activating enzyme (E1, also termed UBE1) via a thioester linkage. Our results show that HSV-1 infection alters protein ubiquitination pattern in host cells, as evidenced by MS spectra and co-immunoprecipitation assays. HSV-1 induced ubiquitination of UBE1a isoform via an isopeptide bond with Lys604. Moreover, we show that ubiquitination of K604 in UBE1a enhances UBE1a activity; that is, the activity of ubiquitin-transfer to E2 enzyme. Subsequently, we investigated the functional role of UBE1a and ubiquitination of K604 in UBE1a. We found that UBE1-knockdown increased HSV-1 DNA replication and viral production. Furthermore, overexpression of UBE1a, but not a UBE1a K604A mutant, suppressed viral replication. Furthermore, we found that UBE1a and ubiquitination at K604 in UBE1a retarded expression of HSV-1 major capsid protein, ICP5. Our findings show that UBE1a functions as an antiviral factor that becomes activated upon ubiquitination at Lys604.


Assuntos
Antivirais/metabolismo , Herpes Simples/metabolismo , Herpesvirus Humano 1/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Enzimas Ativadoras de Ubiquitina/metabolismo , Animais , Sobrevivência Celular/genética , Chlorocebus aethiops , Cromatografia Líquida , Doxiciclina/farmacologia , Células HeLa , Herpes Simples/enzimologia , Herpes Simples/genética , Herpesvirus Humano 1/genética , Interações Hospedeiro-Patógeno/genética , Humanos , Ligação Proteica , Domínios Proteicos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , RNA Interferente Pequeno , Espectrometria de Massas em Tandem , Tetraciclina/farmacologia , Transfecção , Enzimas Ativadoras de Ubiquitina/genética , Ubiquitinação/efeitos dos fármacos , Células Vero , Replicação Viral/efeitos dos fármacos
10.
Med Hypotheses ; 146: 110447, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33383524

RESUMO

The pathogen burden, defined by the frequency of antibodies to several viruses and a parasite, is greater in Hispanic whites and black populations than it is in non-Hispanic whites, in the USA. The poor and those without higher education also have higher pathogen burdens. The most frequent pathogen that was measured, was the Herpes simplex virus type 1 (HSV-1). This virus can inactivate most of the elements in the immune system, that are designed to protect against the incursions of viruses, bacteria and other pathogens. HSV-1 can also damage the blood brain barrier (BBB), which prevents the entry of pathogens into the central nervous system. Without the help of HSV-1, the COVID-19 virus may not be able to cause serious illness or death in humans. A prophylactic treatment to contain HSV-1, could be vital in the fight against COVID-19.


Assuntos
/epidemiologia , Grupos Étnicos , Herpes Simples/epidemiologia , Herpesvirus Humano 1/patogenicidade , Modelos Biológicos , Afro-Americanos , Barreira Hematoencefálica , /virologia , Grupo com Ancestrais do Continente Europeu , Herpes Simples/prevenção & controle , Herpes Simples/virologia , Hispano-Americanos , Interações entre Hospedeiro e Microrganismos , Humanos , Pandemias , Estados Unidos/epidemiologia
11.
Elife ; 92020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33350386

RESUMO

Herpes simplex virus-1 (HSV-1) establishes a latent infection in neurons and periodically reactivates to cause disease. The stimuli that trigger HSV-1 reactivation have not been fully elucidated. We demonstrate HSV-1 reactivation from latently infected mouse neurons induced by forskolin requires neuronal excitation. Stimuli that directly induce neurons to become hyperexcitable also induced HSV-1 reactivation. Forskolin-induced reactivation was dependent on the neuronal pathway of DLK/JNK activation and included an initial wave of viral gene expression that was independent of histone demethylase activity and linked to histone phosphorylation. IL-1ß is released under conditions of stress, fever and UV exposure of the epidermis; all known triggers of clinical HSV reactivation. We found that IL-1ß induced histone phosphorylation and increased the excitation in sympathetic neurons. Importantly, IL-1ß triggered HSV-1 reactivation, which was dependent on DLK and neuronal excitability. Thus, HSV-1 co-opts an innate immune pathway resulting from IL-1 stimulation of neurons to induce reactivation.


Assuntos
Herpesvirus Humano 1/fisiologia , Interleucina-1beta/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Neurônios/virologia , Ativação Viral/fisiologia , Animais , Herpes Simples/imunologia , Herpes Simples/metabolismo , Camundongos , Latência Viral/fisiologia
12.
Rev. Hosp. Ital. B. Aires (2004) ; 40(4): 219-222, dic. 2020. ilus
Artigo em Espanhol | LILACS | ID: biblio-1145550

RESUMO

La erupción variceliforme de Kaposi es una infección cutánea diseminada, causada en la mayor parte de los casos por el virus Herpes simple tipo 1. Se suele presentar en pacientes con alteraciones preexistentes de la barrera cutánea, especialmente en niños con dermatitis atópica. Se comunica el caso de un paciente de 84 años, quien negaba enfermedades cutáneas previas, que consultó por lesiones dolorosas y pruriginosas, en la piel del tórax y el abdomen, de 3 semanas de evolución. Con sospecha de una enfermedad infecciosa viral, bacteriana, ampollar o neutrofílica, se realizó inmunofluorescencia directa para herpes, cultivo y biopsia de piel para estudio histológico. La inmunofluorescencia fue positiva para Herpes simple tipo 1 y el estudio histopatológico mostró cambios compatibles con infección herpética y enfermedad de Darier. La enfermedad de Darier es una genodermatosis infrecuente que se suele manifestar en la adolescencia. Si bien su diagnóstico en la ancianidad es excepcional, este caso ilustra que se debe considerar en todos los pacientes que presenten erupción variceliforme. (AU)


Kaposi's varicelliform rash is a disseminated cutaneous infection, caused by Herpes virus 1. It usually presents in patients with pre-existing skin barrier disorders, especially in children with atopic dermatitis. We report the case of an 84-year-old patient, who reported having no previous skin diseases, who consulted for painful, itchy, 3-week-old skin lesions. As we suspected viral, bacterial, bullous or neutrophilic disease, direct immunofluorescence, culture, and skin biopsy for histological study were performed. Immunofluorescence was positive for Herpes simplex type 1 and the histopathological study showed changes compatible with herpetic infection and Darier's disease. Darier's disease is a rare genodermatosis that usually manifests in adolescence. Although its diagnosis in old age is anecdotal, it should be considered in patients with a varicelliform rash. (AU)


Assuntos
Humanos , Masculino , Idoso de 80 Anos ou mais , Erupção Variceliforme de Kaposi/diagnóstico , Doença de Darier/diagnóstico , Aciclovir/administração & dosagem , Foscarnet/uso terapêutico , Herpesvirus Humano 1/patogenicidade , Técnica Direta de Fluorescência para Anticorpo , Herpes Simples/complicações , Erupção Variceliforme de Kaposi/etiologia , Erupção Variceliforme de Kaposi/patologia , Erupção Variceliforme de Kaposi/tratamento farmacológico , Doença de Darier/etiologia
14.
Viruses ; 13(1)2020 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-33374862

RESUMO

Viruses encode for structural proteins that participate in virion formation and include capsid and envelope proteins. In addition, viruses encode for an array of non-structural accessory proteins important for replication, spread, and immune evasion in the host and are often linked to virus pathogenesis. Most virus accessory proteins are non-essential for growth in cell culture because of the simplicity of the infection barriers or because they have roles only during a state of the infection that does not exist in cell cultures (i.e., tissue-specific functions), or finally because host factors in cell culture can complement their absence. For these reasons, the study of most nonessential viral factors is more complex and requires development of suitable cell culture systems and in vivo models. Approximately half of the proteins encoded by the herpes simplex virus 1 (HSV-1) genome have been classified as non-essential. These proteins have essential roles in vivo in counteracting antiviral responses, facilitating the spread of the virus from the sites of initial infection to the peripheral nervous system, where it establishes lifelong reservoirs, virus pathogenesis, and other regulatory roles during infection. Understanding the functions of the non-essential proteins of herpesviruses is important to understand mechanisms of viral pathogenesis but also to harness properties of these viruses for therapeutic purposes. Here, we have provided a comprehensive summary of the functions of HSV-1 non-essential proteins.


Assuntos
Regulação Viral da Expressão Gênica , Herpes Simples/virologia , Herpesvirus Humano 1/fisiologia , Interações Hospedeiro-Patógeno , Proteínas Virais/genética , Proteínas Virais/metabolismo , Replicação Viral , Animais , Endonucleases/genética , Endonucleases/metabolismo , Inativação Gênica , Herpes Simples/imunologia , Herpes Simples/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Ácidos Nucleicos/metabolismo , Fosfotransferases/genética , Fosfotransferases/metabolismo , Transativadores , Proteínas Virais Reguladoras e Acessórias/genética , Proteínas Virais Reguladoras e Acessórias/metabolismo , Virulência
15.
Viruses ; 12(12)2020 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-33322225

RESUMO

Acyclovir is the drug of choice for the treatment of herpes simplex virus (HSV) infections. Acyclovir-resistant HSV strains may emerge, especially during long-term drug use, and subsequently cause difficult-to-treat exacerbations. Previously, we set up a novel treatment approach, based on enzymatically synthesized pools of siRNAs, or siRNA swarms. These swarms can cover kilobases-long target sequences, reducing the likelihood of resistance to treatment. Swarms targeting the UL29 essential gene of HSV-1 have demonstrated high efficacy against HSV-1 in vitro and in vivo. Here, we assessed the antiviral potential of a UL29 siRNA swarm against circulating strains of HSV-1, in comparison with acyclovir. All circulating strains were sensitive to both antivirals, with the half-maximal inhibitory concentrations (IC50) in the range of 350-1911 nM for acyclovir and 0.5-3 nM for the UL29 siRNA swarm. Additionally, we showed that an acyclovir-resistant HSV-1, devoid of thymidine kinase, is highly sensitive to UL29 siRNA treatment (IC50 1.0 nM; Imax 97%). Moreover, the detected minor variations in the RNAi target of the HSV strains had no effect on the potency or efficacy of UL29 siRNA swarm treatment. Our findings support the development of siRNA swarms for the treatment of HSV-1 infections, in order to circumvent any potential acyclovir resistance.


Assuntos
Aciclovir/farmacologia , Proteínas de Ligação a DNA/genética , Herpes Simples/virologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Proteínas Virais/genética , Aciclovir/uso terapêutico , Animais , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Herpes Simples/terapia , Herpesvirus Humano 1/classificação , Herpesvirus Humano 1/isolamento & purificação , Humanos , Concentração Inibidora 50 , Células Vero
16.
Viruses ; 12(12)2020 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-33322659

RESUMO

Glycoprotein G (gG) from herpes simplex virus type 1 and 2 (HSV-1 and HSV-2, respectively) functions as a viral chemokine binding protein (vCKBP). Soluble recombinant forms of gG of HSV-1 and HSV-2 (SgG1 and SgG2, respectively) enhance chemokine-mediated leukocyte migration, in contrast to most known vCKBPs, including those from animal alpha-herpesviruses. Furthermore, both proteins bind to nerve growth factor (NGF), but only SgG2 enhances NGF-dependent neurite outgrowth. The basis and implications of this functional difference between the two proteins are still unknown. While gG1 and gG2 are positional homologues in the genome, they share very limited sequence homology. In fact, US4, the open reading frame encoding gG is the most divergent genetic locus between these viruses. Full-length gG1 and gG2 are type I transmembrane proteins located on the plasma membrane of infected cells and at the viral envelope. However, gG2 is larger than gG1 and is cleaved during protein maturation, secreting the N-terminal domain to the supernatant of infected cells, whereas gG1 is not. The enzyme involved in gG2 cleavage and the functional relevance of gG2 cleavage and secretion are unknown. We aim to identify the gG2 sequence required for cleavage to determine its functional role in future experiments. Our results prove the existence of at least two cleavage motifs in gG2 within the amino acid region 314-343. Transfer of this sequence to a fusion protein results in cleavage. Finally, we show that propeptide convertases like furin are responsible for gG2 cleavage.


Assuntos
Herpes Simples/virologia , Herpesvirus Humano 2/fisiologia , Domínios e Motivos de Interação entre Proteínas , Proteínas do Envelope Viral/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Linhagem Celular , Cromatografia Líquida , Expressão Gênica , Genes Reporter , Humanos , Espectrometria de Massas , Proteólise
17.
J Clin Neurosci ; 82(Pt A): 63-70, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33317741

RESUMO

There is growing evidence demonstrating the relationship between herpes simplex virus type 1 (HSV-1) infection and Alzheimer's disease (AD). We searched PubMed, Embase, and Cochrane databases for relevant articles. The Newcastle-Ottawa Scale (NOS) was used to evaluate the qualities of these studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random-effects models. We also performed subgroup analyses stratified by apolipoprotein ε4 (APOE ε4), NOS score, and the method of confirming AD. A total of 21 studies between 1990 and 2020 were identified. The pooled OR suggested that HSV-1 infection is a risk factor of AD: pooled OR 1.40 (95% CI: 1.13-1.75; I2 = 3%, P = 0.42). In the subgroup analyses, the pooled ORs of HSV-1 infection associated with AD were 0.75 (95% CI: 0.24-2.37) among the APOE ε4-positive individuals; 0.85 (95% CI: 0.61-1.17) among the APOE ε4-negative individuals; 1.51 (95% CI: 1.10-2.06) in the high NOS score studies; 1.23 (95% CI: 0.85-1.76) in the moderate NOS score studies; 1.47 (95% CI: 1.16-1.87) in the clinical diagnosis group, and 1.20 (95% CI: 0.77-1.87) in the autopsy group. Our up-to-date systematic review and meta-analysis suggest that HSV-1 infection is a risk factor of AD.


Assuntos
Doença de Alzheimer/virologia , Herpes Simples/complicações , Herpesvirus Humano 1 , Humanos , Razão de Chances , Fatores de Risco
18.
Ter Arkh ; 92(8): 108-117, 2020 Sep 03.
Artigo em Russo | MEDLINE | ID: mdl-33346470

RESUMO

Among the many causes of the inflammatory process in the esophagus, infectious diseases are becoming increasingly important due to their steady growth. Previously esophageal infections have traditionally been associated with immunodeficiency syndromes, but now in clinical practice, these disorders are becoming increasingly recognized in immunocompetent individuals. Early diagnosis of infectious esophagitis is necessary to develop effective treatment tactics, and, as a result, reduce the risk of complications and adverse outcomes of the disease. This study reviewed the most clinical relevant pathogens of infectious esophagitis, both among patients with immunodeficiency and among healthy individuals. Specific diagnostic, risk factors, clinical presentation and therapeutic features were considered depending on the immune status of patients.


Assuntos
Doenças do Esôfago , Esofagite , Herpes Simples , Esofagite/diagnóstico , Esofagite/terapia , Humanos , Hospedeiro Imunocomprometido
20.
PLoS Pathog ; 16(12): e1009166, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33370402

RESUMO

Herpes simplex virus 1 (HSV-1) infects skin and mucosal epithelial cells and then travels along axons to establish latency in the neurones of sensory ganglia. Although viral gene expression is restricted during latency, the latency-associated transcript (LAT) locus encodes many RNAs, including a 2 kb intron known as the hallmark of HSV-1 latency. Here, we studied HSV-1 infection and the role of the LAT locus in human skin xenografts in vivo and in cultured explants. We sequenced the genomes of our stock of HSV-1 strain 17syn+ and seven derived viruses and found nonsynonymous mutations in many viral proteins that had no impact on skin infection. In contrast, deletions in the LAT locus severely impaired HSV-1 replication and lesion formation in skin. However, skin replication was not affected by impaired intron splicing. Moreover, although the LAT locus has been implicated in regulating gene expression in neurones, we observed only small changes in transcript levels that were unrelated to the growth defect in skin, suggesting that its functions in skin may be different from those in neurones. Thus, although the LAT locus was previously thought to be dispensable for lytic infection, we show that it is a determinant of HSV-1 virulence during lytic infection of human skin.


Assuntos
Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/patogenicidade , MicroRNAs/genética , Pele/virologia , Virulência/genética , Animais , Xenoenxertos , Humanos , Camundongos , Fatores de Virulência/genética
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