RESUMEN
Herpes simplex virus 1 (HSV-1) or simplexvirus humanalpha 1 is a neurotropic virus that is responsible for orofacial infections in humans. More than 70% of the world's population may have seropositivity for HSV-1, and this virus is a leading cause of sporadic lethal encephalitis in humans. The role of toll-like receptors (TLRs) in defending against HSV-1 infection has been explored, including the consequences of lacking these receptors or other proteins in the TLR pathway. Cell and mouse models have been used to study the importance of these receptors in combating HSV-1, how they relate to the innate immune response, and how they participate in the orchestration of the adaptive immune response. Myeloid differentiation factor 88 (MyD88) is a protein involved in the downstream activation of TLRs and plays a crucial role in this signaling. Mice with functional MyD88 or TLR2 and TLR9 can survive HSV-1 infection. However, they can develop encephalitis and face a 100% mortality rate in a dose-dependent manner when MyD88 or TLR2 plus TLR9 proteins are non-functional. In TLR2/9 knockout mice, an increase in chemokines and decreases in nitric oxide (NO), interferon (IFN) gamma, and interleukin 1 (IL-1) levels in the trigeminal ganglia (TG) have been correlated with mortality.
Asunto(s)
Encefalitis , Herpes Simple , Herpesvirus Humano 1 , Humanos , Animales , Ratones , Herpesvirus Humano 1/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Ganglio del Trigémino/metabolismo , Receptores Toll-Like/metabolismo , Ratones Noqueados , Ratones Endogámicos C57BLRESUMEN
Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are highly prevalent in the human population. These viruses cause lifelong infections by establishing latency in neurons and undergo sporadic reactivations that promote recurrent disease and new infections. The success of HSVs in persisting in infected individuals is likely due to their multiple molecular determinants involved in escaping the host antiviral and immune responses. Importantly, HSVs infect and negatively modulate the function of dendritic cells (DCs), key immune cells that are involved in establishing effective and balanced immunity against viruses. Here, we review and discuss several molecular and cellular processes modulated by HSVs in DCs, such as autophagy, apoptosis, and the unfolded protein response. Given the central role of DCs in establishing optimal antiviral immunity, particular emphasis should be given to the outcome of the interactions occurring between HSVs and DCs.
Asunto(s)
Herpes Simple , Herpesvirus Humano 1 , Antivirales/metabolismo , Células Dendríticas , Herpesvirus Humano 1/metabolismo , HumanosRESUMEN
Besides overcoming physical constraints, such as extreme temperatures, reduced humidity, elevated pressure, and natural predators, human pathogens further need to overcome an arsenal of antimicrobial components evolved by the host to limit infection, replication and optimally, reinfection. Herpes simplex virus-1 (HSV-1) and herpes simplex virus-2 (HSV-2) infect humans at a high frequency and persist within the host for life by establishing latency in neurons. To gain access to these cells, herpes simplex viruses (HSVs) must replicate and block immediate host antiviral responses elicited by epithelial cells and innate immune components early after infection. During these processes, infected and noninfected neighboring cells, as well as tissue-resident and patrolling immune cells, will sense viral components and cell-associated danger signals and secrete soluble mediators. While type-I interferons aim at limiting virus spread, cytokines and chemokines will modulate resident and incoming immune cells. In this paper, we discuss recent findings relative to the early steps taking place during HSV infection and replication. Further, we discuss how HSVs evade detection by host cells and the molecular mechanisms evolved by these viruses to circumvent early antiviral mechanisms, ultimately leading to neuron infection and the establishment of latency.
Asunto(s)
Antivirales/química , Herpes Simple/virología , Herpesvirus Humano 1/metabolismo , Animales , Apoptosis , Supervivencia Celular , Quimiocinas/metabolismo , Citocinas/metabolismo , Células Epiteliales/virología , Herpes Simple/inmunología , Humanos , Inmunidad Innata , Interferones/metabolismo , Neuronas/metabolismo , Neuronas/virología , Transducción de Señal , Replicación ViralRESUMEN
Polyfunctionalized stigmasterol derivatives, (22S,23S)-22,23-dihydroxystigmast-4-en-3-one (compound 1) and (22S,23S)-3ß-bromo-5α,22,23-trihydroxystigmastan-6-one (compound 2), inhibit herpes simplex virus type 1 (HSV-1) replication and spreading in human epithelial cells derived from ocular tissues. Both compounds reduce the incidence and severity of lesions in a murine model of herpetic stromal keratitis when administered in different treatment modalities. Since encephalitis caused by HSV-1 is another immunopathology of viral origin, we evaluate here the antiviral effect of both compounds on HSV-1 infected nervous cell lines as well as their anti-inflammatory action. We found that both stigmasterol derivatives presented low cytotoxicity in the three nervous cell lines assayed. Regarding the antiviral activity, in all cases both compounds prevented HSV-1 multiplication when added after infection, as well as virus propagation. Additionally, both compounds were able to hinder interleukin-6 and Interferon-gamma secretion induced by HSV-1 infection in Neuro-2a cells. We conclude that compounds 1 and 2 have exerted a dual antiviral and anti-inflammatory effect in HSV-1 infected nervous cell lines, which makes them interesting molecules to be further studied.
Asunto(s)
Antivirales/farmacología , Colestanonas/farmacología , Herpesvirus Humano 1/efectos de los fármacos , Estigmasterol/análogos & derivados , Estigmasterol/farmacología , Replicación Viral/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Línea Celular , Chlorocebus aethiops , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Herpesvirus Humano 1/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Interferón gamma/metabolismo , Interleucina-6/metabolismo , Ratones , Células Vero/efectos de los fármacosRESUMEN
Meliacine (MA), an antiviral principle present in partially purified leaf extracts of Melia azedarach L., reduces viral load and abolishes the inflammatory reaction and neovascularization during the development of herpetic stromal keratitis in mice. 1-cinnamoyl-3,11-dihydroxymeliacarpin (CDM), obtained from MA, displays anti-herpetic and immunomodulatory activities in vitro. We investigated whether CDM interferes with the angiogenic process. CDM impeded VEGF transcription in LPS-stimulated and HSV-1-infected cells. It proved to have neither cytotoxic nor antiproliferative effect in HUVEC and to restrain HUVEC migration and formation of capillary-like tubes. Moreover, MA inhibits LMM3 tumor-induced neovascularization in vivo. We postulate that the antiangiogenic activity of CDM displayed in vitro as a consequence of their immunomodulatory properties is responsible for the antiangiogenic activity of MA in vivo, which would be associated with the lack of neovascularization in murine HSV-1-induced ocular disease.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Antivirales/farmacología , Factores Inmunológicos/farmacología , Animales , Proliferación Celular , Química Farmacéutica/métodos , Quimiotaxis , Diseño de Fármacos , Femenino , Regulación de la Expresión Génica , Herpesvirus Humano 1/metabolismo , Humanos , Lipopolisacáridos/metabolismo , Melia/metabolismo , Ratones , Ratones Endogámicos BALB C , Neoplasias/metabolismo , Neoplasias/patología , Neovascularización Patológica , Péptidos/farmacología , Extractos Vegetales/farmacología , Proteínas de Plantas/farmacología , Factor A de Crecimiento Endotelial Vascular/biosíntesisRESUMEN
The need to develop novel antiviral agents encouraged us to assess the antiviral activity of synthetic sterol analogues with a diamide side chains. Cytotoxicity and antiviral activity of a family of azasterol previously synthesized was evaluated against herpes simplex virus 1 (HSV-1) (KOS and B2006) and vesicular stomatitis virus (VSV). This family of compounds was extended by the synthesis of novel analogs using an Ugi multicomponent reaction and their ability to inhibit viral multiplication was also evaluated. The results show that some of the compounds tested exert an antiviral activity. Besides, the effect of the azasterols on the intracellular localization of viral glycoproteins was examined. Strikingly, alteration on the glycoprotein D (gD) of HSV-1 fluorescence pattern was observed with both the antiherpetic compounds and the inactive azasterols.
Asunto(s)
Antivirales/química , Diamida/química , Herpesvirus Humano 1/efectos de los fármacos , Esteroles/química , Proteínas del Envoltorio Viral/metabolismo , Antivirales/aislamiento & purificación , Antivirales/farmacología , Herpesvirus Humano 1/metabolismo , Humanos , Espacio Intracelular/metabolismo , Esteroles/aislamiento & purificación , Esteroles/farmacología , Replicación Viral/efectos de los fármacosRESUMEN
UNLABELLED: Viruses such as HIV, HCV, Mayaro and HCMV affect cellular metabolic pathways, including glycolysis. Although some studies have suggested that the inhibition of glycolysis affects HSV-1 replication and that HSV-1-infected eyes have increased lactate production, the mechanisms by which HSV-1 induces glycolysis have never been investigated in detail. In this study, we observed an increase in glucose uptake, lactate efflux and ATP content in HSV-1-infected cells. HSV-1 triggered a MOI-dependent increase in the activity of phosphofructokinase-1 (PFK-1), a key rate-limiting enzyme of the glycolytic pathway. After HSV-1 infection, we observed increased PFK-1 expression, which increased PFK-1 total activity, and the phosphorylation of this enzyme at serine residues. HSV-1-induced glycolysis was associated with increased ATP content, and these events were critical for viral replication. In summary, our results suggest that HSV-1 triggers glycolysis through a different mechanism than other herpesviruses, such as HCMV. Thus, this study contributes to a better understanding of HSV-1 pathogenesis and provides insights into novel targets for antiviral therapy. HIGHLIGHTS: âºHSV-1 activates glycolysis by PFK-1 activation. âºIn HSV-1-infected cells PFK-1 synthesis is up-regulated and phosphorylated at serine residues. âºPFK-1 knockdown impairs HSV-1 replication. âºHSV-1-mediated glycolysis activation increases ATP content.
Asunto(s)
Glucosa/metabolismo , Herpesvirus Humano 1/metabolismo , Fosfofructoquinasa-1/metabolismo , Animales , Supervivencia Celular , Chlorocebus aethiops , Activación Enzimática , Glucólisis , Herpes Simple/metabolismo , Fosfofructoquinasa-1/antagonistas & inhibidores , Fosfofructoquinasa-1/química , Células VeroRESUMEN
Stromal keratitis resulting from ocular infection with Herpes simplex virus type 1 (HSV-1) is a common cause of blindness. This report investigates the antiviral and anti-inflammatory properties of two new synthetic stigmastane analogs in the experimental model of HSV-1-induced ocular disease in mice. (22S,23S)-22,23-dihydroxystigmast-4-en-3-one (1) and (22S,23S)-22,23-dihydroxystigmasta-1,4-dien-3-one (2) exhibited anti-HSV-1 activity in vitro and ameliorated the signs of murine herpetic stromal keratitis (HSK), although none of the compounds showed antiviral activity in vivo. We discuss that the improvement of HSK could be due to an immunomodulatory effect of both compounds.
Asunto(s)
Antiinflamatorios/farmacología , Antivirales/síntesis química , Antivirales/farmacología , Estigmasterol/análogos & derivados , Estigmasterol/síntesis química , Animales , Antivirales/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Epitelio Corneal/efectos de los fármacos , Epitelio Corneal/metabolismo , Formazáns/metabolismo , Herpesvirus Humano 1/metabolismo , Humanos , Concentración 50 Inhibidora , Queratitis Herpética/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Espectrofotometría , Sales de Tetrazolio/metabolismo , Factores de Tiempo , Células Vero , beta-Galactosidasa/metabolismoRESUMEN
We describe in this paper that the alkaloid 4-methylaaptamine, isolated from the marine sponge Aaptos aaptos, inhibited HSV-1 infection. We initially observed that 4-methylaaptamine inhibited HSV-1 replication in Vero cells in a dose-dependent manner with an EC50 value of 2.4 microM. Moreover, the concentration required to inhibit HSV-1 replication was not cytotoxic, since the CC50 value of 4-methylaaptamine was equal to 72 microM. Next, we found that 4-methylaaptamine sustained antiherpetic activity even when added to HSV-1-infected Vero cells at 4 h after infection, suggesting that this compound inhibits initial events during HSV-1 replication. We observed that 4-methylaaptamine impaired HSV-1 penetration without affecting viral adsorption. In addition, the tested compound could inhibit, in an MOI-dependent manner, the expression of an HSV-1 immediate-early protein, ICP27, thus preventing the inhibition of macromolecular synthesis induced by this virus. Our results warrant further investigation on the pharmacokinetics of 4-methylaaptamine and propose that this alkaloid could be considered as a potential compound for HSV-1 therapy.
Asunto(s)
Antivirales/farmacología , Herpesvirus Humano 1/efectos de los fármacos , Fitoterapia , Extractos Vegetales/farmacología , Poríferos , Alcaloides/administración & dosificación , Alcaloides/farmacología , Alcaloides/uso terapéutico , Animales , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Herpes Simple/tratamiento farmacológico , Herpesvirus Humano 1/metabolismo , Pruebas de Sensibilidad Microbiana , Naftiridinas/administración & dosificación , Naftiridinas/farmacología , Naftiridinas/uso terapéutico , Extractos Vegetales/administración & dosificación , Extractos Vegetales/uso terapéutico , Células Vero , Replicación Viral/efectos de los fármacosRESUMEN
Brassinosteroids are a novel group of steroids that appear to be ubiquitous in plants and are essential for normal plant growth and development. It has been previously reported that brassinosteroid analogues exert an antiviral activity against herpes simplex virus type 1 (HSV-1) and arenaviruses. In the present study, we report the chemical synthesis of compounds (22S,23S)-3beta-bromo-5alpha,22,23-trihydroxystigmastan-6-one (2), (22S,23S)-5alpha-fluoro-3beta-22,23-trihydroxystigmastan-6-one (3), (22S,23S)-3beta,5alpha,22,23-tetrahydroxy-stigmastan-6-one (4) as well as their antiherpetic activity both in a human conjunctive cell line (IOBA-NHC) and in the murine herpetic stromal keratitis (HSK) experimental model. All compounds prevented HSV-1 multiplication in NHC cells in a dose dependent manner when added after infection with no cytotoxicity. Administration of compounds 2, 3, and 4 to the eyes of mice at 1, 2, and 3 days post-infection delayed and reduced the incidence of HSK, consisting mainly of inflammation, vascularization, and necrosis, compared to untreated, infected mice. However, viral titers of eye washes showed no differences among samples from treated and untreated mice. Since the decrease in the percentage of mice with ocular lesions occurred 5 days after treatment had ended, we suggest that brassinosteroids 2, 3, and 4 did not exert a direct antiviral effect in vivo, but rather may play a role in immune-mediated stromal inflammation, which would explain the improvement of the clinical signs of HSK observed.