Michael Diamond

..This Review focuses on recent advances in identifying the unique mechanisms of action of IFIT and IFITM proteins, which explain their broad-spectrum activity against the replication, spread and pathogenesis of a range of human viruses...

..We will focus on defining the current state of knowledge of WNV entry, tropism, and host immune response in the CNS, all of which affect the balance between injury and successful clearance...

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..This review describes the molecular virology, epidemiology, pathogenesis, and highlights recent progress regarding diagnosis and vaccination against WNV infections...

..Currently, there are no licensed vaccines or antiviral drugs to prevent or treat dengue infections. Biodegradable nanoparticles coated with proteins represent a promising method for in vivo delivery of vaccines...

..In general, mice vaccinated with P28-adjuvated vaccines produced higher IgG titers than mice vaccinated with non-adjuvanted vaccines...

..Here, we examine the ability of exogenous small interfering RNAs (siRNAs) to block the replication of West Nile virus in human cells...

..This review will summarize our current understanding of how mammalian cells recognize flaviviruses to induce an inhibitory IFN response and the countermeasures this group of viruses has evolved to antagonize this response...

..This review describes the epidemiology, clinical presentation and pathogenesis of West Nile virus infection, and highlights recent progress towards an effective therapy...

..This review describes the current state of knowledge on epidemiology, clinical presentation, pathogenesis, and immunobiology of WNV infection, and highlights progress toward an effective therapy...

..In this review, we discuss the structural, molecular, and immunologic basis for antibody-mediated protection against WNV, and its implications for novel therapeutic or vaccine strategies...

..We conclude that antibodies and B cells play a critical early role in the defense against disseminated infection by WNV...

..Recently, the crystal structure of the Ebola virus glycoprotein in complex with a human neutralizing antibody was illuminated, providing a path from the shadows toward understanding cellular attachment, viral fusion, and immune evasion...

..Thus, the induction of a specific, neutralizing IgM response early in the course of WNV infection limits viremia and dissemination into the central nervous system, and protects against lethal infection...

..The study highlights a possible risk in targeting this receptor for the prevention and/or treatment of infectious diseases...

..These findings are analyzed in the context of recent approaches to vaccine development and immunotherapy against WNV...

..A more thorough understanding of these principles could lead to improved models for viral pathogenesis and to strategies for the development of novel antiviral agents...

..This review will focus on the interactions between WNV and the protective and pathogenic host immune responses...

..In contrast, in these cells the IFN-beta response remained largely intact. Our data suggest that the early protective IFN-alpha response against WNV occurs through an IRF-7-dependent transcriptional signal...

..Taken together, our data suggest that TLR3 serves a protective role against WNV in part, by restricting replication in neurons...

..Collectively, our data suggest that cell-specific IRF-3 responses protect against WNV infection through both IFN-dependent and -independent programs...

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..Our data are most consistent with a model in which interaction of TNF-alpha with TNF-R1 protects against WNV infection by regulating migration of protective inflammatory cells into the brain during acute infection...

..Thus, passive transfer of immune antibody improves clinical outcome even after WNV has disseminated into the central nervous system...

..Collectively, our experiments suggest that, while specific antibody is responsible for terminating viremia, CD8(+) T cells have an important function in clearing infection from tissues and preventing viral persistence...

..Our results suggest that individual pathways of complement activation control WNV infection by priming adaptive immune responses through distinct mechanisms...

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..Our experiments suggest that MyD88 restricts WNV by inhibiting replication in subsets of cells and modulating expression of chemokines that regulate immune cell migration into the central nervous system...

..Collectively, our data suggest that IFN-alpha/beta controls WNV infection by restricting tropism and viral burden and by preventing death of infected neurons...

..These findings may be relevant for generating novel therapeutic MAbs or vaccines against flaviviruses that target the NS1 protein...

..Beside its role in maturation of antibody responses, our experiments suggest a novel function of CD40-CD40L interactions: to facilitate T-cell migration across the blood-brain barrier to control WNV infection...

..Overall, these results suggest that complement controls WNV infection, in part through its ability to induce a protective antibody response...

..IgG subclasses that avidly bind C1q induced minimal ADE in the presence of C1q. These findings add a layer of complexity for the analysis of humoral immunity and flavivirus infection...

..Importantly, rejection of highly immunogenic syngeneic tumors was impaired in Batf3-/- mice. These results suggest an important role for CD8alpha+ dendritic cells and cross-presentation in responses to viruses and in tumor rejection...

..CR4348 and CR4354 human MAbs neutralize infection at a postattachment step in the viral life cycle, likely by inhibiting acid-induced fusion within the endosome...

..These studies establish that caspase 3-dependent apoptosis contributes to the pathogenesis of lethal WNV encephalitis and suggest possible novel therapeutic targets to restrict CNS injury...

..Our experiments suggest that the dominant protective role of CD4(+) T cells during primary WNV infection is to provide help for antibody responses and sustain WNV-specific CD8(+) T-cell responses in the CNS that enable viral clearance...

..In postexposure therapeutic trials in mice, a single dose of humanized E16 protected mice against WNV-induced mortality, and may therefore be a viable treatment option against WNV infection in humans...

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..Collectively, our results suggest that a vaccine strategy targeting the dominant DIII epitope may elicit safe and effective immune responses against flaviviral diseases...

..Overall, the NS1-based capture ELISA is a sensitive readout of infection and could be an important tool for diagnosis or screening small molecule inhibitors of WNV infection...

..Our data suggest that PKR and RNase L contribute to IFN-mediated protection in a cell-restricted manner and control WNV infection in peripheral tissues and some neuronal subtypes...

..Overall, our data suggest that distinct regions of NS1 can elicit protective humoral immunity against WNV through different mechanisms...

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..Our studies show that MBL recognizes terminal mannose-containing carbohydrates on flaviviruses, resulting in neutralization and efficient clearance in vivo...

..Overall, these studies define the structural and functional complexity of antibodies against DENV-2 with protective potential...

..Here, we present our current understanding of the innate and adaptive immune responses that limit dissemination to the CNS from WNV infection and the antiviral immune responses within the CNS that intervene when they fail...

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..Thus, whereas the immune evasion capabilities and lifelong persistence of herpesviruses are commonly viewed as solely pathogenic, our data suggest that latency is a symbiotic relationship with immune benefits for the host...

..Antibodies that bind to this epitope are particularly inhibitory because they block infection at a post-attachment step and at concentrations that result in a low occupancy of the available sites on the virion...

..Overall, our experiments define adjacent and structurally distinct epitopes on DIII of DENV-2 which elicit type-specific, subcomplex-specific, and cross-reactive antibodies with different neutralizing potentials...

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..Collectively, our experiments suggest that the dominant protective role of IFN-gamma against WNV is antiviral in nature, occurs in peripheral lymphoid tissues, and prevents viral dissemination to the CNS...

..Moreover, mda-5-/- mice exhibited a selectively impaired antiviral response to encephalomyocarditis picornavirus, indicating functional specialization of mda-5 in vivo...

..The benefits of enhanced CD8(+) T cell infiltration suggest that pharmacologic targeting of CXCR4 may have therapeutic utility for the treatment of acute viral infections of the CNS...

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..Overall, these results enhance our mechanistic understanding of how complement controls flavivirus infections...

..These results suggest that neuronal TNF-alpha expression during WNV encephalitis may be an adaptive response to diminish CXCL10-induced death...

..Taken together, our data suggest that despite the risk of immunopathogenesis, CD8+ T cells use a perforin-dependent mechanism to clear WNV from infected neurons...

..Overall, our data suggest that castanospermine has a strong antiviral effect on dengue virus infection and warrants further development as a possible treatment in humans...

..Nonetheless, DI and DII MAbs protect against WNV infection in mice, albeit with lower efficiency than DIII-specific neutralizing MAbs...

..Thus, a strongly neutralizing anti-WNV MAb with therapeutic potential is potently inhibitory because it blocks viral fusion and thereby promotes clearance by delivering virus to the lysosome for destruction...

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..Overall, our data suggest that CD8+ T cells also utilize FasL effector mechanisms to contain WNV infection in Fas-expressing neurons in the CNS...

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..Overall, these compounds comprise a novel class of promising inhibitors for therapy against WNV and other flavivirus infections in humans...

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..Based on this, we conclude that CTL responses against immundominant WNV epitopes confer protective immunity and thus should be targets for inclusion in new vaccines...

..Our experiments suggest that viperin restricts the infection of WNV in a tissue- and cell-type-specific manner and may be an important ISG for controlling viral infections that cause CNS disease...

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..Collectively, these results suggest that IFN-β controls WNV pathogenesis by restricting infection in key cell types and by modulating T cell regulatory networks...

..Collectively, these studies help to define the structural and functional complexity of antibodies against HCV E2 protein with neutralizing potential...

..Thus, WNV(KUN) is attenuated primarily through its enhanced restriction by type I interferon- and IRF-3-dependent mechanisms...

..Thus, neutralization is best described by a model requiring "multiple hits" with the cumulative functional outcome determined by interplay between antibody affinity and epitope accessibility...

..These results indicate that WNV differentially induces CXCL10 within neuronal populations and suggest a novel model for nonredundancy in chemokine-mediated inflammation among CNS compartments...

..These experiments suggest that humanized MAbs with potent neutralizing activity are a possible treatment for human patients after WNV has infected neurons in the central nervous system...

..These recombinant human scFvs are potential candidates for immunoprophylaxis and therapy of flavivirus infections...

..3 microg/ml or higher. Overall, these data suggest that in hamsters hE16 can ameliorate neurological disease after significant viral replication has occurred, although there is a time window that limits therapeutic efficacy...

..Thus, in addition to a role in facilitating viral entry, changes in E protein arrangement associated with maturation modulate neutralization sensitivity and introduce an additional layer of complexity into humoral immunity against WNV...

..WNV RVPs are capable of only a single round of infection, can be used under BSL-2 conditions, and offer a rapid and quantitative approach for detecting virus entry and its inhibition by neutralizing antibody...

..These insights have identified factors that govern the potency of neutralizing antibodies and will inform the design and evaluation of novel vaccines...

..How recent advances in this area have the potential to improve the development of safe and effective vaccines and immunotherapeutics is also addressed...

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..Overall, our findings represent a foundation for in-depth mechanistic and structural studies as well as for the design of novel and efficient inhibitors of WNV NS3...

..The changes in the structure of the viral surface are presumably responsible for inhibiting attachment to cells...

..Moreover, antibody therapeutics directly inhibit transneuronal spread of WNV infection and prevent the development of paralysis in vivo...

..We speculate that E proteins could pivot around the fusion loop-pocket junction, allowing virion conformational transitions while minimizing fusion loop exposure...

..We anticipate this DNA-based, infectious WNV reporter virus will allow novel approaches for the study of WNV infection and its inhibition both in vitro and in vivo...

..Consistent with this finding, the virulence of MAD78 was unmasked upon infection of mice lacking IFNAR. Thus, control of the innate host response and IFN actions is a key feature of WNV pathogenesis and replication fitness...

..Overall, the generation of strongly protective humanized MAbs against CHIKV will foster the clinical development of immunotherapeutic agents against CHIKV infection. ..

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..In Specific Aim 4, we will develop epitope-based diagnostic assays and immunogens for DENV. Collectively, these studies may be of significant importance in ongoing and future DENV vaccine development programs. ..

..In Specific Aim 4, we will develop epitope-based diagnostic assays and immunogens for DENV. Collectively, these studies may be of significant importance in ongoing and future DENV vaccine development programs. ..

..These studies are an essential first step in the generation of humanized mAbs that have utility as therapeutic agents against WNV in humans. ..

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