Virología molecular de la rabia: un enfoque clínico / Rabies molecular virology: a clinical approach

Introducción: La rabia es una enfermedad zoonótica asociada al virus RABV, el cual tiene características neurotrópicas. El virus se transmite por el contacto con saliva de animales infectados; la mordedura de un perro es la causa más común. Es un virus que causa la muerte de miles de personas cada año. Objetivo: Describir a profundidad los principios moleculares de la infección por rabia, así como su patogenia, diagnóstico y tratamiento. Métodos: Se realizó una búsqueda de bibliografía en PubMed, SciELO, Scopus, Researchgate; se consultaron 163 referencias y se seleccionaron 51 fuentes que contenían la información más relevante para cumplir con el objetivo del trabajo. Conclusión: Actualmente es posible entender de mejor manera los mecanismos de transmisión y propagación del virus en el organismo; existe nuevo conocimiento sobre los receptores involucrados, así como la función de estos en la replicación viral. Sin embargo, el objetivo de la erradicación de la rabia a corto plazo es complejo. La invasión de territorios selváticos vuelve a la rabia un posible patógeno reemergente; la vacunación de especies transmisoras es el medio ideal para conseguir el control de la enfermedad.

Introduction: Rabies is a zoonotic disease associated with the RABV virus, which has neurotropic characteristics. The virus is transmitted by contact with saliva from infected animals; a dog's bite is the most common cause. This virus causes the death of thousands of people every year. Objective: To describe in depth the molecular principles of rabies infection, as well as its pathogenesis, diagnosis and treatment. Methods: A literature search was conducted in PubMed, SciELO, Scopus, and Researchgate. A total of 163 references were consulted, and 51 sources containing the most relevant information were selected to fulfill the objective of the work. Conclusions: It is currently possible to better understand the mechanisms of transmission and spread of the virus in the organism; there is new knowledge about the receptors involved, as well as their function in viral replication. However, the goal of eradicating rabies in the short term is complex. The invasion of wild territories makes rabies a possible re-emerging pathogen; vaccination of transmitting species is the ideal means to achieve disease control.

Rabies virus monitoring in bat populations in Rondônia state, Brazil

Abstract INTRODUCTION: The Jirau hydroelectric power plant built in Rondônia state has environmental impacts that could be relevant to rabies outbreaks. METHODS: Bat populations were monitored for rabies by fluorescent antibody testing and simplified fluorescent inhibition microtesting between 2010 and 2015. RESULTS: All 1,183 bats tested negative for rabies. The prevalence of rabies antibodies was 17.5% in 1,049 bats. CONCLUSIONS: The rabies antibody dosage was not reactive in samples collected before the environmental changes, and there was a progressive increase in subsequent collections that could indicate an increase in rabies virus circulation among bats and risk of a rabies outbreak.

Short interfering RNAs targeting a vampire-bat related rabies virus phosphoprotein mRNA

Abstract The aim of this study was to assess the in vitro and in vivo effects of short-interfering RNAs (siRNAs) against rabies virus phosphoprotein (P) mRNA in a post-infection treatment for rabies as an extension of a previous report (Braz J Microbiol. 2013 Nov 15;44(3):879-82). To this end, rabies virus strain RABV-4005 (related to the Desmodus rotundus vampire bat) were used to inoculate BHK-21 cells and mice, and the transfection with each of the siRNAs was made with Lipofectamine-2000™. In vitro results showed that siRNA 360 was able to inhibit the replication of strain RABV-4005 with a 1 log decrease in virus titter and 5.16-fold reduction in P mRNA, 24 h post-inoculation when compared to non-treated cells. In vivo, siRNA 360 was able to induce partial protection, but with no significant difference when compared to non-treated mice. These results indicate that, despite the need for improvement for in vivo applications, P mRNA might be a target for an RNAi-based treatment for rabies.

Evaluation of short-interfering RNAs treatment in experimental rabies due to wild-type virus

ABSTRACTWe have evaluated the efficacy of short-interfering RNAs targeting the nucleoprotein gene and also the brain immune response in treated and non-treated infected mice. Mice were inoculated with wild-type virus, classified as dog (hv2) or vampire bat (hv3) variants and both groups were treated or leaved as controls. No difference was observed in the lethality rate between treated and non-treated groups, although clinical evaluation of hv2 infected mice showed differences in the severity of clinical disease (p = 0.0006). Evaluation of brain immune response 5 days post-inoculation in treated hv2 group showed no difference among the analyzed genes, whereas after 10 days post-inoculation there was increased expression of 2',5'-oligoadenylate synthetase 1, tumor necrosis factor alpha, interleukin 12, interferon gamma, and C-X-C motif chemokine 10 associated with higher expression of Ngene in the same period (p < 0.0001). In hv2 non-treated group only higher interferon beta expression was found at day 5. The observed differences in results of the immune response genes between treated and non-treated groups is not promising as they had neither impact on mortality nor even a reduction in the expression of N gene in siRNA treated animals. This finding suggests that the use of pre-designed siRNA alone may not be useful in rabies treatment.

Raiva no Estado do Rio de Janeiro, Brasil: análise das ações de vigilância e controle no âmbito municipal / Rabies in the State of Rio de Janeiro, Brazil: analysis of surveillance and control actions in the municipal field

A raiva é uma antropozoonose caracterizada por encefalite viral aguda, com letalidade próxima de 100%, e que vem passando por uma transição epidemiológica na qual o ciclo envolvendo quirópteros vem crescendo em importância. O objetivo da presente pesquisa foi analisar as ações de vigilância e controle da raiva desenvolvidas em municípios do Estado do Rio de Janeiro. Foram aplicados questionários a uma amostra representativa de gestores dos serviços de controle de zoonoses, proporcionalmente calculada em função das Regiões de Saúde, de acordo com o Plano Diretor de Regionalização do Estado. Os dados foram tabulados e trabalhados com técnicas de estatística descritiva. Com base nos resultados encontrados pode-se concluir que as ações de vigilância e controle da raiva estavam sendo desenvolvidas de maneira insatisfatória, principalmente nos itens monitoramento das colônias de morcegos hematófagos, vigilância da circulação viral, notificação e acompanhamento de animais suspeitos ou agressores, quantificação da população canina e controle populacional de cães não domiciliados. A vigilância e o controle da raiva estavam sendo negligenciados e não eram uma prioridade dos serviços de saúde dos municípios avaliados.

Rabies is an anthropozoonosis characterized by acute viral encephalitis with a lethality rate close to 100%, and it has undergone an epidemiologic transition in which the cycle involving chiroptera is increasing in importance. The scope of this research sought to analyze the rabies surveillance and control actions carried out in municipalities in the State of Rio de Janeiro. Questionnaires were distributed to a representative sample of zoonosis control service managers proportionately calculated in accordance with the Health Regions, according to the State Regionalization Guidance Plan. The data gathered was recorded and analyzed using descriptive statistical techniques. Based on the results attained, the conclusion reached is that the rabies surveillance and control actions were being unsatisfactorily conducted, especially for items related to the monitoring of vampire bat colonies, viral circulation surveillance, notification and monitoring of suspect or aggressive animals, quantification of dog population and population control of stray dogs. The surveillance and control of rabies was being neglected, and was not a priority in the health services in the municipalities evaluated.

Circulation of the rabies virus in non-hematophagous bats in the city of Rio de Janeiro, Brazil, during 2001-2010 / Circulação do vírus da raiva em morcegos não-hematófagos na cidade do Rio de Janeiro no período entre 2001-2010

INTRODUCTION: Rabies is one of the most known lethal zoonosis, responsible for 55,000 human deaths per year. It is transmitted to humans mainly by the bite of domestic or wild animals infected with the virus. This paper shows the circulation of this virus in non-hematophagous bats in the City of Rio de Janeiro, Brazil. METHODS: A survey was performed on the number of bats that had been sent for diagnosis by the Seção de Virologia of the Instituto Municipal de Medicina Veterinária Jorge Vaitsman and were positive for rabies. The positive animals were identified, and the isolated viruses were sent for antigenic typification with indirect immunofluorescence. The results were compared with the antigenic panel of the Centers for Disease Control and Prevention. RESULTS: During 2001-2010, the laboratory received 555 non-hematophagous bats for rabies diagnosis, with 198 (35.7%) from Rio de Janeiro City. A total of 11 (5.5%) animals were positive for this disease. Antigenic typification revealed the predominance of variant 3 in 9 (81.8%) of the isolated viruses; 1 virus was classified as variant 4 and 1 variant was identified that segregated with the viruses in insectivorous bats. CONCLUSIONS: The data obtained in this study showed the presence of the rabies virus in synanthropic populations of non-hematophagous bats in the City of Rio de Janeiro. The circulation of this agent in these animals represents a serious risk to human and animal health and requires attention and control measures by the authorities.

INTRODUÇÃO: A raiva é uma das mais letais zoonoses conhecidas, responsável pelo óbito de 55 mil pessoas anualmente. É transmitida ao homem principalmente pela mordida de animais, domésticos ou silvestres, infectados pelo vírus. O presente estudo mostra a circulação deste agente em morcegos não-hematófagos no município do Rio de Janeiro, Brasil. MÉTODOS: Na Seção de Virologia do Instituto Municipal de Medicina Veterinária Jorge Vaitsman, foi realizado um levantamento do número de morcegos recebidos positivos para o diagnóstico. Os animais positivos foram identificados, e o vírus isolado foi submetido à tipificação de variantes antigênicas pela técnica de imunofluorescência indireta, com os resultados comparados com o painel antigênico utilizado pelo Centro de Controle de Doenças (Center of Disease Control -CDC). RESULTADOS: Entre 2001-2010, o laboratório recebeu 555 morcegos nãohematófagos para o diagnóstico da raiva, sendo 135 (35,5%) do município do Rio de Janeiro. Um total de 11 (5,5%) animais foram positivos para a doença. A tipificação antigênica revelou a predominância da variante 3, com nove (81,9%) vírus isolados, um pertencente a variante 4 e outro de uma variante que segrega com a presente em morcegos insetívoros. CONCLUSÕES: Os dados observados no presente estudo demonstraram a presença do vírus da raiva em populações sinantrópicas de morcegos não-hematófagos no município do Rio de Janeiro. A circulação deste agente nesses animais representa um grave risco a saúde humana e animal, e requer atenção e medidas de controle e prevenção por parte das autoridades competentes.

Characterization of rabies virus isolated from a colony of Eptesicus furinalis bats in Brazil / Caracterização do vírus da raiva isolado de uma colônia de morcegos Eptesicus furinalis, do Brasil

Some bat species have adapted to the expanding human population by acquiring the ability to roost in urban buildings, increasing the exposure risk for people and domestic animals, and consequently, the likelihood of transmitting rabies. Three dead bats were found in the yard of a house in an urban area of Jundiaí city in the state of São Paulo in southeast Brazil. Two of the three bats tested positive for rabies, using Fluorescent Antibody and Mouse Inoculation techniques. A large colony of Eptesicus furinalis was found in the house's attic, and of the 119 bats captured, four more tested positive for rabies. The objectives of this study were to report the rabies diagnosis, characterize the isolated virus antigenically and genetically, and study the epidemiology of the colony.

Algumas espécies de morcegos têm se adaptado ao uso de abrigos em construções urbanas, aumentando a possibilidade de contato desses morcegos com pessoas e animais domésticos e conseqüentemente, o potencial risco de transmissão de raiva. Três morcegos foram encontrados no jardim de uma casa na área urbana da cidade de Jundiaí, Estado de São Paulo, Sudeste do Brasil, dois deles foram positivos para raiva pelas técnicas de imunofluorescência e inoculação em camundongos. Uma grande colônia de E. furinalis foi identificada, vivendo no sótão da casa e 119 morcegos foram encaminhados para diagnóstico de raiva, com mais quatro morcegos positivos. O objetivo desse estudo é apresentar a caracterização genética e antigênica do vírus da raiva isolado desses morcegos e o estudo epidemiológico da colônia.

Genetic characterization of rabies virus isolated from bovines and equines between 2007 and 2008, in the States of São Paulo and Minas Gerais / Caracterização genética de vírus da raiva isolado de bovinos e equinos entre 2007 e 2008, nos Estados de São Paulo e Minas Gerais

INTRODUCTION: Rabies is an acute disease of the central nervous system and is responsible for the deaths of thousands of humans, wild animals and livestock, particularly cattle, as well as causing major economic losses. This study describes the genetic characterization of rabies virus variants that circulate in Desmodus rotundus populations and are transmitted to herbivores. METHODS: Fifty rabies virus isolates from bovines and equines in the States of São Paulo and Minas Gerais, Brazil, were genetically characterized and compared with sequences retrieved from GenBank. RESULTS: Two clusters (I and II) with mean nucleotide identities of 99.1 and 97.6 percent were found. The first of these contained nearly all the samples analyzed. Lineages from other Brazilian states grouped in cluster II. CONCLUSIONS: Analysis of the amino acid sequences of the N proteins revealed the existence of genetic markers that may indicate possible variations between geographic regions, although the biologically active regions are conserved within the species over space and time.

INTRODUÇÃO: A raiva é uma doença aguda do sistema nervoso central e é responsável por mortes de milhares de humanos, animais silvestres e animais de criação - especialmente bovinos - além de causar elevadas perdas econômicas. Este trabalho descreve a caracterização genética das variantes do vírus da raiva que circulam em populações de Desmodus rotundus e são transmitidas aos herbívoros. MÉTODOS: Cinquenta isolados de vírus da raiva de bovinos e equinos provenientes dos Estados de São Paulo e Minas Gerais, Brasil, foram caracterizadas geneticamente e comparadas com sequências recuperadas do GenBank. RESULTADOS: Dois clusters, I e II, apresentando identidades médias de nucleotídeos de 99,1 e 97,6 por cento, foram obtidos, sendo o primeiro composto de quase a totalidade das amostras analisadas. Linhagens de outros estados do Brasil "clustered" no II. CONCLUSÕES: A análise das sequências de aminoácidos da proteína N revelou que existem marcadores genéticos que podem determinar uma possível regionalidade embora as regiões biologicamente ativas apresentem-se conservadas dentro das espécies ao longo do tempo e espaço.

A Bayesian approach to estimate the accuracy of "in-house" ELISA assay to measure rabies antibodies from compulsory vaccinated dogs and cattle

Rabies is a vaccine-preventable disease that causes acute encephalitis in mammals, and it is still a significant public health problem in numerous countries. lnfected dogs represent the main vectors involved in human rabies. Additionally, cattle rearing close to geographic areas where vampire bats are found presents an important connection with rural epidemiology. We applied two "in-house" enzyme-linked immunosorbent assay (ELISA) methodologies, considered alternatives to measure antibodies from vaccinated dogs and cattle, without employing the gold standard approach. The ELISA assays were performed on individual serum samples taken from domestic adult dogs and cows compulsory vaccinated against rabies (147 urban dogs and 64 cows; n equal 211). The sandwich and liquid-phase competitive ELISA (scELlSA and ipcELlSA). considered "in-house" assays. were performed according to previous works. The only statistical methodology that allows this study is the Bayesian approach, developed to replace the conventional Hui-Walter paradigm. For conditional independent Bayesian model (one population, two tests and no gold standard) the prior information for sensitivity and specificity of each test, mode, prevalence and transformed (alpha, beta) were submitted to Bayesian inference. The "in-house" IpcELISA revealed 16 - out of 261 serum samples - negative results, whereas in scELISA all results were positive. The Bayesian approach showed that prior information was specified for all parameters; posterior medians were SescELISA 89%, SpscELISA 88%, SPipcELISA 95% SeipcELISA 98%, and prevalence (pi) of 99%, without the use of gold standard analysis to measure specific anti-rabies antibodies

Rabia en Chile: 1989-2005 / Rabies in Chile: 1989-2005

A retrospective epidemiological study about epidemiology of rabies in Chile between years 1989 and 2005 was done. A data base of 39793 national registries of rabies samples was analyzed by means of statistical packages. Out of 39793 analyzed cases, 719 bats, 7 dogs, 7 cats, 1 bovine and 1 human were positive to rabies throughout the 17 years of this study. The statistical analysis established a significant increase in the proportions of positivity in bats, with predominance of variant 4 between the reservoirs. Given the complexity of the wild cycle of the rabies in Chile, it is necessary to maintain a program control of rabies, directed to educate people for a responsible possession of domestic animals, due to the risk of rabies transmission from bat to the susceptible species.

Se realizó este estudio para actualizar el conocimiento epidemiológico de la rabia en Chile, entre los años 1989 y 2005. Se trabajó con una base de datos de 39.793 registros históricos nacionales de muestras para el diagnóstico de rabia que mantiene el Instituto de Salud Pública de Chile, analizando los datos mediante paquetes estadísticos. De los 39.793 casos analizados se detectaron positivos a rabia en murciélagos (n: 719), perros (n: 7), gatos (n: 7), bovino (n: 1) y humano (n:l) a lo largo de los 17 años de estudio; estos representan el total de casos confirmados en Chile durante ese período. El análisis estadístico determinó un aumento lento pero significativo de positividad a rabia en murciélagos con un predominio de la variante 4 entre los reservónos circulantes. Dada la complejidad del ciclo silvestre de la rabia en Chile, es necesario mantener un programa de control de rabia dirigido a la educación de la población en pro de la tenencia responsable de los animales domésticos; existe riesgo de transmisión de la rabia desde murciélago a las especies susceptibles.

Vírus da raiva em quirópteros naturalmente infectados no Estado de São Paulo, Brasil / Rabies virus in naturally infected bats in the State of São Paulo, Southeastern Brazil

OBJETIVO: Identificar as espécies de morcegos envolvidas na manutenção do ciclo da raiva, verificar a distribuição do vírus da raiva em tecidos e órgãos de morcegos e os períodos de mortalidade dos camundongos inoculados. MÉTODOS: A positividade para o vírus da raiva foi avaliada por imunofluorescência direta em morcegos de municípios do Estado de São Paulo, de abril de 2002 a novembro de 2003. A distribuição do vírus nos morcegos foi avaliada pela inoculação de camundongos e infecção de células N2A, com suspensões a 20 por cento preparadas a partir de fragmentos de diversos órgãos e tecidos, além de cérebro e glândula salivar. A mortalidade dos camundongos foi observada diariamente, após inoculação intracerebral. RESULTADOS: Dos 4.393 morcegos pesquisados, 1,9 por cento foram positivos para o vírus da raiva, pertencentes a dez gêneros, com predomínio de insetívoros. A média do período máximo de mortalidade dos camundongos pós-inoculação a partir de cérebros e glândulas salivares de morcegos hematófagos foi de 15,33±2,08 dias e 11,33±2,30 dias; insetívoros, 16,45±4,48 dias e 18,91±6,12 dias; e frugívoros, 12,60±2,13 dias e 15,67±4,82 dias, respectivamente. CONCLUSÕES: As espécies infectadas com o vírus da raiva foram: Artibeus lituratus, Artibeus sp., Myotis nigricans, Myotis sp., Eptesicus sp., Lasiurus ega, Lasiurus cinereus, Nyctinomops laticaudatus, Tadarida brasiliensis, Histiotus velatus, Molossus rufus, Eumops sp. e Desmodus rotundus. A pesquisa de vírus em diferentes tecidos e órgãos mostrou-se que os mais apropriados para o isolamento foram cérebro e glândulas salivares.

OBJECTIVE: To identify the species of bats involved in maintaining the rabies cycle; to investigate the distribution of the rabies virus in the tissues and organs of bats and the time taken for mortality among inoculated mice. METHODS: From April 2002 to November 2003, bats from municipalities in the State of São Paulo were screened for the presence of the rabies virus, by means of direct immunofluorescence. The virus distribution in the bats was evaluated by inoculating mice and N2A cells with 20 percent suspensions prepared from fragments of different organs and tissues, plus the brain and salivary glands. The time taken for mortality among the mice was monitored daily, following intracerebral inoculation. RESULTS: Out of the 4,395 bats received, 1.9 percent were found positive for the rabies virus. They belonged to ten genera, with predominance of insectivores. The maximum mean times taken for mortality among the mice following inoculation with brain and salivary gland material were 15.33±2.08 days and 11.33±2.30 days for vampire bats, 16.45±4.48 days and 18.91±6.12 days for insectivorous bats, and 12.60±2.13 days and 15.67±4.82 days for frugivorous bats, respectively. CONCLUSIONS: The species infected with the rabies virus were: Artibeus lituratus, Artibeus sp., Myotis nigricans, Myotis sp., Eptesicus sp., Lasiurus ega, Lasiurus cinereus, Nyctinomops laticaudatus, Tadarida brasiliensis, Histiotus velatus, Molossus rufus, Eumops sp. and Desmodus rotundus. Virus investigation in the different tissues and organs showed that the brain and salivary glands were the most suitable sites for virus isolation.

Ultrastructural description of rabies virus infection in cultured sensory neurons

Primary cultures were made from adult mouse spinal ganglia for depicting an ultrastructural description of rabies virus (RABV) infection in adult mouse sensory neuron cultures; they were infected with rabies virus for 24, 36, and 48 h. The monolayers were processed for transmission electron microscopy and immunochemistry studies at the end of each period. As previously reported, sensory neurons showed great susceptibility to infection by RABV; however, in none of the periods evaluated were assembled virions observed in the cytoplasm or seen to be associated with the cytoplasmic membrane. Instead, fibril matrices of aggregated ribonucleoprotein were detected in the cytoplasm. When infected culture lysate were inoculated into normal animals via intra-cerebral route it was observed that these animals developed clinical symptoms characteristic of infection and transmission electron microscopy revealed assembled virions in the cerebral cortex and other areas of the brain. Sensory neurons infected in vitro by RABV produced a large amount of unassembled viral ribonucleoprotein. However, this intracellular material was able to produce infection and virions on being intra-cerebrally inoculated. It can thus be suggested that the lack of intracellular assembly in sensory neurons forms part of an efficient dissemination strategy.

Application of immunofluorescence and sandwich ELISA with double-antibodies in detection of human rabies / 法医学杂志

OBJECTIVE@#To explore the application of immunofluorescence and sandwich ELISA with double-antibodies in detection of human rabies.@*METHODS@#The cerebrum, cerebellum, brainstem, and hippocampus of four patients died of rabies identified by clinical diagnosis were collected and kept in freezer at -70 degrees C or in formaldehyde solution separately. The rat brain tissue infected by CVS strain of rabies virus was used as a positive control and the brain tissue of a patient died of acute pancreatitis was used as a negative control.@*RESULTS@#Rabies virus was detected in the tissues kept in freezer at -70 degrees C and the positive control but was not detected in the tissues kept in formaldehyde solution and the negative control.@*CONCLUSION@#Immunofluorescence and Sandwich ELISA with double-antibodies could be used in detection of human rabies. The samples should be kept in deep frozen temperature condition instead of in formaldehyde solution.

Diagnosis of human rabies cases by polymerase chain reaction of neck-skin samples

Rapid diagnosis of rabies in suspected human cases influences post-exposure prophylaxis for potential contacts of the patient and ensures appropriate patient management. Apart from the central nervous system (CNS), rabies virus (RABV) is usually present in small sensory nerves adjacent to hair follicles of infected humans. We used an RT-PCR, with primers targeted to the 3' terminal portion of the nucleoprotein gene (N), to test neck-skin samples of nine patients who had rabies in order to validate a diagnostic method that could serve as an additional tool for rabies diagnosis, particularly in antemortem samples. Six of eight postmortem samples were found to be positive for rabies by RT-PCR, and one of two samples collected antemortem was positive with this same technique. Results were confirmed by DNA sequencing; this validates RT-PCR and neck-skin as a suitable technique and type of sample, respectively, for use in the diagnosis of human rabies. RT-PCR applied to neck-skin biopsies could allow early diagnosis and lead to more effective rabies treatment.

Digoxigenin-labeled probe for rabies virus nucleoprotein gene detection

A digoxigenin-labeled probe was produced from the Pasteur virus strain for the detection of the rabies virus N gene. The probe hybridization was performed from amplified N gene obtained by reverse transcription polymerase chain reaction and the results by RT-PCR and hybridization showed 100 percent agreement. The hybridization, when carried out in products amplified by RT-PCR, increases the sensitivity of this technique even more and confers specificity to the diagnosis. The technique described in this work will be useful in rabies diagnosis laboratories, once the cost is compatible with traditional rabies diagnostic techniques.

Dimorfismo ultraestructural y opciones no utilizadas previamente para el tratamiento de la encefalitis rábica humana / Ultrastructural dimorphism and unused options in the management of human rabies encephatitis

Se hace una revisión de diferentes tratamientos experimentales en cultivo de células y en ratones con rabdovirus rábico fijo que no ha tenido aplicación práctica. Se plantean tratamientos opcionales no utilizados previamente para la encefalitis rábica humana, basados en hipótesis congruentes. Se señala el empleo del agente quimioterápico 5 fluorouracilo (5-FU). Se sugiere la anestesia por éter, dado que este compuesto a baja concentración inhibe el crecimiento viral. Otra opción sería la radioterapia como la empleada para tumores cerebrales. También se ha sugerido la craniectomía descomprensiva bilateral complementaria y el empleo de inhibidores no-nucleósidos de transcriptasas virales.