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colorimetric detection of dengue by single tube reverse-transcription-loop-mediated isothermal amplification.dengue is usually diagnosed by isolation of the virus, serology or molecular diagnostic methods. several commercial kits for the diagnosis of dengue are existing, but concerns have arisen regarding to the affordability and performance characteristics of these kits. hence, the loop-mediated isothermal amplification (lamp) is potentially ideal to be used especially in resource limited environments. serum was collected from healthy donors and patients diagnosed with dengue infection. rna extracted ...201526384248
mosquito rasputin interacts with chikungunya virus nsp3 and determines the infection rate in aedes albopictus.chikungunya virus (chikv) is an arthritogenic alphavirus (family togaviridae), transmitted by aedes species mosquitoes. chikv re-emerged in 2004 with multiple outbreaks worldwide and recently reached the americas where it has infected over a million individuals in a rapidly expanding epidemic. while alphavirus replication is well understood in general, the specific function (s) of non-structural protein nsp3 remain elusive. chikv nsp3 modulates the mammalian stress response by preventing stress ...201526384002
autophagy knocked down by high-risk hpv infection and uterine cervical carcinogenesis.cervical cancer is a leading cause of cancer death among women in the world. the specific etiopathogenesis of cervical cancer is indeed complex. even so, we should make arduous efforts to have a precise understanding of the complicate cellular/molecular mechanisms underlying initiation, progression and/or prevention of the cervical cancer. the high-risk human papillomavirus (hrhpv) is considered as the major causative agent of cervical cancer. but with the existence of hrhpv only is not sufficie ...201526379821
retargeting oncolytic vesicular stomatitis virus to human t-cell lymphotropic virus type 1-associated adult t-cell leukemia.adult t cell leukemia/lymphoma (atl) is an aggressive cancer of cd4/cd25(+) t lymphocytes, the etiological agent of which is human t-cell lymphotropic virus type 1 (htlv-1). atl is highly refractory to current therapies, making the development of new treatments a high priority. oncolytic viruses such as vesicular stomatitis virus (vsv) are being considered as anticancer agents since they readily infect transformed cells compared to normal cells, the former appearing to exhibit defective innate i ...201526378177
syndromic approach to arboviral diagnostics for global travelers as a basis for infectious disease surveillance.arboviruses have overlapping geographical distributions and can cause symptoms that coincide with more common infections. therefore, arbovirus infections are often neglected by travel diagnostics. here, we assessed the potential of syndrome-based approaches for diagnosis and surveillance of neglected arboviral diseases in returning travelers.201526372010
protective and pathogenic responses to chikungunya virus infection.chikungunya virus (chikv) is an arbovirus responsible for causing epidemic outbreaks of human disease characterized by painful and often debilitating arthralgia. recently chikv has moved into the caribbean and the americas resulting in massive outbreaks in naïve human populations. given the importance of chikv as an emerging disease, a significant amount of effort has gone into interpreting the virus-host interactions that contribute to protection or virus-induced pathology following chikv infec ...026366337
japanese encephalitis virus replicon-based vaccine expressing enterovirus-71 epitope confers dual protection from lethal challenges.to construct safer recombinant flavivirus vaccine, we exploited japanese encephalitis virus (jev) replicon-based platform to generate single-round infectious particles (srips) that expressed heterologous neutralizing epitope sp70 derived from enterovirus-71 (ev71). such pseudo-infectious virus particles, named srip-sp70, although are not genuine viable viruses, closely mimic live virus infection to elicit immune responses within one round of viral life cycle.201526362772
fiat luc: bioluminescence imaging reveals in vivo viral replication dynamics. 201526356297
kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor 1 interacts with a member of the interferon-stimulated gene 15 pathway.kaposi's sarcoma-associated herpesvirus (kshv) is a gammaherpesvirus known to establish lifelong latency in the human host. we and others have previously shown that three kshv homologs of cellular interferon regulatory factors (irfs), known as viral irfs (virfs), participate in evasion of the host interferon (ifn) response. we report that virf1 interacts with the cellular interferon-stimulated gene 15 (isg15) e3 ligase, herc5, in the context of toll-like receptor 3 (tlr3) activation and ifn indu ...201526355087
therapeutic vaccine strategies against human papillomavirus.high-risk types of human papillomavirus (hpv) cause over 500,000 cervical, anogenital and oropharyngeal cancer cases per year. the transforming potential of hpvs is mediated by viral oncoproteins. these are essential for the induction and maintenance of the malignant phenotype. thus, hpv-mediated malignancies pose the unique opportunity in cancer vaccination to target immunologically foreign epitopes. therapeutic hpv vaccination is therefore an ideal scenario for proof-of-concept studies of canc ...201426344626
recent developments in preclinical dna vaccination.the advantages of genetic immunization of the new vaccine using plasmid dnas are multifold. for example, it is easy to generate plasmid dnas, increase their dose during the manufacturing process, and sterilize them. furthermore, they can be stored for a long period of time upon stabilization, and their protein encoding sequences can be easily modified by employing various dna-manipulation techniques. although dna vaccinations strongly increase th1-mediated immune responses in animals, several pr ...201426344468
enhanced delivery and potency of self-amplifying mrna vaccines by electroporation in situ.nucleic acid-based vaccines such as viral vectors, plasmid dna (pdna), and mrna are being developed as a means to address limitations of both live-attenuated and subunit vaccines. dna vaccines have been shown to be potent in a wide variety of animal species and several products are now licensed for commercial veterinary but not human use. electroporation delivery technologies have been shown to improve the generation of t and b cell responses from synthetic dna vaccines in many animal species an ...201326344119
differential phosphatidylinositol-3-kinase-akt-mtor activation by semliki forest and chikungunya viruses is dependent on nsp3 and connected to replication complex internalization.many viruses affect or exploit the phosphatidylinositol-3-kinase (pi3k)-akt-mammalian target of rapamycin (mtor) pathway, a crucial prosurvival signaling cascade. we report that this pathway was strongly activated in cells upon infection with the old world alphavirus semliki forest virus (sfv), even under conditions of complete nutrient starvation. we mapped this activation to the hyperphosphorylated/acidic domain in the c-terminal tail of sfv nonstructural protein nsp3. viruses with a deletion ...201526339054
hur displaces polypyrimidine tract binding protein to facilitate la binding to the 3' untranslated region and enhances hepatitis c virus replication.hur is a ubiquitous, rna binding protein that influences the stability and translation of several cellular mrnas. here, we report a novel role for hur, as a regulator of proteins assembling at the 3' untranslated region (utr) of viral rna in the context of hepatitis c virus (hcv) infection. hur relocalizes from the nucleus to the cytoplasm upon hcv infection, interacts with the viral polymerase (ns5b), and gets redistributed into compartments of viral rna synthesis. depletion in hur levels leads ...201526339049
flavivirus sfrna suppresses antiviral rna interference in cultured cells and mosquitoes and directly interacts with the rnai machinery.productive arbovirus infections require mechanisms to suppress or circumvent the cellular rna interference (rnai) pathway, a major antiviral response in mosquitoes. in this study, we demonstrate that two flaviviruses, dengue virus and kunjin virus, significantly repress sirna-mediated rnai in infected human cells as well as during infection of the mosquito vector culex quinquefasciatus. arthropod-borne flaviviruses generate a small structured non-coding rna from the viral 3' utr referred to as s ...201526331679
structural and functional characterization of anti-a33 antibodies reveal a potent cross-species orthopoxviruses neutralizer.vaccinia virus a33 is an extracellular enveloped virus (eev)-specific type ii membrane glycoprotein that is essential for efficient eev formation and long-range viral spread within the host. a33 is a target for neutralizing antibody responses against eev. in this study, we produced seven murine anti-a33 monoclonal antibodies (mabs) by immunizing mice with live vacv, followed by boosting with the soluble a33 homodimeric ectodomain. five a33 specific mabs were capable of neutralizing eev in the pr ...201526325270
dna-launched alphavirus replicons encoding a fusion of mycobacterial antigens acr and ag85b are immunogenic and protective in a murine model of tb infection.there is an urgent need for effective prophylactic measures against mycobacterium tuberculosis (mtb) infection, particularly given the highly variable efficacy of bacille calmette-guerin (bcg), the only licensed vaccine against tuberculosis (tb). most studies indicate that cell-mediated immune responses involving both cd4+ and cd8+ t cells are necessary for effective immunity against mtb. genetic vaccination induces humoral and cellular immune responses, including cd4+ and cd8+ t-cell responses, ...201526317509
viral polymerase-helicase complexes regulate replication fidelity to overcome intracellular nucleotide depletion.to date, the majority of work on rna virus replication fidelity has focused on the viral rna polymerase, while the potential role of other viral replicase proteins in this process is poorly understood. previous studies used resistance to broad-spectrum rna mutagens, such as ribavirin, to identify polymerases with increased fidelity that avoid misincorporation of such base analogues. we identified a novel variant in the alphavirus viral helicase/protease, nonstructural protein 2 (nsp2) that opera ...201526311883
differences in processing determinants of nonstructural polyprotein and in the sequence of nonstructural protein 3 affect neurovirulence of semliki forest virus.the a7(74) strain of semliki forest virus (sfv; genus alphavirus) is avirulent in adult mice, while the l10 strain is virulent in mice of all ages. it has been previously demonstrated that this phenotypic difference is associated with nonstructural protein 3 (nsp3). consensus clones of l10 (designated sfv6) and a7(74) (designated a774wt) were used to construct a panel of recombinant viruses. the insertion of nsp3 from a774wt into the sfv6 backbone had a minor effect on the virulence of the resul ...201526311875
a potent neutralizing igm mab targeting the n218 epitope on e2 protein protects against chikungunya virus pathogenesis.chikungunya virus (chikv) is a medically important human viral pathogen that causes chikungunya fever accompanied with debilitating and persistent joint pain. host-elicited or passively-transferred monoclonal antibodies (mab) are essential mediators of chikv clearance. therefore, this study aimed to generate and characterize a panel of mabs for their neutralization efficacy against chikv infection in a cell-based and murine model. to evaluate their antigenicity and neutralization profile, indire ...201526305993
oncolytic viral therapy for neuroblastoma cells with sindbis virus ar339 strain.with current treatment regimens, high-risk neuroblastoma (nb) remains largely incurable. oncolytic viral therapy uses replication-competent viruses, like sindbis virus (sinv), to kill cancers. the sinv ar339 strain is blood borne and relatively non-virulent. we evaluated the feasibility of sinv ar339 for treating human nb.201526298056
semliki forest virus and sindbis virus, but not vaccinia virus, require glycolysis for optimal replication.viruses are obligate intracellular pathogens which rely on the cell's machinery to produce the energy and macromolecules required for replication. infection is associated with a modified metabolic profile and one pathway which can be modified is glycolysis. in this study, we investigated if the glycolysis pathway is required for alphavirus replication. pre-treatment of vero cells with three different glycolysis inhibitors (2-deoxyglucose, lonidamine and oxamate) resulted in a significant reducti ...201526297236
x-ray structural and functional studies of the three tandemly linked domains of non-structural protein 3 (nsp3) from murine hepatitis virus reveal conserved functions.murine hepatitis virus (mhv) has long served as a model system for the study of coronaviruses. non-structural protein 3 (nsp3) is the largest nsp in the coronavirus genome, and it contains multiple functional domains that are required for coronavirus replication. despite the numerous functional studies on mhv and its nsp3 domain, the structure of only one domain in nsp3, the small ubiquitin-like domain 1 (ubl1), has been determined. we report here the x-ray structure of three tandemly linked dom ...201526296883
the virus-host interplay: biogenesis of +rna replication complexes.positive-strand rna (+rna) viruses are an important group of human and animal pathogens that have significant global health and economic impacts. notable members include west nile virus, dengue virus, chikungunya, severe acute respiratory syndrome (sars) coronavirus and enteroviruses of the picornaviridae family.unfortunately, prophylactic and therapeutic treatments against these pathogens are limited. +rna viruses have limited coding capacity and thus rely extensively on host factors for succes ...201526287230
comparative mapping of host-pathogen protein-protein interactions.pathogens usurp a variety of host pathways via protein-protein interactions to ensure efficient pathogen replication. despite the existence of an impressive toolkit of systematic and unbiased approaches, we still lack a comprehensive list of these ppis and an understanding of their functional implications. here, we highlight the importance of harnessing genetic diversity of hosts and pathogens for uncovering the biochemical basis of pathogen restriction, virulence, fitness, and pathogenesis. we ...201526275922
antiviral defense mechanisms in honey bees.honey bees are significant pollinators of agricultural crops and other important plant species. high annual losses of honey bee colonies in north america and in some parts of europe have profound ecological and economic implications. colony losses have been attributed to multiple factors including rna viruses, thus understanding bee antiviral defense mechanisms may result in the development of strategies that mitigate colony losses. honey bee antiviral defense mechanisms include rna-interference ...026273564
flavivirus rna synthesis in vitro.establishment of in vitro systems to study mechanisms of rna synthesis for positive strand rna viruses have been very useful in the past and have shed light on the composition of protein and rna components, optimum conditions, the nature of the products formed, cis-acting rna elements and trans-acting protein factors required for efficient synthesis. in this review, we summarize our current understanding regarding the requirements for flavivirus rna synthesis in vitro. we describe details of rea ...201526272247
microrna-attenuated clone of virulent semliki forest virus overcomes antiviral type i interferon in resistant mouse ct-2a glioma.glioblastoma is a terminal disease with no effective treatment currently available. among the new therapy candidates are oncolytic viruses capable of selectively replicating in cancer cells, causing tumor lysis and inducing adaptive immune responses against the tumor. however, tumor antiviral responses, primarily mediated by type i interferon (ifn-i), remain a key problem that severely restricts viral replication and oncolysis. we show here that the semliki forest virus (sfv) strain sfv4, which ...201526269187
sec14l2 enables pan-genotype hcv replication in cell culture.since its discovery in 1989, efforts to grow clinical isolates of the hepatitis c virus (hcv) in cell culture have met with limited success. only the jfh-1 isolate has the capacity to replicate efficiently in cultured hepatoma cells without cell culture-adaptive mutations. we hypothesized that cultured cells lack one or more factors required for the replication of clinical isolates. to identify the missing factors, we transduced huh-7.5 human hepatoma cells with a pooled lentivirus-based human c ...201526266980
hexokinase 2 controls cellular stress response through localization of an rna-binding protein.subcellular localization of rna-binding proteins is a key determinant of their ability to control rna metabolism and cellular stress response. using an rnai-based kinome-wide screen, we identified hexokinase 2 (hk2) as a regulator of the cytoplasmic accumulation of hnrnp a1 in response to hypertonic stress and human rhinovirus infection (hrv). we show that inhibition of hk2 expression or pharmacological inhibition of hk2 activity blocks the cytoplasmic accumulation of heterogeneous nuclear ribon ...201526247723
rate of novel host invasion affects adaptability of evolving rna virus lineages.although differing rates of environmental turnover should be consequential for the dynamics of adaptive change, this idea has been rarely examined outside of theory. in particular, the importance of rna viruses in disease emergence warrants experiments testing how differing rates of novel host invasion may impact the ability of viruses to adaptively shift onto a novel host. to test whether the rate of environmental turnover influences adaptation, we experimentally evolved 144 sindbis virus linea ...026246544
potential antileukemia effect and structural analyses of srpk inhibition by n-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (srpin340).dysregulation of pre-mrna splicing machinery activity has been related to the biogenesis of several diseases. the serine/arginine-rich protein kinase family (srpks) plays a critical role in regulating pre-mrna splicing events through the extensive phosphorylation of splicing factors from the family of serine/arginine-rich proteins (sr proteins). previous investigations have described the overexpression of srpk1 and srpk2 in leukemia and other cancer types, suggesting that they would be useful ta ...201526244849
analysis of site-specific n-glycan remodeling in the endoplasmic reticulum and the golgi.the hallmark of n-linked protein glycosylation is the generation of diverse glycan structures in the secretory pathway. dynamic, non-template-driven processes of n-glycan remodeling in the endoplasmic reticulum and the golgi provide the cellular setting for structural diversity. we applied newly developed mass spectrometry-based analytics to quantify site-specific n-glycan remodeling of the model protein pdi1p expressed in insect cells. molecular dynamics simulation, mutational analysis, kinetic ...201526240167
mammalian synthetic circuits with rna binding proteins for rna-only delivery.synthetic regulatory circuits encoded in rna rather than dna could provide a means to control cell behavior while avoiding potentially harmful genomic integration in therapeutic applications. we create post-transcriptional circuits using rna-binding proteins, which can be wired in a plug-and-play fashion to create networks of higher complexity. we show that the circuits function in mammalian cells when encoded in modified mrna or self-replicating rna.201526237515
effect of osmotic pressure on the stability of whole inactivated influenza vaccine for coating on microneedles.enveloped virus vaccines can be damaged by high osmotic strength solutions, such as those used to protect the vaccine antigen during drying, which contain high concentrations of sugars. we therefore studied shrinkage and activity loss of whole inactivated influenza virus in hyperosmotic solutions and used those findings to improve vaccine coating of microneedle patches for influenza vaccination. using stopped-flow light scattering analysis, we found that the virus underwent an initial shrinkage ...201526230936
unraveling host-vector-arbovirus interactions by two-gene high resolution melting mosquito bloodmeal analysis in a kenyan wildlife-livestock interface.the blood-feeding patterns of mosquitoes are directly linked to the spread of pathogens that they transmit. efficient identification of arthropod vector bloodmeal hosts can identify the diversity of vertebrate species potentially involved in disease transmission cycles. while molecular bloodmeal analyses rely on sequencing of cytochrome b (cyt b) or cytochrome oxidase 1 gene pcr products, recently developed bloodmeal host identification based on high resolution melting (hrm) analyses of cyt b pc ...201526230507
antiviral phosphorodiamidate morpholino oligomers are protective against chikungunya virus infection on cell-based and murine models.chikungunya virus (chikv) infection in human is associated with debilitating and persistent arthralgia and arthritis. currently, there is no specific vaccine or effective antiviral available. anti-chikv phosphorodiamidate morpholino oligomer (cpmo) was evaluated for its antiviral efficacy and cytotoxcity in human cells and neonate murine model. two cpmos were designed to block translation initiation of a highly conserved sequence in chikv non-structural and structural polyprotein, respectively. ...201526224141
alphavirus rna synthesis and non-structural protein functions.the members of the genus alphavirus are positive-sense rna viruses, which are predominantly transmitted to vertebrates by a mosquito vector. alphavirus disease in humans can be severely debilitating, and depending on the particular viral species, infection may result in encephalitis and possibly death. in recent years, alphaviruses have received significant attention from public health authorities as a consequence of the dramatic emergence of chikungunya virus in the indian ocean islands and the ...201526219641
neurons versus herpes simplex virus: the innate immune interactions that contribute to a host-pathogen standoff.herpes simplex virus (hsv) is a prevalent neurotropic virus, which establishes lifelong latent infections in the neurons of sensory ganglia. despite our long-standing knowledge that hsv predominately infects sensory neurons during its life cycle, little is known about the neuronal antiviral response to hsv infection. recent studies show that while sensory neurons have impaired intrinsic immunity to hsv infection, paracrine ifn signaling can potentiate a potent antiviral response. additionally, a ...026213562
quantitative proteomics identifies serum response factor binding protein 1 as a host factor for hepatitis c virus entry.hepatitis c virus (hcv) enters human hepatocytes through a multistep mechanism involving, among other host proteins, the virus receptor cd81. how cd81 governs hcv entry is poorly characterized, and cd81 protein interactions after virus binding remain elusive. we have developed a quantitative proteomics protocol to identify hcv-triggered cd81 interactions and found 26 dynamic binding partners. at least six of these proteins promote hcv infection, as indicated by rnai. we further characterized ser ...201526212323
production of a sindbis/eastern equine encephalitis chimeric virus inactivated cell culture antigen.eastern equine encephalitis virus (eeev) is a medically important pathogen that can cause severe encephalitis in humans, with mortality rates ranging from 30 to 80%. unfortunately there are no antivirals or licensed vaccines available for human use, and laboratory diagnosis is essential to differentiate eeev infection from other pathogens with similar clinical manifestations. the arboviral diseases branch (adb) reference laboratory at the cdc division of vector-borne diseases (dvbd) produces ref ...201526205552
going viral with fluorescent proteins.many longstanding questions about dynamics of virus-cell interactions can be answered by combining fluorescence imaging techniques with fluorescent protein (fp) tagging strategies. successfully creating a fp fusion with a cellular or viral protein of interest first requires selecting the appropriate fp. however, while viral architecture and cellular localization often dictate the suitability of a fp, a fp's chemical and physical properties must also be considered. here, we discuss the challenges ...201526202231
antiviral activities of whey proteins.milk contains an array of proteins with useful bioactivities. many milk proteins encompassing native or chemically modified casein, lactoferrin, alpha-lactalbumin, and beta-lactoglobulin demonstrated antiviral activities. casein and alpha-lactalbumin gained anti-hiv activity after modification with 3-hydroxyphthalic anhydride. many milk proteins inhibited hiv reverse transcriptase. bovine glycolactin, angiogenin-1, lactogenin, casein, alpha-lactalbumin, beta-lactoglobulin, bovine lactoferrampin, ...201526198883
early events in chikungunya virus infection-from virus cell binding to membrane fusion.chikungunya virus (chikv) is a rapidly emerging mosquito-borne alphavirus causing millions of infections in the tropical and subtropical regions of the world. chikv infection often leads to an acute self-limited febrile illness with debilitating myalgia and arthralgia. a potential long-term complication of chikv infection is severe joint pain, which can last for months to years. there are no vaccines or specific therapeutics available to prevent or treat infection. this review describes the crit ...201526198242
the interferon-inducible mouse apolipoprotein l9 and prohibitins cooperate to restrict theiler's virus replication.apolipoprotein l9b (apol9b) is an interferon-stimulated gene (isg) that has antiviral activity and is weakly expressed in primary mouse neurons as compared to other cell types. here, we show that both apol9 isoforms (apol9b and apol9a) inhibit replication of theiler's murine encephalomyelitis virus (tmev) but not replication of vesicular stomatitis virus (vsv), murid herpesvirus-4 (muhv-4), or infection by a lentiviral vector. apol9 genes are strongly expressed in mouse liver and, to a lesser ex ...201526196674
knockout silkworms reveal a dispensable role for juvenile hormones in holometabolous life cycle.insect juvenile hormones (jhs) prevent precocious metamorphosis and allow larvae to undergo multiple rounds of status quo molts. however, the roles of jhs during the embryonic and very early larval stages have not been fully understood. we generated and characterized knockout silkworms (bombyx mori) with null mutations in jh biosynthesis or jh receptor genes using genome-editing tools. we found that embryonic growth and morphogenesis are largely independent of jhs in bombyx and that, even in the ...201526195792
using the hepatitis c virus rna-dependent rna polymerase as a model to understand viral polymerase structure, function and dynamics.viral polymerases replicate and transcribe the genomes of several viruses of global health concern such as hepatitis c virus (hcv), human immunodeficiency virus (hiv) and ebola virus. for this reason they are key targets for therapies to treat viral infections. although there is little sequence similarity across the different types of viral polymerases, all of them present a right-hand shape and certain structural motifs that are highly conserved. these features allow their functional properties ...201526193306
neuroanatomy goes viral!the nervous system is complex not simply because of the enormous number of neurons it contains but by virtue of the specificity with which they are connected. unraveling this specificity is the task of neuroanatomy. in this endeavor, neuroanatomists have traditionally exploited an impressive array of tools ranging from the golgi method to electron microscopy. an ideal method for studying anatomy would label neurons that are interconnected, and, in addition, allow expression of foreign genes in t ...201526190977
targeting transmission pathways for emerging zoonotic disease surveillance and control.we used literature searches and a database of all reported emerging infectious diseases (eids) to analyze the most important transmission pathways (e.g., vector-borne, aerosol droplet transmitted) for emerging zoonoses. our results suggest that at the broad scale, the likelihood of transmission occurring through any one pathway is approximately equal. however, the major transmission pathways for zoonoses differ widely according to the specific underlying drivers of eid events (e.g., land-use cha ...026186515
tissue barriers to arbovirus infection in mosquitoes.arthropod-borne viruses (arboviruses) circulate in nature between arthropod vectors and vertebrate hosts. arboviruses often cause devastating diseases in vertebrate hosts, but they typically do not cause significant pathology in their arthropod vectors. following oral acquisition of a viremic bloodmeal from a vertebrate host, the arbovirus disease cycle requires replication in the cellular environment of the arthropod vector. once the vector has become systemically and persistently infected, the ...201526184281
full length and protease domain activity of chikungunya virus nsp2 differ from other alphavirus nsp2 proteases in recognition of small peptide substrates.alphavirus nsp2 proteins are multifunctional and essential for viral replication. the protease role of nsp2 is critical for virus replication as only the virus protease activity is used for processing of the viral non-structural polypeptide. chikungunya virus is an emerging disease problem that is becoming a world-wide health issue. we have generated purified recombinant chikungunya virus nsp2 proteins, both full length and a truncated protease domain from the c-terminus of the nsp2 protein. enz ...201526182358
la crosse virus field detection and vector competence of culex mosquitoes.la crosse virus (lacv), a leading cause of arboviral pediatric encephalitis in the united states, is emerging in appalachia. here, we report field and laboratory evidence that suggest lacv may be using culex mosquitoes as additional vectors in this region. this bunyavirus was detected by reverse-transcriptase polymerase chain reaction in two pools of culex mosquitoes in southwestern virginia and in six pools in west virginia. to assess vector competence, we offered lacv blood meals to field-coll ...201526175029
cd8 t-cell priming upon mrna vaccination is restricted to bone-marrow-derived antigen-presenting cells and may involve antigen transfer from myocytes.self-amplifying mrnas (sam(®) ) are a novel class of nucleic acid vaccines, delivered by a non-viral delivery system. they are effective at eliciting potent and protective immune responses and are being developed as a platform technology with potential to be used for a broad range of targets. however, their mechanism of action has not been fully elucidated. to date, no evidence of in vivo transduction of professional antigen-presenting cells (apcs) by sam vector has been reported, while the anti ...201526173587
ultraviolet light (uv) inactivation of porcine parvovirus in liquid plasma and effect of uv irradiated spray dried porcine plasma on performance of weaned pigs.a novel ultraviolet light irradiation (uv-c, 254 nm) process was designed as an additional safety feature for manufacturing of spray dried porcine plasma (sdpp). in exp. 1, three 10-l batches of bovine plasma were inoculated with 10(5.2 ± 0.12) tissue culture infectious dose 50 (tcid50) of porcine parvovirus (ppv) per ml of plasma and subjected to uv-c ranging from 0 to 9180 j/l. no viable ppv was detected in bovine plasma by micro-titer assay in sk6 cell culture after uv-c at 2295 j/l. in exp. ...201526171968
design, synthesis, antiviral and cytotoxic evaluation of novel acyclic phosphonate nucleotide analogues with a 5,6-dihydro-1h-[1,2,3]triazolo[4,5-d]pyridazine-4,7-dione system.a series of diethyl 2-(4,5-dimethoxycarbonyl-1h-1,2,3-triazol-1-yl)alkylphosphonates was synthesised from ω-azidoalkylphosphonates and dimethyl acetylenedicarboxylate and was further transformed into the respective diamides, dihydrazides, and 5,6-dihydro-1h-[1,2,3]triazolo[4,5-d]pyridazine-4,7-diones as phosphonate analogues of acyclic nucleosides having nucleobases replaced with substituted 1,2,3-triazoles. all compounds containing p-c-c-triazole or p-c-c-ch2-triazole moieties exist in single c ...201426166892
a genome-wide rnai screening method to discover novel genes involved in virus infection.systematic and comprehensive analysis of host cell proteins involved in virus infection has been difficult in large part due to the lack of robust unbiased methods for their identification. recent technological breakthroughs allowing development of cell-based genetic screens have greatly facilitated our understanding of virus-host interactions. these include instrumentation for processing in microtiter plates (e.g., 384 well), coupled with sensitive readers and off-the-shelf analysis and informa ...201526164699
proteomic analysis of purified turkey adenovirus 3 virions.turkey adenovirus 3 (tadv-3) causes high mortality and significant economic losses to the turkey industry. however, little is known about the molecular determinants required for viral replication and pathogenesis. moreover, tadv-3 does not grow well in cell culture, thus detailed structural studies of the infectious particle is particularly challenging. to develop a better understanding of virus-host interactions, we performed a comprehensive proteomic analysis of proteinase k treated purified t ...201526159706
macroautophagy proteins assist epstein barr virus production and get incorporated into the virus particles.epstein barr virus (ebv) persists as a latent herpes virus infection in the majority of the adult human population. the virus can reactivate from this latent infection into lytic replication for virus particle production. here, we report that autophagic membranes, which engulf cytoplasmic constituents during macroautophagy and transport them to lysosomal degradation, are stabilized by lytic ebv replication in infected epithelial and b cells. inhibition of autophagic membrane formation compromise ...201426137519
double-stranded rna is detected by immunofluorescence analysis in rna and dna virus infections, including those by negative-stranded rna viruses.early biochemical studies of viral replication suggested that most viruses produce double-stranded rna (dsrna), which is essential for the induction of the host immune response. however, it was reported in 2006 that dsrna could be detected by immunofluorescence antibody staining in double-stranded dna and positive-strand rna virus infections but not in negative-strand rna virus infections. other reports in the literature seemed to support these observations. this suggested that negative-strand r ...201526136565
interleukin-10 is a critical regulator of white matter lesion containment following viral induced demyelination.neurotropic coronavirus induces an acute encephalomyelitis accompanied by focal areas of demyelination distributed randomly along the spinal column. the initial areas of demyelination increase only slightly after the control of infection. these circumscribed focal lesions are characterized by axonal sparing, myelin ingestion by macrophage/microglia, and glial scars associated with hypertrophic astrocytes, which proliferate at the lesion border. accelerated virus control in mice lacking the anti- ...201526132901
viroporins, examples of the two-stage membrane protein folding model.viroporins are small, α-helical, hydrophobic virus encoded proteins, engineered to form homo-oligomeric hydrophilic pores in the host membrane. viroporins participate in multiple steps of the viral life cycle, from entry to budding. as any other membrane protein, viroporins have to find the way to bury their hydrophobic regions into the lipid bilayer. once within the membrane, the hydrophobic helices of viroporins interact with each other to form higher ordered structures required to correctly p ...201526131957
haploid genetic screen reveals a profound and direct dependence on cholesterol for hantavirus membrane fusion.hantaviruses cause hemorrhagic fever with renal syndrome (hfrs) in the old world and a highly fatal hantavirus cardiopulmonary syndrome (hcps) in the new world. no vaccines or antiviral therapies are currently available to prevent or treat hantavirus disease, and gaps in our understanding of how hantaviruses enter cells challenge the search for therapeutics. we performed a haploid genetic screen in human cells to identify host factors required for entry by andes virus, a highly virulent new worl ...201526126854
a novel system for visualizing alphavirus assembly.alphaviruses are small, enveloped rna viruses that form infectious particles by budding through the cellular plasma membrane. to help visualize and understand the intracellular assembly of alphavirus virions we have developed a bimolecular fluorescence complementation-based system (bifc) that allows visualization of capsid and e2 subcellular localization and association in live cells. in this system, n- or c-terminal venus fluorescent protein fragments (vn- and vc-) are fused to the n-terminus o ...201526122073
suramin inhibits chikungunya virus replication through multiple mechanisms.chikungunya virus (chikv) is a mosquito-borne alphavirus that causes severe and often persistent arthritis. in recent years, millions of people have been infected with this virus for which registered antivirals are still lacking. using our recently established in vitro assay, we discovered that the approved anti-parasitic drug suramin inhibits chikv rna synthesis (ic50 of ∼5μm). the compound inhibited replication of various chikv isolates in cell culture with an ec50 of ∼80μm (cc50>5mm) and was ...201526112648
viral membrane channels: role and function in the virus life cycle.viroporins are small, hydrophobic trans-membrane viral proteins that oligomerize to form hydrophilic pores in the host cell membranes. these proteins are crucial for the pathogenicity and replication of viruses as they aid in various stages of the viral life cycle, from genome uncoating to viral release. in addition, the ion channel activity of viroporin causes disruption in the cellular ion homeostasis, in particular the calcium ion. fluctuation in the calcium level triggers the activation of t ...201526110585
the effect of oral administration of dsrna on viral replication and mortality in bombus terrestris.israeli acute paralysis virus (iapv), a single-stranded rna virus, has a worldwide distribution and affects honeybees as well as other important pollinators. iapv infection in honeybees has been successfully repressed by exploiting the rna interference (rnai) pathway of the insect's innate immune response with virus-specific double stranded rna (dsrna). here we investigated the effect of iapv infection in the bumblebee bombus terrestris and its tissue tropism. b. terrestris is a common pollinato ...201526110584
isolation and full-length genome analysis of mosquito-borne manzanilla virus from yunnan province, china.there have been four strains on manzanilla virus (manv) identified to date. here, we identify a novel manv strain (dhl10m107) isolated from culex tritaeniorhynchus giles mosquitoes from ruili city, dehong prefecture, yunnan province, in the people's republic of china.201526100251
impact of vesicular stomatitis virus m proteins on different cellular functions.three different matrix (m) proteins termed m1, m2 and m3 have been described in cells infected with vesicular stomatitis virus (vsv). individual expression of vsv m proteins induces an evident cytopathic effect including cell rounding and detachment, in addition to a partial inhibition of cellular protein synthesis, likely mediated by an indirect mechanism. analogous to viroporins, m1 promotes the budding of new virus particles; however, this process does not produce an increase in plasma membra ...201526091335
important role of the il-32 inflammatory network in the host response against viral infection.the pro-inflammatory cytokine interleukin (il)-32 has gained much attention recently because of its important role in the inflammatory network. since the discovery of il-32 in 2005, our appreciation for its diverse roles continues to grow. recent studies have discovered the antiviral effects induced by il-32 and its associated regulatory mechanisms. the interactions between il-32 and various cytokines including cyclooxygenase 2 (cox-2), inducible nitric oxide synthase (inos), interferon (ifn)-λ1 ...201526087456
calcium flux-independent nmda receptor activity is required for aβ oligomer-induced synaptic loss.synaptic loss is one of the major features of alzheimer's disease (ad) and correlates with the degree of dementia. n-methyl-d-aspartate receptors (nmdars) have been shown to mediate downstream effects of the β-amyloid peptide (aβ) in ad models. nmdars can trigger intracellular cascades via ca(2+) entry, however, also ca(2+)-independent (metabotropic) functions of nmdars have been described. we aimed to determine whether ionotropic or metabotropic nmdar signaling is required for the induction of ...201526086964
lentiviral protein transfer vectors are an efficient vaccine platform and induce a strong antigen-specific cytotoxic t cell response.to induce and trigger innate and adaptive immune responses, antigen-presenting cells (apcs) take up and process antigens. retroviral particles are capable of transferring not only genetic information but also foreign cargo proteins when they are genetically fused to viral structural proteins. here, we demonstrate the capacity of lentiviral protein transfer vectors (ptvs) for targeted antigen transfer directly into apcs and thereby induction of cytotoxic t cell responses. targeting of lentiviral ...201526085166
circumsporozoite protein as a potential target for antimalarials.since the discovery of circumsporozoite protein (csp), a major sporozoite surface antigen, by ruth nussenzweig and victor nussenzweig in the early 1980s, the role of csp in protection against malaria has been extensively investigated. several monoclonal antibodies against csp have been generated to date, with some of them mediating antimalarial protection upon passive transfer into animals. genetically engineered transgenic mosquitoes producing the anti-csp antibody have recently been generated ...201526081442
antiviral activity of silymarin against chikungunya virus.the mosquito-borne chikungunya virus (chikv) causes chikungunya fever, with clinical presentations such as severe back and small joint pain, and debilitating arthritis associated with crippling pains that persist for weeks and even years. although there are several studies to evaluate the efficacy of drugs against chikv, the treatment for chikungunya fever is mainly symptom-based and no effective licensed vaccine or antiviral are available. here, we investigated the antiviral activity of three t ...201526078201
amino-terminal arginylation targets endoplasmic reticulum chaperone bip for autophagy through p62 binding.we show that ate1-encoded arg-transfer rna transferase (r-transferase) of the n-end rule pathway mediates n-terminal arginylation of multiple endoplasmic reticulum (er)-residing chaperones, leading to their cytosolic relocalization and turnover. n-terminal arginylation of bip (also known as grp78), protein disulphide isomerase and calreticulin is co-induced with autophagy during innate immune responses to cytosolic foreign dna or proteasomal inhibition, associated with increased ubiquitylation. ...201526075355
electron tomography analysis of tick-borne encephalitis virus infection in human neurons.tick-borne encephalitis virus (tbev) causes serious, potentially fatal neurological infections that affect humans in endemic regions of europe and asia. neurons are the primary target for tbev infection in the central nervous system. however, knowledge about this viral infection and virus-induced neuronal injury is fragmental. here, we directly examined the pathology that occurs after tbev infection in human primary neurons. we exploited the advantages of advanced high-pressure freezing and free ...201526073783
spinoculation enhances hbv infection in ntcp-reconstituted hepatocytes.hepatitis b virus (hbv) infection and its sequelae remain a major public health burden, but both hbv basic research and the development of antiviral therapeutics have been hindered by the lack of an efficient in vitro infection system. recently, sodium taurocholate cotransporting polypeptide (ntcp) has been identified as the hbv receptor. we herein report that we established a ntcp-complemented hepg2 cell line (hepg2-ntcp12) that supports hbv infection, albeit at a low infectivity level followin ...201526070202
distinct sets of piwi proteins produce arbovirus and transposon-derived pirnas in aedes aegypti mosquito cells.the piwi-interacting rna (pirna) pathway is essential for transposon silencing in many model organisms. its remarkable efficiency relies on a sophisticated amplification mechanism known as the ping-pong loop. in alphavirus-infected aedes mosquitoes, pirnas with sequence features that suggest ping-pong-dependent biogenesis are produced from viral rna. the piwi family in aedes mosquitoes is expanded when compared to other model organisms, raising the possibility that individual piwi proteins have ...201526068474
the chikungunya virus capsid protein contains linear b cell epitopes in the n- and c-terminal regions that are dependent on an intact c-terminus for antibody recognition.chikungunya virus (chikv) is an arthropod-borne agent that causes severe arthritic disease in humans and is considered a serious health threat in areas where competent mosquito vectors are prevalent. chikv has recently been responsible for several millions of cases of disease, involving over 40 countries. the recent re-emergence of chikv and its potential threat to human health has stimulated interest in better understanding of the biology and pathogenesis of the virus, and requirement for impro ...201526061335
differential action of pateamine a on translation of genomic and subgenomic mrnas from sindbis virus.pateamine a (pat a) is a natural marine product that interacts specifically with the translation initiation factor eif4a leading to the disruption of the eif4f complex. in the present study, we have examined the activity of pat a on the translation of sindbis virus (sinv) mrnas. translation of genomic mrna is strongly suppressed by pat a, as shown by the reduction of nsp1 or nsp2 synthesis. notably, protein synthesis directed by subgenomic mrna is resistant to pat a inhibition when the compound ...201526057151
rnasek is required for internalization of diverse acid-dependent viruses.viruses must gain entry into cells to establish infection. in general, viruses enter either at the plasma membrane or from intracellular endosomal compartments. viruses that use endosomal pathways are dependent on the cellular factors that control this process; however, these genes have proven to be essential for endogenous cargo uptake, and thus are of limited value for therapeutic intervention. the identification of genes that are selectively required for viral uptake would make appealing drug ...201526056282
fragile x proteins fmrp and fxr2p control synaptic glua1 expression and neuronal maturation via distinct mechanisms.fragile x mental retardation protein (fmrp) and its autosomal paralog fxr2p are selective neuronal rna-binding proteins, and mice that lack either protein exhibit cognitive deficits. although double-mutant mice display more severe learning deficits than single mutants, the molecular mechanism behind this remains unknown. in the present study, we discovered that fxr2p (also known as fxr2) is important for neuronal dendritic development. fmrp and fxr2p additively promote the maturation of new neur ...201526051932
an alphavirus temperature-sensitive capsid mutant reveals stages of nucleocapsid assembly.alphaviruses have a nucleocapsid core composed of the rna genome surrounded by an icosahedral lattice of capsid protein. an insertion after position 186 in the capsid protein produced a strongly temperature-sensitive growth phenotype. even when the structural proteins were synthesized at the permissive temperature (28°c), subsequent incubation of the cells at the non-permissive temperature (37°c) dramatically decreased mutant capsid protein stability and particle assembly. electron microscopy co ...201526051211
trapping biases of culex torrentium and culex pipiens revealed by comparison of captures in cdc traps, ovitraps, and gravid traps.we evaluate three trapping methods for their effectiveness at capturing culex pipiens and culex torrentium, both enzootic vectors of bird-associated viruses in europe. the comparisons, performed in two regions in sweden, were among cdc traps baited with carbon dioxide, gravid traps, and ovitraps baited with hay infusion. the proportions of the two culex species in a catch differed between trap types, with cdc traps catching a lower proportion of cx. torrentium than both gravid traps and ovitraps ...201526047196
distinct immune responses in resistant and susceptible strains of mice during neurovirulent alphavirus encephalomyelitis.susceptibility to alphavirus encephalomyelitis is dependent on a variety of factors, including the genetic background of the host. neuroadapted sindbis virus (nsv) causes uniformly fatal disease in adult c57bl/6 (b6) mice, but adult balb/c (bc) mice recover from infection. in b6 mice, fatal encephalomyelitis is immune mediated rather than a direct result of virus infection. to identify the immunological determinants of host susceptibility to fatal nsv-induced encephalomyelitis, we compared virus ...201526041298
mrna capping by venezuelan equine encephalitis virus nsp1: functional characterization and implications for antiviral research.alphaviruses are known to possess a unique viral mrna capping mechanism involving the viral nonstructural protein nsp1. this enzyme harbors methyltransferase (mtase) and nsp1 guanylylation (gt) activities catalyzing the transfer of the methyl group from s-adenosylmethionine (adomet) to the n7 position of a gtp molecule followed by the formation of an m(7)gmp-nsp1 adduct. subsequent transfer of m(7)gmp onto the 5' end of the viral mrna has not been demonstrated in vitro yet. here we report the bi ...201526041283
new insights into the understanding of hepatitis c virus entry and cell-to-cell transmission by using the ionophore monensin a.in our study, we characterized the effect of monensin, an ionophore that is known to raise the intracellular ph, on the hepatitis c virus (hcv) life cycle. we showed that monensin inhibits hcv entry in a pangenotypic and dose-dependent manner. monensin induces an alkalization of intracellular organelles, leading to an inhibition of the fusion step between viral and cellular membranes. interestingly, we demonstrated that hcv cell-to-cell transmission is dependent on the vesicular ph. using the se ...201526041282
sequence-independent characterization of viruses based on the pattern of viral small rnas produced by the host.virus surveillance in vector insects is potentially of great benefit to public health. large-scale sequencing of small and long rnas has previously been used to detect viruses, but without any formal comparison of different strategies. furthermore, the identification of viral sequences largely depends on similarity searches against reference databases. here, we developed a sequence-independent strategy based on virus-derived small rnas produced by the host response, such as the rna interference ...201526040701
the impact of the interferon-lambda family on the innate and adaptive immune response to viral infections.type-iii interferons (ifn-λ, ifnl) are the most recently described family of ifns. this family of innate cytokines are increasingly being ascribed pivotal roles in host-pathogen interactions. herein, we will review the accumulating evidence detailing the immune biology of ifnl during viral infection, and the implications of this novel information on means to advance the development of therapies and vaccines against existing and emerging pathogens. ifnls exert antiviral effects via induction of i ...201426038748
virus-induced translational arrest through 4ebp1/2-dependent decay of 5'-top mrnas restricts viral infection.the mosquito-transmitted bunyavirus, rift valley fever virus (rvfv), is a highly successful pathogen for which there are no vaccines or therapeutics. translational arrest is a common antiviral strategy used by hosts. in response, rvfv inhibits two well-known antiviral pathways that attenuate translation during infection, pkr and type i ifn signaling. despite this, translational arrest occurs during rvfv infection by unknown mechanisms. here, we find that rvfv infection triggers the decay of core ...201526038567
imino sugar glucosidase inhibitors as broadly active anti-filovirus agents.ebola virus and marburg virus are members of the family of filoviridae and are etiological agents of a deadly hemorrhagic fever disease. the clinical symptoms of ebola and marburg hemorrhagic fevers are difficult to distinguish and there are currently no specific antiviral therapies against either of the viruses. therefore, a drug that is safe and effective against both would be an enormous breakthrough. we and others have shown that the folding of the glycoproteins of many enveloped viruses, in ...201326038444
rna interference-mediated antiviral defense in insects.small interfering rna (sirna)-mediated rna interference (rnai) pathways are critical for the detection and inhibition of rna virus replication in insects. recent work has also implicated rnai pathways in the establishment of persistent virus infections and in the control of dna virus replication. accumulating evidence suggests that diverse double-stranded rnas produced by rna and dna viruses can trigger rnai responses yet many viruses have evolved mechanisms to inhibit rnai defenses. therefore, ...026034705
development of a replication-competent lentivirus assay for dendritic cell-targeting lentiviral vectors.it is a current regulatory requirement to demonstrate absence of detectable replication-competent lentivirus (rcl) in lentiviral vector products prior to use in clinical trials. immune design previously described an hiv-1-based integration-deficient lentiviral vector for use in cancer immunotherapy (vp02). vp02 is enveloped with e1001, a modified sindbis virus glycoprotein which targets dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (dc-sign) expressed on dendrit ...201526029728
elevation of intraocular pressure in rodents using viral vectors targeting the trabecular meshwork.rodents are increasingly being used as glaucoma models to study ocular hypertension, optic neuropathy, and retinopathy. a number of different techniques are used to elevate intraocular pressure in rodent eyes by artificially obstructing the aqueous outflow pathway. another successful technique to induce ocular hypertension is to transduce the trabecular meshwork of rodent eyes with viral vectors expressing glaucoma associated transgenes to provide more relevant models of glaucomatous damage to t ...201526025608
cross-species comparative analysis of dicer proteins during sindbis virus infection.in plants and invertebrates rna silencing is a major defense mechanism against virus infections. the first event in rna silencing is dicing of long double stranded rnas into small interfering rnas (sirnas). the dicer proteins involved in this process are phylogenetically conserved and have the same domain organization. accordingly, the production of viral derived sirnas has also been observed in the mouse, but only in restricted cell types. to gain insight on this restriction, we compare the dic ...201526024431
astaxanthin pretreatment attenuates hepatic ischemia reperfusion-induced apoptosis and autophagy via the ros/mapk pathway in mice.hepatic ischemia reperfusion (ir) is an important issue in complex liver resection and liver transplantation. the aim of the present study was to determine the protective effect of astaxanthin (asx), an antioxidant, on hepatic ir injury via the reactive oxygen species/mitogen-activated protein kinase (ros/mapk) pathway.201526023842
herpes simplex virus 1 suppresses the function of lung dendritic cells via caveolin-1.caveolin-1 (cav-1), the principal structural protein of caveolae, has been implicated as a regulator of virus-host interactions. several viruses exploit caveolae to facilitate viral infections. however, the roles of cav-1 in herpes simplex virus 1 (hsv-1) infection have not fully been elucidated. here, we report that cav-1 downregulates the expression of inducible nitric oxide synthase (inos) and the production of nitric oxide (no) in dendritic cells (dcs) during hsv-1 infection. as a result, ca ...201526018534
the baculovirus antiapoptotic p35 protein functions as an inhibitor of the host rna interference antiviral response.rna interference (rnai) is considered an ancient antiviral defense in diverse organisms, including insects. virus infections generate double-strand rnas (dsrnas) that trigger the rnai machinery to process dsrnas into virus-derived short interfering rnas (vsirnas), which target virus genomes, mrnas, or replication intermediates. viruses, in turn, have evolved viral suppressors of rnai (vsrs) to counter host antiviral rnai. following recent discoveries that insects mount an rnai response against d ...201526018163
conformational changes required for reovirus cell entry are sensitive to ph.during cell entry, reovirus particles disassemble to generate isvps. isvps undergo conformational changes to form isvp(*) and this conversion is required for membrane penetration. in tissues where isvp formation occurs within endosomes, isvp-to-isvp(*) conversion occurs at low ph. in contrast, in tissues where isvp formation occurs extracellularly, isvp-to-isvp(*) transition occurs at neutral ph. whether these two distinct ph environments influence the efficiency of cell entry is not known. in t ...201526004253
the broad-spectrum antiviral protein zap restricts human retrotransposition.intrinsic immunity describes the set of recently discovered but poorly understood cellular mechanisms that specifically target viral pathogens. their discovery derives in large part from intensive studies of hiv and siv that revealed restriction factors acting at various stages of the retroviral life cycle. recent studies indicate that some factors restrict both retroviruses and retrotransposons but surprisingly in ways that may differ. we screened known interferon-stimulated antiviral proteins ...201526001115
oncolytic virotherapy for ovarian cancer.in the past two decades, more than 20 viruses with selective tropism for tumor cells have been developed as oncolytic viruses (ovs) for treatments of a variety of malignancies. of these viruses, eleven have been tested in human ovarian cancer models in preclinical studies. so far, nine phase i or ii clinical trials have been conducted or initiated using four different types of ovs in patients with recurrent ovarian cancers. in this article, we summarize the different ovs that are being assessed ...025977900
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