Implication of a retrovirus-like glycoprotein peptide in the immunopathogenesis of Ebola and Marburg viruses

Ebola and Marburg viruses can cause hemorrhagic fever (HF) outbreaks with high mortality in primates. Whereas Marburg (MARV), Ebola Zaire (ZEBOV), and Ebola Sudan (SEBOV) viruses are pathogenic in humans, apes, and monkeys, Ebola Reston (REBOV) is pathogenic only in monkeys. Early immunosuppression may contribute to pathogenesis by facilitating viral replication. Lymphocyte depletion, intravascular apoptosis, and cytokine dysregulation are prominent in fatal cases. Here we functionally characterize a 17 amino acid domain in filoviral glycoproteins that resembles an immunosuppressive motif in retroviral envelope proteins. Activated human or rhesus peripheral blood mononuclear cells (PBMC) were exposed to inactivated ZEBOV or a panel of 17mer peptides representing all sequenced strains of filoviruses, then analyzed for CD4+ and CD8+ T cell activation, apoptosis, and cytokine expression. Exposure of human and rhesus PBMC to ZEBOV, SEBOV, or MARV peptides or inactivated ZEBOV resulted in decreased expression of activation markers on CD4 and CD8 cells; CD4 and CD8 cell apoptosis as early as 12 h postexposure; inhibition of CD4 and CD8 cell cycle progression; decreased interleukin (IL)-2, IFN-gamma, and IL12-p40 expression; and increased IL-10 expression. In contrast, only rhesus T cells were sensitive to REBOV peptides. These findings are consistent with the observation that REBOV is not pathogenic in humans and have implications for understanding the pathogenesis of filoviral HF

Zika virus pathogenesis in rhesus macaques is unaffected by pre-existing immunity to dengue virus

Zika virus (ZIKV) is a re-emerging virus that has recently spread into dengue virus (DENV) endemic regions and cross-reactive antibodies (Abs) could potentially affect ZIKV pathogenesis. Using DENV-immune serum, it has been shown in vitro that antibody-dependent enhancement (ADE) of ZIKV infection can occur. Here we study the effects of pre-existing DENV immunity on ZIKV infection in vivo. We infect two cohorts of rhesus macaques with ZIKV; one cohort has been exposed to DENV 2.8 years earlier and a second control cohort is naïve to flaviviral infection. Our results, while confirming ADE in vitro, suggest that pre-existing DENV immunity does not result in more severe ZIKV disease. Rather our results show a reduction in the number of days of ZIKV viremia compared to naïve macaques and that the previous exposure to DENV may result in modulation of the immune response without resulting in enhancement of ZIKV pathogenesis

Decreased Dengue Replication and an Increased Anti-viral Humoral Response with the use of Combined Toll-Like Receptor 3 and 7/8 Agonists in Macaques

Pathogenic versus protective outcomes to Dengue virus (DENV) infection are associated with innate immune function. This study aimed to determine the role of increased TLR3- and TLR7/8-mediated innate signaling after Dengue infection of rhesus macaques in vivo to evaluate its impact on disease and anti-DENV immune responses.TLR3 and TLR7/8 agonists (emulsified in Montanide) were administered subcutaneously to rhesus macaques at 48 hours and 7 days after DENV infection. The Frequency and activation of myeloid dendritic cells, plasmacytoid dendritic cells, and B cells were measured by flow cytometry while the serum levels of 14 different cytokines and chemokines were quantified. Adaptive immune responses were measured by DENV-specific antibody subtype measurements. Results showed that the combined TLR agonists reduced viral replication and induced the development of a proinflammatory reaction, otherwise absent in Dengue infection alone, without any clear signs of exacerbated disease. Specifically, the TLR-induced response was characterized by activation changes in mDC subsets concurrent with higher serum levels of CXCL-10 and IL-1Ra. TLR stimulation also induced higher titers of anti-DENV antibodies and acted to increase the IgG2/IgG1 ratio of anti-DENV to favor the subtype associated with DENV control. We also observed an effect of DENV-mediated suppression of mDC activation consistent with prior in vitro studies.These data show that concurrent TLR3/7/8 activation of the innate immune response after DENV infection in vivo acts to increase antiviral mechanisms via increased inflammatory and humoral responses in rhesus macaques, resulting in decreased viremia and melioration of the infection. These findings underscore an in vivo protective rather than a pathogenic role for combined TLR3/7/8-mediated activation in Dengue infection of rhesus macaques. Our study provides definitive proof-of-concept into the mechanism by which DENV evades immune recognition and activation in vivo

HIV-1 DNA/MVA vaccination reduces the per exposure probability of infection during repeated mucosal SHIV challenges

Historically, HIV vaccines specifically designed to raise cellular immunity resulted in protection from disease progression but not infection when tested in monkeys challenged with a single high virus exposure. An alternative approach, more analogous to human sexual exposures, is to repetitively challenge immunized monkeys with a much lower dose of virus until systemic infection is documented. Using these conditions to mimic human sexual transmission, we found that a multi-protein DNA/MVA HIV-1 vaccine is indeed capable of protecting rhesus monkeys against systemic infection when repeatedly challenged with a highly heterologous immunodeficiency virus (SHIV). Furthermore, this repetitive challenge approach allowed us to calculate per-exposure probability of infection, an observed vaccine efficacy of 64%, and undertake a systematic analysis for correlates of protection based on exposures needed to achieve infection. Therefore, improved non-human primate models for vaccine efficacy can provide novel insight and perhaps renew expectations for positive outcomes of human HIV clinical trials

Dengue virus envelope protein domain I/II hinge determines long-lived serotype-specific dengue immunity

Dengue virus is the most important arthropod-borne viral disease of humans worldwide, with an estimated 390 million acute infections annually. The best means to control this global health threat is a vaccine, but dengue vaccine development has progressed slowly, partly because the antigenic targets required to stimulate long-term immunity are not well-defined. Here, we show a specific region on the viral surface (the envelope domain I/II hinge) that is the target of protective antibodies after primary human infections. These results are critically important for dengue vaccine design, because we hypothesize that a successful dengue vaccine will stimulate antibodies that target this region. More broadly, this study establishes a template for similar approaches for improving vaccines for influenza, HIV, hepatitis C virus, and other clinically important viral pathogens

Utility, limitations and future of non-human primates for dengue research and vaccine development

Dengue is considered the most important emerging, human arboviruses, with worldwide distribution in the tropics. Unfortunately there are no licensed dengue vaccines available or specific antiviral drugs. The development of a dengue vaccine faces unique challenges. The 4 serotypes co-circulate in endemic areas, and pre-existing immunity to one serotype does not protect against infection with other serotypes, and actually may enhance severity of disease. One foremost constraint to test the efficacy of a dengue vaccine is the lack of an animal model that adequately recapitulates the clinical manifestations of a dengue infection in humans. In spite of this limitation, Non Human Primates (NHP) are considered the best available animal model to evaluate dengue vaccine candidates due to their genetic relatedness to humans and their ability to develop a viremia upon infection and a robust immune response similar to that in humans. Therefore, most dengue vaccines candidates are tested in primates before going into clinical trials. In this article we present a comprehensive review of published studies on dengue vaccine evaluations using the NHP model, and discuss critical parameters affecting the usefulness of the model. In the light of recent clinical data, we assess the ability of the NHP model to predict immunological parameters of vaccine performances in humans and discuss parameters that should be further examined as potential correlates of protection. Finally we propose some guidelines towards a more standardized use of the model to maximize its usefulness and to better compare the performance of vaccine candidates from different research groups

Producción científica sobre e-learning en América Latina, un estudio preliminar desde la base de datos SciELO

In this article some arguments related studies on e-learning in the field of education are clarified. The main objective is focused to present a bibliometric approach of the scientific production of this issue in the context of research in the Latin American region. To identify the key patterns in productivity is used as a reference source the SciELO database, from which was applied the indicators: document typology, productivity of years, journals, countries, language, and research areas. About 610 bibliographical records were obtained for the period 2003-2013, which denotes the increasing of productivity from recent years. Brazilian domain is inserted as the most prolific in terms of language, journals, and country. As part of subject areas from which this topic has been explored are included Educational Sciences and Health Sciences, which emphasizes a strong multidisciplinary projection of the e-learning field