Evasión de la respuesta inmune por virus herpes simplex / Immune evasion by herpes simplex viruses

Herpes simplex viruses and humans have co-existed for tens of thousands of years. This long relationship has translated into the evolution and selection of viral determinants to evade the host immune response and reciprocally the evolution and selection of host immune components for limiting virus infection and damage. Currently there are no vaccines available to avoid infection with these viruses or therapies to cure them. Herpes simplex viruses are neurotropic and reside latently in neurons at the trigeminal and dorsal root ganglia, occasionally reactivating. Most viral recurrences are subclinical and thus, unnoticed. Here, we discuss the initial steps of infection by herpes simplex viruses and the molecular mechanisms they have developed to evade innate and adaptive immunity. A better understanding of the molecular mechanisms evolved by these viruses to evade host immunity should help us envision novel vaccine strategies and therapies that limit infection and dissemination.

Los virus herpes simplex y humanos co-existen desde decenas de miles de años. Esta prolongada relación se ha traducido en la evolución y selección de determinantes virales para evadir la respuesta inmune y recíprocamente la evolución y selección de componentes inmunes del hospedero para limitar la infección viral y el daño que producen. Actualmente no existen vacunas para evitar la infección de estos virus o terapias que la curen. Los virus herpes simplex son neurotrópicos y permanecen latentes en neuronas de ganglios trigémino y dorsales, reactivándose esporádicamente. La mayoría de las recurrencias por virus herpes simplex son sub-clínicas y por tanto pasan inadvertidas. Aquí discutimos los pasos iniciales de la infección porvirus herpes simplex y los mecanismos moleculares que estos virus han desarrollado para evadir la respuesta inmune innata y adaptativa. Una mejor comprensión de los mecanismos moleculares evolucionados por estos virus para evadir la respuesta inmune del hospedero deberían ayudarnos visualizar nuevas estrategias para desarrollar vacunas y terapias que limiten su infección y diseminación.

Soroprevalência de anticorpos contra vírus herpes simples 1-2 no Brasil / Seroprevalencia de anticuerpos contra virus herpes simples 1-2 en Brasil / Seroprevalence of herpes simplex 1-2 antibodies in Brazil

OBJETIVO: Estimar a soroprevalência de anticorpos por vírus herpes simples (HSV-1 e HSV-2) e analisar fatores associados no Brasil. MÉTODOS: Estudo transversal realizado entre 1996 e 1997 em 1.090 indivíduos com idade entre um e 40 anos da população geral, em quatro diferentes regiões geográficas no Brasil. Foram analisadas amostras sangüíneas para detecção de anticorpos para HSV-1 e HSV-2 com teste tipo-específico Elisa. Foram descritas freqüências e proporções, comparadas entre grupos utilizando o teste de Fisher bilateral exato. Foi realizada análise de regressão logística para avaliar influência das variáveis sociodemográficas e histórico de DST, sobre a soroprevalência de HSV-1 e/ou HSV-2. RESULTADOS: As soroprevalências de anticorpos para HSV-1 e HSV-2, ajustadas por idade, foram 67,2 por cento e 11,3 por cento respectivamente, sem diferença quanto ao sexo e maiores na Região Norte...

OBJECTIVE: To estimate the seroprevalence of HSV-1 and HSV-2 antibodies in Brazil and to analyze factors associated. METHODS: Cross-sectional study including subjects aged 1-40 years from the general population in four different geographical areas in Brazil between 1996 and 1997. All subjects were stratified by age and gender and 1,090 of them were included in the final analysis. Blood samples were tested for HSV-1 and HSV-2 antibodies by type-specific (gG1 and gG2) ELISA. Frequencies and proportions were described and compared among groups using two-sided Fisher's exact test. A logistic regression analysis was performed to assess the influence of the variables age, gender, geographical area, socioeconomic condition, past history of STD, seropositivity for anti-HSV-1 or anti-HSV-2 and interactions of any of these factors on the seroprevalence of HSV-1 and/or HSV-2. RESULTS: The age-adjusted seroprevalences of HSV-1 and HSV-2 antibodies were 67.2 percent and 11.3 percent, respectively, without sex differences and being higher in the North region...

OBJETIVO: Estimar la seroprevalencia de anticuerpos por virus herpes simples (HSV-1 y HSV-2) en diferentes áreas geográficas en Brasil y analizar factores asociados. MÉTODOS: Estudio transversal realizado entre 1996 y 1997 con individuos de la población en general en cuatro diferentes áreas geográficas en Brasil y estratificados por edad (de uno a 40 años) y sexo, de los cuales 1.090 fueron incluidos en el análisis final. Fueron analizadas muestras de sangre para detección de anticuerpos para HSV-1 y HSV-2 con prueba tipo-específica ELISA gG1-gG2. Fueron descritas frecuencias y proporciones y comparadas entre grupos utilizando la prueba de Fisher bilateral exacta. Fue realizado análisis de regresión logística para evaluar influencia de las variables edad, sexo, geografía, grupo económico, histórico de DST, seropositividad para anti-HSV-1 o anti-HSV-2 e interacciones de cualquiera de esos factores sobre la seroprevalencia de HSV-1 y/o HSV-2. RESULTADOS: La tasa de seroprevalencia de anticuerpos para HSV-1 ajustada por edad fue de 67,2 por ciento, sin diferencia con relación al sexo, siendo mayor en la Región Norte...

Elevada seroprevalencia de citomegalovirus, virus herpes simplex tipo 1 y virus Epstein Barr en adultos con virus de la inmunodeficiencia humana / High seroprevalence of cytomegalovirus, herpes simplex type 1 virus and Epstein Barr virus infection among human immunodefciency virus-infected adults

Background: Cytomegalovirus (CMV), herpes simplex type 1 (HSV-1) and Epstein Barr virus (EBV) are latent persistent infections. Their reactivation may cause illnesses and death in human immunodefciency virus-infected (HIV) people. World wide seroprevalence of these viruses is over 50 percent. In Chile, information is not available. Aim: To determine the seroprevalence of CMV, HSV-1 and EBV in Chilean HIV-infected adults. Patients and Methods: A total of 400 HIV- infected adults aged 17 to 67 years (340 males) were studied during 2005 and 2006. CMV, HSV-1 and EBV serum antibodies were measured by enzyme-linked immunoabsorbent assay. Results: The mean lapse from the diagnosis of HIV and serum testing was 67 months and 69.5 percent patients received antiretroviral therapy. Sixty seven percent of the sample were men who had sex with men (MSM). The seroprevalence for CMV, HSV-1 and EBV were 98.5, 92.2 and 99.7 percent, respectively. No patient had negative antibodies for all three viruses. Male patients that were negative for HSV-1 had a lower frequency of MSM than the rest of males (26 percent vs 62 percent, p < 0.01). Conclusions: There is a high prevalence of positive antibodies against CMV, HSV-1 and EBV in Chilean adults infected with HIV. Specifc diagnostic tests and antiviral therapy should be available for these patients.

Modulation of protective immunity against herpes simplex virus via mucosal genetic co-transfer of DNA vaccine with beta2-adrenergic agonist

Cholera toxin, which has been frequently used as mucosal adjuvant, leads to an irreversible activation of adenylyl cyclase, thereby accumulating cAMP in target cells. Here, it was assumed that beta2-adrenergic agonist salbutamol may have modulatory functions of immunity induced by DNA vaccine, since beta2-adrenergic agonists induce a temporary cAMP accumulation. To test this assumption, the present study evaluated the modulatory functions of salbutamol co-administered with DNA vaccine expressing gB of herpes simplex virus (HSV) via intranasal (i.n.) route. We found that the i.n. co-administration of salbutamol enhanced gB-specific IgG and IgA responses in both systemic and mucosal tissues, but optimal dosages of co-administered salbutamol were required to induce maximal immune responses. Moreover, the mucosal co-delivery of salbutamol with HSV DNA vaccine induced Th2-biased immunity against HSV antigen, as evidenced by IgG isotypes and Th1/Th2-type cytokine production. The enhanced immune responses caused by co-administration of salbutamol provided effective and rapid responses to HSV mucosal challenge, thereby conferring prolonged survival and reduced inflammation against viral infection. Therefore, these results suggest that salbutamol may be an attractive adjuvant for mucosal genetic transfer of DNA vaccine.

Terapia a laser no tratamento de herpes simples em pacientes HIV: relato de caso / Laser therapy for herpes simplex treatment in HIV patients: case report

O herpes simples é uma infecção ulcerativa mucocutânea de característica crônica e que pode ser recorrente e que tem como agente etiológico duas cepas do vírus herpes simples (HSV). Como advento da AIDS, houve aumento de manifestações clínicas atípicas exacerbadas pela imunossupressão, podendo estas alterar o curso de uma afecção oral, requerendo um tratamento mais incisivo, e vertendo maiores complicações que possam comprometer o estado imunológico do paciente. Relato de caso de indivíduo HIV positivo em tratamento sob administração de HAART recebendo aplicações seriadas de laserterapia nas áreas afetadas pelo vírus do herpes simples. Na presença de sintomas, o herpes pode ser uma fonte de dores, desconforto e de ansiedade e um tratamento adequado faz-se necessário. A laserterapia promoveu uma remissão do quadro de dor e aumentou o nível de conforto do paciente. O laser de baixa potência é usado para obter-se efeitos terapêuticos precisos de bioestimulação de células, analgesia e função anti-inflamatória, favorecendo rápida evolução do quadro e evitando interação medicamentosa com a HAART, promovendo bem-estar e melhora na qualidade de vida desses pacientes.

Herpes simplex is a mucocutaneous ulcerative infection which has a chronic characteristic of being recurrent and it has as an etiologic agent two types of the herpes simplex virus (HSV). With the outbreaking of AIDS, there was an increment in the atypical clinical manifestations mainly because of the immunosupression, as they can alter the path of an oral affection, then requiring a more aggressive treatment and creating more complications that may compromise the individual's immunological status. The case presents an HIV positive individual under treatment administering HAART receiving serial laser therapy applications in the areas affected by the herpes simplex virus. In the presence of symptoms herpes simplex may be a source of pain, discomfort and anxiety and a suitable treatment is necessary. The laser therapy promoted the remission of the pain pattern and increased the comfort level for the patient. The low density laser is used to create precise therapeutical effects of cell biostimulation, analgesy and anti-inflammatory function, promoting rapid evolution of the disease avoiding interaction with the HAART and promoting well being and improvement in the life quality of these patients.

Human herpes simplex virus infections: epidemiology, pathogenesis, symptomatology, diagnosis, and managemenT

Eight of the more than 80 known herpesviruses are human pathogens. Human herpes simplex virus (HSV) is a contagious infection with a large reservoir in the general population. It has a potential for significant complications in the immunocompromised host. In addition, psychological distress caused by the negative stigma associated with genital herpes and visible facial lesions in those experiencing frequent outbreaks renders it a challenging clinical dilemma. This article reviews the epidemiology, pathogenesis, and diagnostic features of HSV infections, providing the clinician with an up-to-date understanding of the available management strategies for mucocutaneous HSV-induced disease.

In vivo ligation of glucocorticoid-induced TNF receptor enhances the T-cell immunity to herpes simplex virus type 1

GITR (glucocorticoid-induced TNF receptor) is a recently identified member of the TNF receptor superfamily. The receptor is preferentially expressed on CD4+CD25+ regulatory T cells and GITR signals break the suppressive activity of the subset. In this study, we wanted to reveal the in vivo function of GITR in herpes simplex virus type 1 (HSV-1) infection. A single injection of anti-GITR mAb (DTA-1) immediately after viral infection significantly increased the number of CD4+ and CD8+ T cells expressing CD25, an activation surface marker, and secreting IFN-gamma. We confirmed these in vivo observations by showing ex vivo that re-stimulation of CD4+ or CD8+ T cells with a CD4+ or CD8+ T-cell-specific HSV-1 peptide, respectively, induced a significant elevation in cell proliferation and in IFN-gamma secretion. Our results indicate that GITR signals play a critical role in the T-cell immunity to HSV-1.

Nuevos métodos diagnósticos para virus herpes simplex (HSV): importancia de la serología / New diagnostic methods for herpes simplex virus (HSV): the importance of serology

En los últimos años el gran avance de la biología molecular aplicada al diagnóstico de agentes infecciosos ha dado como resultado nuevas metodologías, más sensibles, específicas y rápidas, al alcance del médico clínico. Para el diagnóstico de los virus herpes simplex (HSV), los métodos de detección genómica y las nuevas técnicas específicas de serología han cubierto nuevas posibilidades de confirmación etiológica frente a la sospecha clínica, todo lo cual resulta finalmente en un mejor manejo terapéutico y epidemiológico.

In recent years, the great advances in the field of molecular biology, applied to diagnosis of infectious agents have resulted in new, more sensible, specific and faster methods that are more accessible to the physician. In the case of herpes simplex virus (HSV), genomic methods and specific serology have opened new possibilities for etiologic confirmation, resulting in better therapeutic and epidemiological management.

Respuesta de inmunoglobulinas y linfocitos T en niños con eccema atópico y lesiones por virus herpes simplex tipo I (HSV-I) / Immunoglobulins and T lymphocytes responses in children with atopic eczema and herpes simplex virus type I (HSV-I) lesions

Objetivos: investigar en niños con eccema atópico y lesiones herpéticas en curso o pasadas: anticuerpos anti-VHS tipo I, niveles de IgG, IgA, IgM, IgE en suero, IgAS en secreción salival y recuento de subpoblación de linfocitos T. Materiales y métodos: se estudiaron 30 niños alérgicos de 1 a 14 años con eccema atópico y lesiones herpéticas. Se determinaron anti-HSV I, por inmunofluorescencia indirecta, en improntas de células Vero infectadas. Se cuantificó IgG, IgA, IgM en suero e IgAS en secreción salival por inmunodifusión radial e IgE en suero por EIA. Se cuatificaron de linfocitos T por la técnica de Rosetas espontáneas con eritrocitos de carnero. Fueron controles 7 niños sin lesiones por HSV-I. Resultados: el 88 por ciento de los niños con infección en curso y el 56 por ciento con infección pasada mostraron anticuerpos anti-HSV-I. Los niveles promedio de IgG, IgA, IgM séricas no mostraron diferencias estadísticas entre los grupos considerados. En el 52 por ciento de los casos se observaron niveles de IgAS por debajo de 5mg/ml. La IgE sérica total estuvo elevada en el 89 por ciento de los casos sin diferencias significativas entre ambos grupos. En el 50 por ciento de los niños con infección en curso los linfocitos T estaban por debajo de los niveles normales. Los pacientes con infección pasada tuvieron niveles normales de linfocitos T. La diferencia entre ambos grupos fue significativa p<0,0005. Los valores de linfocitos T en el grupo de infección pasada fueron más altos que en los controles (p<0,01). Conclusiones: los niños alérgicos con infección en curso mostraron títulos mayores de anticuerpos específicos que los niños con infección pasada. Los frecuentes niveles disminuídos de IgAS serían predisponentes de las lesiones virales. El incremento de los niveles de linfocitos T en los períodos de latencia controló y limitó la exacerbación de las lesiones

Characteristics of a macrophage culture persistently infected with herpes simplex virus type 1

Background. Persistence of herpes simples type 1 (HSV-1) has been reported in sensory neurons, corneal epithelium, and lymphosytes, although other cell types such as macrophages should also be considered as hosts for HSV-1 persistence. Here we report the establishment and characterization of HSV-1 persistence in an immortalized murine macrophage-like cell line (P388D1). Methods. The persistently HSV-1 infected culture (P388D1per) was obtained from surviving PO388D1 macrophages infectes with HSV-1 MP strain at multiplicity of 0.001. P388D1per was characterized by: extracellular production of viruses, cells expressing viral antigens, and cells releasing inctious viruses. Viral plaque size and cytophatic effect were determined in viruses (HSV A and HSV B) obtained from two different P388D1per passages. Host and virual proteins were detected in P388D1per and in P388D1 cells infected with HSV-1 by metabolic [35S]-methionine lebeling assays. Results. P388D1per culture was characterised by cyclic production of infectious viruses from non-detectable to 10-6 TCID50/mL; from 0.008 to 12.5 percent. Differences in viral plaque size and cytophatic effect morphology between HSV A, HSV B and HSV-1 were observed. Similar patterns of viral protein were observed in P388D1per and in P388D1 infected with HSV-1. Nonetheless, the characteristic interference effect of HSV-1 on host protein synthesis was not observed in P388D1per culture. Conclusions. An HSV-1 persistently infected immortalized macrophage culture was established and characterized. Virus produced during presistence showed phenotypic alterations with respect to the original virus. P388D1per cell protein synthesis was not affected by the presence of HSV-1

Detecciòn de anticuerpos para el virus del Herpes simple tipo 1 y 2 (VHS 1 y 2), por el mètodo de Elisa en trabajadoras del sexo / Annual reports 1996 / detection of antibodies for herpes simplex virus 1 and 2 by the Elisa method in sex workers

Las tècnicas màs comùnmente utilizadas para el diagnòstico de la infecciòn por el virus del herpes simple (VHS) son: aislamiento del virus en cultivo de tejidos, examinaciòn citològica, ensayos serològicos como inmunofluorescencia indirecta, radioinmunoanàlisis, fijaciòn de complemento, hemaglutinaciòn indirecta y el mètodo de ELISA. Los ensayos serològicos mencionados podrìan distinguir infecciones por VHS-1 del 2. El objetivo de este trabajo fue determinar la presencia de anticuerpos de tipo IgG e IgM para el VHS-1 y 2, utilizando una tècnica de ELISA, en trabajadoras del sexo. Para tal efecto fueron estudiadas 56 trabajadoras del sexo, provenientes de las ciudades de Encarnaciòn, Edelira y Ayolas. El 78,5 por ciento de la poblaciòn en estudio presentò anticuerpos contra el virus VHS-1 y el 91 por ciento para el VHS-2. El 71 por ciento presentò anticuerpos del tipo IGG y el 74,1 por ciento del tipo IgM para ambos serotipos virales, respectivamente. Nuestros hallazgos podrìan indicar o una especificidad del mètodo de ELISA utilizado para la discriminaciòn del VHS-1 del 2 o la existencia de co-infecciòn en las mujeres estudiadas. Debido al alto porcentaje de anticuerpos contra VHS-2 detectados en las trabajadoras del sexo del Paraguay, consideramos de suma importancia ampliar el numero de pacientes y comparar el ELISA con otras tècnicas serològicas.

Detecciòn de anticuerpos para el virus del Herpes simple tipo 1 y 2 (VHS 1 y 2), por el mètodo de Elisa en trabajadoras del sexo / Annual reports 1996 / Detection of antibodies for herpes simplex virus 1 and 2 by the Elisa method in sex workers

Las tècnicas màs comùnmente utilizadas para el diagnòstico de la infecciòn por el virus del herpes simple (VHS) son: aislamiento del virus en cultivo de tejidos, examinaciòn citològica, ensayos serològicos como inmunofluorescencia indirecta, radioinmunoanàlisis, fijaciòn de complemento, hemaglutinaciòn indirecta y el mètodo de ELISA. Los ensayos serològicos mencionados podrìan distinguir infecciones por VHS-1 del 2. El objetivo de este trabajo fue determinar la presencia de anticuerpos de tipo IgG e IgM para el VHS-1 y 2, utilizando una tècnica de ELISA, en trabajadoras del sexo. Para tal efecto fueron estudiadas 56 trabajadoras del sexo, provenientes de las ciudades de Encarnaciòn, Edelira y Ayolas. El 78,5 por ciento de la poblaciòn en estudio presentò anticuerpos contra el virus VHS-1 y el 91 por ciento para el VHS-2. El 71 por ciento presentò anticuerpos del tipo IGG y el 74,1 por ciento del tipo IgM para ambos serotipos virales, respectivamente. Nuestros hallazgos podrìan indicar o una especificidad del mètodo de ELISA utilizado para la discriminaciòn del VHS-1 del 2 o la existencia de co-infecciòn en las mujeres estudiadas. Debido al alto porcentaje de anticuerpos contra VHS-2 detectados en las trabajadoras del sexo del Paraguay, consideramos de suma importancia ampliar el numero de pacientes y comparar el ELISA con otras tècnicas serològicas

Medición de anticuerpos contra HSV-1 / Measurement of antibodies against HSV-1

El herpes simple tipo I (HSV I) es una de las patologías de mayor prevalencia en la población humana siendo los odontólogos un grupo de los más afectados. El presente estudio se realizó en 56 estudiantes de décimo semestre de la Pontificia Universidad Javeriana durante el primer período de 1997. Se hizo a través de un inmunotest y relacionaba la presencia de anticuerpos contra el HSV I y las manifestaciones clínicas, observando los anticuepos IgG específicos para el virus. En los hombres se encontró una alta incidencia de la enfermedad con títulos variables de IgG en suero sin que existiera una respuesta protectora en el caso de recurrencia. Asimismo en el estudio se evidencian individuos que presentan la enfermedad sin que existan títulos séricos de la inmunoglobulina estudiada.

Teste de imunidade celular em pacientes com herpes siples / The cellular immunity tests in patients with herpes simplex

Os autores estudaram a resposta aos testes de imunidade celular em 12 pacientes portadores de herper simples. A maioria apresentou imunidade celular preservada, respondendo positivamente aos testes cutaneos.

Herpetic Uveitis: a case report

We present a patient with severe, unilateral panuveitis associated with retinal detachment, which did not respond to standard treatment for uveitis. Titers of antibodies against herpes simplex virus [HSV], cytomegalovirus, and toxoplasmosis were measured in the aqueous and in the serum. A high anti-HSV antibody titer was found in the aqueous humor. The Goldmann Witmer coefficient was 4, suggesting the synthesis of antibody within the eye. Systemic intravenous and oral acyclovir resulted in complete resolution of the uveitis

Herpes simplex specific IgA antibody in patients with primary or recurrent genital herpes

By using the ELISA test, IgA antibody HSV was detected in 69% of acute phase sera while a corresponding value for convalescent phase sera was 87.5% in patients with first episode genital HSV infection. The equivalent of a four-fold rise in HSV IgA antibody titer was detected in 40% of patients. The serum level of IgA peaked at 11-21 days after illness. In recurrent genital HSV infection, 15% of the patients had no detectable IgA antibody peaked earlier than for first episode HSV infection. A significant inverse correlation [P < 0.0005] was found between the titre of HSV antibody and the frequency of recurrences