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Cholesterol-rich Microdomains as Docking Platforms for Respiratory Syncytial Virus in Normal Human Bronchial Epithelial Cells.Respiratory syncytial virus (RSV) is one of the major causes of respiratory infections in children and it is the main pathogen causing bronchiolitis in infants. The binding and entry mechanism by which RSV infects respiratory epithelial cells has not yet been determined. In this study, the earliest stages of RSV infection in normal human bronchial epithelial cells were probed by tracking virions with fluorescent lipophilic dyes in their membranes. Virions colocalized with cholesterol-containing ...201122090136
INTERACTIONS OF THE CYTOPLASMIC DOMAIN OF SINDBIS VIRUS E2 WITH NUCLEOCAPSID CORES PROMOTE ALPHAVIRUS BUDDING.Alphavirus budding from the plasma membrane occurs through the specific interaction of the nucleocapsid core with the cytoplasmic domain of the E2 glycoprotein (cdE2). Structural studies of the Sindbis virus capsid protein (CP) have suggested that these critical interactions are mediated by the binding of cdE2 into a hydrophobic pocket in the CP. Several molecular genetic studies have implicated amino acids Y400 and L402 in cdE2 as important for the budding of alphaviruses. In this study, we cha ...201122190727
image-based genome-wide sirna screen identifies selective autophagy factors.selective autophagy involves the recognition and targeting of specific cargo, such as damaged organelles, misfolded proteins, or invading pathogens for lysosomal destruction. yeast genetic screens have identified proteins required for different forms of selective autophagy, including cytoplasm-to-vacuole targeting, pexophagy and mitophagy, and mammalian genetic screens have identified proteins required for autophagy regulation. however, there have been no systematic approaches to identify molecu ...201122020285
PD 404,182 is a virucidal small molecule that disrupts hepatitis C virus and human immunodeficiency virus.We describe a virucidal small molecule, PD 404,182, effective against hepatitis C virus (HCV) and human immunodeficiency virus (HIV). The median IC(50) values for the antiviral effect of PD 404,182 against HCV and HIV in cell culture are 11 µM and 1 µM, respectively. The antiviral activity of PD 404,182 is due to physical disruption of virions that is accompanied to varying degrees (depending on the virus and exposure temperature/time) by release of viral nucleic acids into the surrounding mediu ...201122083468
oncolytic sindbis virus targets tumors defective in the interferon response and induces significant bystander antitumor immunity in vivo.sindbis virus (sbv) has been shown to possess oncolytic potential in many human xenograft tumor models in immunocompromised mice. however, the mechanism underlying the tumor selectivity of sbv remains undetermined. in this study, we provide evidence that the tumor tropism of sbv infection is not determined by the levels of sbv receptor but by the status of the type i interferon (ifn) response in the tumors. our results demonstrate that cells with defects in the ifn response (in either ifn-β prod ...201122068428
a brain slice culture model of viral encephalitis reveals an innate cns cytokine response profile and the therapeutic potential of caspase inhibition.viral encephalitis is a significant cause of human morbidity and mortality in large part due to suboptimal diagnosis and treatment. murine reovirus infection serves as a classic experimental model of viral encephalitis. infection of neonatal mice with t3 reoviruses results in lethal encephalitis associated with neuronal infection, apoptosis, and cns tissue injury. we have developed an ex vivo brain slice culture (bsc) system that recapitulates the basic pathological features and kinetics of vira ...201121241693
Alphaviruses: Semliki forest virus and Sindbis virus vectors for gene transfer into neurons.Alphaviral vectors based on Semliki Forest virus and Sindbis virus infect many host cell types, causing rapid and high-level transgene expression. In the CNS, Semliki Forest virus and Sindbis virus exhibit an outstanding preference for neurons rather than glial cells, compared to other viruses. Generation of high-titer virus stocks is rapid (less than two days) and typically requires biosafety level 1 or 2 containment. Wild-type vectors are cytotoxic, permitting short-term transgene expression. ...201121971849
Baculovirus GP64-mediated entry into mammalian cells.The baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) serves as an efficient viral vector not only for abundant gene expression in insect cells but also for gene delivery into mammalian cells. Lentivirus vectors pseudotyped with the baculovirus envelope glycoprotein GP64 have been shown to acquire more potent gene transduction than those with vesicular stomatitis virus (VSV) envelope glycoprotein G. However, there are conflicting hypotheses about the molecular mechanisms ...201122190715
Munc13-1 is required for presynaptic long-term potentiation.Long-lasting forms of synaptic plasticity involve modification of presynaptic strength in many brain regions. Although a presynaptic site for expression is well established, the detailed molecular mechanisms that lead to sustained changes in neurotransmitter release remain unclear. Here, we use acute in vivo genetic manipulation of synaptic proteins to investigate the molecular basis for presynaptic long-term potentiation (LTP) at hippocampal mossy fiber synapses. Munc13 proteins are active zone ...201121849565
Evaluation of a Sindbis virus vector displaying an immunoglobulin-binding domain: antibody-dependent infection of neurons in living mice.Viral vectors that genetically incorporate an immunoglobulin-binding domain on their surfaces provide many advantages because of the availability of a spectrum of antibodies that allow the selection of a wide range of target cells. However, the specificity and the effectiveness of this system have not been evaluated in the field of neuroscience. We investigated the effectiveness and specificity of a recombinant Sindbis virus displaying an antibody-binding domain of bacterial protein A (ZZ Sindbi ...201121925217
the mechanism of translation initiation on aichivirus rna mediated by a novel type of picornavirus ires.picornavirus mrnas contain iress that sustain their translation during infection, when host protein synthesis is shut off. the major classes of picornavirus iress (types 1 and 2) have distinct structures and sequences, but initiation on both is determined by their specific interaction with eif4g. we report here that aichivirus (av), a member of the kobuvirus genus of picornaviridae, contains an ires that differs structurally from type 1 and type 2 iress. its function similarly involves interacti ...201121873976
Genome scale phylogeny of the Alphavirus genus suggests a marine origin.The genus Alphavirus comprises a diverse group of viruses, including some that cause severe disease. Using full-length sequences of all known alphaviruses, we produced a robust and comprehensive phylogeny of the Alphavirus genus, presenting a more complete evolutionary history of these viruses compared to previous studies based on partial sequences. Our phylogeny suggests the origin of the alphaviruses occurred in the southern oceans and spread equally through the Old and New World. Since lice a ...201122190718
West Nile virus encodes a microRNA-like small RNA in the 3' untranslated region which up-regulates GATA4 mRNA and facilitates virus replication in mosquito cells.West Nile virus (WNV) belongs to a group of medically important single-stranded, positive-sense RNA viruses causing deadly disease outbreaks around the world. The 3' untranslated region (3'-UTR) of the flavivirus genome, in particular the terminal 3' stem-loop (3'SL) fulfils multiple functions in virus replication and virus-host interactions. Using the Kunjin strain of WNV (WNV(KUN)), we detected a virally encoded small RNA, named KUN-miR-1, derived from 3'SL. Transcription of WNV(KUN) pre-miRNA ...201122080551
targeting lentiviral vectors for cancer immunotherapy.delivery of tumour-associated antigens (taa) in a way that induces effective, specific immunity is a challenge in anti-cancer vaccine design. circumventing tumour-induced tolerogenic mechanisms in vivo is also critical for effective immunotherapy. effective immune responses are induced by professional antigen presenting cells, in particular dendritic cells (dc). this requires presentation of the antigen to both cd4(+) and cd8(+) t cells in the context of strong co-stimulatory signals. lentiviral ...201122983382
imaging early steps of sindbis virus infection by total internal reflection fluorescence microscopy.sindbis virus (sinv) is an alphavirus that has a broad host range and has been widely used as a vector for recombinant gene transduction, dna-based vaccine production, and oncolytic cancer therapy. the mechanism of sinv entry into host cells has yet to be fully understood. in this paper, we used single virus tracking under total internal reflection fluorescence microscopy (tirfm) to investigate sinv attachment to cell surface. biotinylated viral particles were labeled with quantum dots, which re ...201122312345
replication of alphaviruses: a review on the entry process of alphaviruses into cells.alphaviruses are small, enveloped viruses, ~70 nm in diameter, containing a single-stranded, positive-sense, rna genome. viruses belonging to this genus are predominantly arthropod-borne viruses, known to cause disease in humans. their potential threat to human health was most recently exemplified by the 2005 chikungunya virus outbreak in la reunion, highlighting the necessity to understand events in the life-cycle of these medically important human pathogens. the replication and propagation of ...201122312336
synthesis of 4'-ethynyl-2'-deoxy-4'-thioribonucleosides and discovery of a highly potent and less toxic nrti.the synthesis of 4'-ethynyl-2'-deoxy-4'-thioribonucleosides was carried out utilizing an electrophilic glycosidation in which 4-ethynyl-4-thiofuranoid glycal 16 served as a glycosyl donor. electrophilic glycosidation between 16 and the silylated nucleobases (n (4)-acetylcytosine, n (6)-benzoyladenine and n (2)-acetyl-o (6)-diphenylcarbamoylguanine) was carried out in the presence of n-iodosuccinimide (nis) leading to the exclusive formation of the desired β-anomers 29, 33 and 36. anti-hiv studie ...201123795238
self replicating gene vaccine carrying p1-2a gene of fmdv serotype o and its effects on the immune responses of cattle.dna vaccines are considered as alternatives to live attenuated ones for those diseases like foot-and-mouth disease (fmd) where the production and application of live vaccines have been found unsuccessful. however, stability of dna and the quantity of antigen expressed are the major limitation with naked dna vaccines. to address these issues self replicating gene vaccine construct was made for foot-and-mouth disease virus (fmdv) type 'o' and studied. the vector for vaccine construct, designated a ...201123637502
mosquito vectors survey in the al-ahsaa district of eastern saudi arabia.the present study aimed to identify the mosquito vectors distributed throughout al-ahsaa district situated in the eastern region of saudi arabia. mosquito larvae were collected seasonally for one year (october 2009 to september 2010) from different breeding sites in seven rural areas utilizing long aquatic nets. salinity and ph of these breeding sites were also measured seasonally. the survey revealed the presence of five mosquito species, aedes caspius pallas (diptera: culicidae), anopheles mul ...201122958070
altered response to deet repellent after infection of aedes aegypti (diptera: culicidae) with sindbis virus.to determine whether a sindbis virus (family togaviridae, genus alphavirus, sinv) infection in aedes aegypti (l.) (diptera: culicidae) affected its response to the repellent deet, we orally exposed ae. aegypti to an artificial bloodmeal containing sinv or diluent and then allowed to feed on a 10% sucrose suspension containing 3% deet. when tested seven or more days after the initial bloodmeal, although none of the diluent-exposed mosquitoes fed on the deet-sucrose suspension, at least 60% of the ...201122238883
inhibition of sars pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans.it has been reported that lactoferrin (lf) participates in the host immune response against severe acute respiratory syndrome coronavirus (sars-cov) invasion by enhancing nk cell activity and stimulating neutrophil aggregation and adhesion. we further investigated the role of lf in the entry of sars pseudovirus into hek293e/ace2-myc cells. our results reveal that lf inhibits sars pseudovirus infection in a dose-dependent manner. further analysis suggested that lf was able to block the binding of ...201121887302
carbocyclic 5'-nor "reverse" fleximers. design, synthesis, and preliminary biological activity.a series of 5'-nor carbocyclic "reverse" flexible nucleosides or "fleximers" have been designed wherein the nucleobase scaffold resembles a "split" purine as well as a substituted pyrimidine. this modification was employed to explore recognition by both purine and pyrimidine metabolizing enzymes. the synthesis of the carbocyclic fleximers and the results of their preliminary biological screening are described herein.201124312722
detection of nucleic acid lesions during photochemical inactivation of rna viruses by treatment with methylene blue and light using real-time pcr.the mechanism of bacteriophage photoinactivation by methylene blue and light (mb+l) involves genomic rna damage. in this study, two rna viruses, sindbis virus (sinv) and hepatitis c virus were treated by mb+l and their nucleic acids were amplified to show that rna lesions occurred during inactivation. during mb+l inactivation, the viral load of both viruses was significantly reduced as mb+l exposure increased. the nucleic acid amplification of treated viral rna was inhibited in a time-dependent ...201121138441
selective autophagy and viruses.in recent years, the process of selective autophagy has received much attention with respect to the clearance of protein aggregates, damaged mitochondria and bacteria. however, until recently, there have been virtually no studies on the selective autophagy of viruses, although they are perhaps one of the most ubiquitous unwanted constituents in human cells. recently, we have shown that the ability of neuronal atg5 to protect against lethal sindbis virus central nervous system (cns) infection in ...201121150267
immunization delivered by lentiviral vectors for cancer and infectious diseases.the increasing level of understanding of the lentivirus biology has been instrumental in shaping the design strategy of creating therapeutic lentiviral delivery vectors. as a result, lentiviral vectors have become one of the most powerful gene transfer vehicles. they are widely used for therapeutic purposes as well as in studies of basic biology, due to their unique characteristics. lentiviral vectors have been successfully employed to mediate durable and efficient antigen expression and present ...201121198664
biological challenges and technological opportunities for respiratory syncytial virus vaccine development.respiratory syncytial virus (rsv) is an important cause of respiratory disease causing high rates of hospitalizations in infants, significant morbidity in children and adults, and excess mortality in the elderly. major barriers to vaccine development include early age of rsv infection, capacity of rsv to evade innate immunity, failure of rsv-induced adaptive immunity to prevent reinfection, history of rsv vaccine-enhanced disease, and lack of an animal model fully permissive to human rsv infecti ...201121198670
selective autophagy mediated by autophagic adapter proteins.mounting evidence suggests that autophagy is a more selective process than originally anticipated. the discovery and characterization of autophagic adapters, like p62 and nbr1, has provided mechanistic insight into this process. p62 and nbr1 are both selectively degraded by autophagy and able to act as cargo receptors for degradation of ubiquitinated substrates. a direct interaction between these autophagic adapters and the autophagosomal marker protein lc3, mediated by a so-called lir (lc3-inte ...201121189453
identification and sequencing of a novel rodent gammaherpesvirus that establishes acute and latent infection in laboratory mice.gammaherpesviruses encode numerous immunomodulatory molecules that contribute to their ability to evade the host immune response and establish persistent, lifelong infections. as the human gammaherpesviruses are strictly species specific, small animal models of gammaherpesvirus infection, such as murine gammaherpesvirus 68 (γhv68) infection, are important for studying the roles of gammaherpesvirus immune evasion genes in in vivo infection and pathogenesis. we report here the genome sequence and ...201121209105
a new rapid protocol for eyeblink conditioning to assess cerebellar motor learning.mice with spontaneous and induced mutations causing cerebellar phenotypes have provided key insights into how motor-related memories are stored in cerebellar circuits. delayed eyeblink conditioning is a form of associative motor learning that depends on the cerebellum. however, neurochemical investigation of the underlying mechanisms has been hampered by the long training period (usually several days) required to establish conditioning. here, we report a new rapid-training protocol that reliably ...201121221776
darpins: an efficient targeting domain for lentiviral vectors.we have recently developed a retargeting system for lentiviral vectors (lvs) that relies on the pseudotyping of lvs with engineered measles virus (mv) glycoproteins (hemagglutinin (h) and fusion protein (f)). specificity is provided through display of a single-chain antibody (scfv) as targeting domain by fusion to the mv-h protein. as an alternative to scfv, designed ankyrin repeat proteins (darpins) can be selected to become high-affinity binders to any kind of target molecule. in this study si ...201121224833
recombinant sendai viruses expressing fusion proteins with two furin cleavage sites mimic the syncytial and receptor-independent infection properties of respiratory syncytial virus.cell entry by paramyxoviruses requires fusion between viral and cellular membranes. paramyxovirus infection also gives rise to the formation of multinuclear, fused cells (syncytia). both types of fusion are mediated by the viral fusion (f) protein, which requires proteolytic processing at a basic cleavage site in order to be active for fusion. in common with most paramyxoviruses, fusion mediated by sendai virus f protein (f(sev)) requires coexpression of the homologous attachment (hemagglutinin- ...201121228237
establishment of infectious hcv virion-producing cells with newly designed full-genome replicon rna.hepatitis c virus (hcv) replicon systems enable in-depth analysis of the life cycle of hcv. however, the previously reported full-genome replicon system is unable to produce authentic virions. on the basis of these results, we constructed newly designed full-genomic replicon rna, which is composed of the intact 5'-terminal-half rna extending to the ns2 region flanked by an extra selection marker gene. huh-7 cells harboring this full-genomic rna proliferated well under g418 selection and secreted ...201121246385
requirement for the amino-terminal domain of sindbis virus nsp4 during virus infection.the sindbis virus rna-dependent rna polymerase nsp4 possesses an amino-terminal region that is unique to alphaviruses and is predicted to be disordered. to determine the importance of this region during alphavirus replication, 29 mutations were introduced, and resultant viruses were assessed for growth defects. three small plaque mutants, d41a, g83l, and the triple mutant gpg((8-10))vav, had defects in subgenome synthesis, minus-strand synthesis, and overall levels of viral rna synthesis, respec ...201121248049
interactions between laminin receptor and the cytoskeleton during translation and cell motility.human laminin receptor acts as both a component of the 40s ribosomal subunit to mediate cellular translation and as a cell surface receptor that interacts with components of the extracellular matrix. due to its role as the cell surface receptor for several viruses and its overexpression in several types of cancer, laminin receptor is a pathologically significant protein. previous studies have determined that ribosomes are associated with components of the cytoskeleton, however the specific ribos ...201121249134
identification and characterization of the host protein dnajc14 as a broadly active flavivirus replication modulator.viruses in the flavivirus genus of the flaviviridae family are arthropod-transmitted and contribute to staggering numbers of human infections and significant deaths annually across the globe. to identify cellular factors with antiviral activity against flaviviruses, we screened a cdna library using an iterative approach. we identified a mammalian hsp40 chaperone protein (dnajc14) that when overexpressed was able to mediate protection from yellow fever virus (yfv)-induced cell death. further stud ...201121249176
persistence of virus-specific immune responses in the central nervous system of mice after west nile virus infection.west nile virus (wnv) persists in humans and several animal models. we previously demonstrated that wnv persists in the central nervous system (cns) of mice for up to 6 months post-inoculation. we hypothesized that the cns immune response is ineffective in clearing the virus.201121251256
pick1 inhibition of the arp2/3 complex controls dendritic spine size and synaptic plasticity.activity-dependent remodelling of dendritic spines is essential for neural circuit development and synaptic plasticity, but the precise molecular mechanisms that regulate this process are unclear. activators of arp2/3-mediated actin polymerisation are required for spine enlargement; however, during long-term depression (ltd), spines shrink via actin depolymerisation and arp2/3 inhibitors in this process have not yet been identified. here, we show that pick1 regulates spine size in hippocampal ne ...201121252856
t cell-, interleukin-12-, and gamma interferon-driven viral clearance in measles virus-infected brain tissue.genetic studies with immunocompetent mice show the importance of both t cells and gamma interferon (ifn-?) for survival of a measles virus (mv) challenge; however, the direct role of t cells and ifn-? within the mv-infected brain has not been addressed. organotypic brain explants represent a successful ex vivo system to define central nervous system (cns)-specific mechanisms of leukocyte migration, activation, and mv clearance. within the heterogeneous, brain-derived, primed leukocyte population ...201121270150
akap79/150 impacts intrinsic excitability of hippocampal neurons through phospho-regulation of a-type k+ channel trafficking.kv4.2, as the primary a-subunit of rapidly inactivating, a-type voltage-gated k(+) (kv) channels expressed in hippocampal ca1 pyramidal dendrites, plays a critical role in regulating their excitability. activity-dependent trafficking of kv4.2 relies on c-terminal protein kinase a (pka) phosphorylation. a-kinase-anchoring proteins (akaps) target pka to glutamate receptor and ion channel complexes to allow for discrete, local signaling. as part of a previous study, we showed that akap79/150 intera ...201121273417
the role of iap antagonist proteins in the core apoptosis pathway of the mosquito disease vector aedes aegypti.while apoptosis regulation has been studied extensively in drosophila melanogaster, similar studies in other insects, including disease vectors, lag far behind. in d. melanogaster, the inhibitor of apoptosis (iap) protein diap1 is the major negative regulator of caspases, while iap antagonists induce apoptosis, in part, by binding to diap1 and inhibiting its ability to regulate caspases. in this study, we characterized the roles of two iap antagonists, michelob_x (mx) and imp, in apoptosis in th ...201121274634
production of lentiviral vectors with enhanced efficiency to target dendritic cells by attenuating mannosidase activity of mammalian cells. 201121276219
the nlrp3 inflammasome detects encephalomyocarditis virus and vesicular stomatitis virus infection.inflammasomes are cytosolic protein complexes that regulate caspase-1 activation and the secretion of interleukin-1ß (il-1ß) and il-18. several different inflammasome complexes have been identified, but the nlrp3 inflammasome is particularly notable because of its central role in diseases of inflammation. recent work has demonstrated an essential role for the nlrp3 inflammasome in host defense against influenza virus. we show here that two other rna viruses, encephalomyocarditis virus (emcv) and ...201121289120
lipid raft redox signaling: molecular mechanisms in health and disease.lipid rafts, the sphingolipid and cholesterol-enriched membrane microdomains, are able to form different membrane macrodomains or platforms upon stimulations, including redox signaling platforms, which serve as a critical signaling mechanism to mediate or regulate cellular activities or functions. in particular, this raft platform formation provides an important driving force for the assembling of nadph oxidase subunits and the recruitment of other related receptors, effectors, and regulatory co ...201121294649
preferential and bidirectional labeling of the rubrospinal tract with adenovirus-gfp for monitoring normal and injured axons.the rodent rubrospinal tract (rst) has been studied extensively to investigate regeneration and remodeling of central nervous system (cns) axons. currently no retrograde tracers can specifically label rubrospinal axons and neurons (rsns). the rst can be anterogradely labeled by injecting tracers into the red nucleus (rn), but accurately locating the rn is a technical challenge. here we developed a recombinant adenovirus carrying a green fluorescent protein reporter gene (adv-gfp) which can prefe ...201121299337
probing the attenuation and protective efficacy of a candidate chikungunya virus vaccine in mice with compromised interferon (ifn) signaling.chikungunya virus (chikv) is a mosquito-borne alphavirus that causes explosive outbreaks of febrile illness associated with rash, and painful arthralgia. the chik vaccine strain 181/clone25 (181/25) developed by the united states army medical research institute of infectious diseases (usamriid) was shown to be well-tolerated and highly immunogenic in phase i and ii clinical trials although it induced transient arthralgia in some healthy adult volunteers. in an attempt to better understand the ho ...201121300099
the proapoptotic bcl-2 protein bax plays an important role in the pathogenesis of reovirus encephalitis.encephalitis induced by reovirus serotype 3 (t3) strains results from the apoptotic death of infected neurons. extrinsic apoptotic signaling is activated in reovirus-infected neurons in vitro and in vivo, but the role of intrinsic apoptosis signaling during encephalitis is largely unknown. bax plays a key role in intrinsic apoptotic signaling in neurons by allowing the release of mitochondrial cytochrome c. we found bax activation and cytochrome c release in neurons following infection of neonat ...201121307199
the irf-3/bax-mediated apoptotic pathway, activated by viral cytoplasmic rna and dna, inhibits virus replication.induction of apoptosis in cells infected by sendai virus (sev), which triggers the cytosolic rig-i pathway, requires the presence of interferon regulatory factor 3 (irf-3). independent of irf-3's transcriptional role, a novel irf-3 activation pathway causes its interaction with the proapoptotic protein bax and its mitochondrial translocation to induce apoptosis. here we report that two other rna viruses, vesicular stomatitis virus (vsv) and encephalomyocarditis virus (emcv), may also activate th ...201121307205
discovery of a small arterivirus gene that overlaps the gp5 coding sequence and is important for virus production.the arterivirus family (order nidovirales) of single-stranded, positive-sense rna viruses includes porcine respiratory and reproductive syndrome virus and equine arteritis virus (eav). their replicative enzymes are translated from their genomic rna, while their seven structural proteins are encoded by a set of small, partially overlapping genes in the genomic 3'-proximal region. the latter are expressed via synthesis of a set of subgenomic mrnas that, in general, are functionally monocistronic ( ...201121307223
activity-dependent regulation of surface glucose transporter-3.glucose transporter 3 (glut3) is the main facilitative glucose transporter in neurons. glucose provides neurons with a critical energy source for neuronal activity. however, the mechanism by which neuronal activity controls glucose influx via glut3 is unknown. we investigated the influence of synaptic stimulation on glut3 surface expression and glucose import in primary cultured cortical and hippocampal neurons. synaptic activity increased surface expression of glut3 leading to an elevation of i ...201121307237
diversity in viral anti-pkr mechanisms: a remarkable case of evolutionary convergence.most viruses express during infection products that prevent or neutralize the effect of the host dsrna activated protein kinase (pkr). translation of sindbis virus (sinv) mrna escapes to pkr activation and eif2 phosphorylation in infected cells by a mechanism that requires a stem loop structure in viral 26s mrna termed dlp to initiate translation in the absence of functional eif2. unlike the rest of viruses tested, we found that alphavirus infection allowed a strong pkr activation and eif2a phos ...201121311764
exclusive and common targets of neostriatofugal projections of rat striosome neurons: a single neuron-tracing study using a viral vector.the rat neostriatum has a mosaic organization composed of striosome/patch compartments embedded in a more extensive matrix compartment, which are distinguished from each other by the input-output organization as well as by the expression of many molecular markers. the matrix compartment gives rise to the dual ?-aminobutyric acid (gaba)ergic striatofugal systems, i.e. direct and indirect pathway neurons, whereas the striosome compartment is considered to involve direct pathway neurons alone. alth ...201121314848
the reverse genetics applied to fish rna viruses.abstract: aquaculture has expanded rapidly to become a major economic and food-producing sector worldwide these last 30 years. in parallel, viral diseases have emerged and rapidly spread from farm to farm causing enormous economic losses. the most problematic viruses encountered in the field are mainly, but not exclusively, rna viruses belonging to the novirhabdovirus, aquabirnavirus, alphavirus and betanodavirus genera. the recent establishment of reverse genetics systems to recover infectious ...201121314978
newly recognized mosquito-associated viruses in mainland china, in the last two decades.there are four principal arboviruses in mainland china. two kinds of them are mosquito-borne viruses, namely japanese encephalitis virus and dengue virus, which lead to japanese encephalitis, and dengue fever/dengue hemorrhagic fever respectively; the other two are tick-borne viruses, namely tick-borne encephalitis virus and crimean-congo hemorrhagic fever virus (also known as xinjiang hemorrhagic fever virus), which contribute to tick-borne encephalitis and xinjiang hemorrhagic fever respective ...201121314994
activity-induced notch signaling in neurons requires arc/arg3.1 and is essential for synaptic plasticity in hippocampal networks.notch signaling in the nervous system has been most studied in the context of cell fate specification. however, numerous studies have suggested that notch also regulates neuronal morphology, synaptic plasticity, learning, and memory. here we show that notch1 and its ligand jagged1 are present at the synapse, and that notch signaling in neurons occurs in response to synaptic activity. in addition, neuronal notch signaling is positively regulated by arc/arg3.1, an activity-induced gene required fo ...201121315255
sindbis virus replication, is insensitive to rapamycin and torin1, and suppresses akt/mtor pathway late during infection in hek cells.genetically engineered sindbis viruses (sin) are excellent oncolytic agents in preclinical models. several human cancers have aberrant akt signaling, and kinase inhibitors including rapamycin are currently tested in combination therapies with oncolytic viruses. therefore, it was of interest to delineate possible cross-regulation between sin replication and pi3k/akt/mtor signaling. here, using hek293t cells as host, we report the following key findings: (a) robust sin replication occurs in the pr ...201121316343
a complex adenovirus vaccine against chikungunya virus provides complete protection against viraemia and arthritis.chikungunya virus, a mosquito-borne alphavirus, recently caused the largest epidemic ever seen for this virus. chikungunya disease primarily manifests as a painful and debilitating arthralgia/arthritis, and no effective drug or vaccine is currently available. here we describe a recombinant chikungunya virus vaccine comprising a non-replicating complex adenovirus vector encoding the structural polyprotein cassette of chikungunya virus. a single immunisation with this vaccine consistently induced ...201121320541
stat2 mediates innate immunity to dengue virus in the absence of stat1 via the type i interferon receptor.dengue virus (denv) is a mosquito-borne flavivirus, and symptoms of infection range from asymptomatic to the severe dengue hemorrhagic fever/dengue shock syndrome (dhf/dss). high viral loads correlate with disease severity, and both type i & ii interferons (ifns) are crucial for controlling viral replication. we have previously reported that signal transducer and activator of transcription (stat) 1-deficient mice are resistant to denv-induced disease, but little is known about this stat1-indepen ...201121379341
malaria and other vector-borne infection surveillance in the u.s. department of defense armed forces health surveillance center-global emerging infections surveillance program: review of 2009 accomplishments.vector-borne infections (vbi) are defined as infectious diseases transmitted by the bite or mechanical transfer of arthropod vectors. they constitute a significant proportion of the global infectious disease burden. united states (u.s.) department of defense (dod) personnel are especially vulnerable to vbis due to occupational contact with arthropod vectors, immunological naivet+® to previously unencountered pathogens, and limited diagnostic and treatment options available in the austere and uns ...201121388569
a respiratory syncytial virus replicon that is noncytotoxic and capable of long-term foreign gene expression.respiratory syncytial virus (rsv) infection of most cultured cell lines causes cell-cell fusion and death. cell fusion is caused by the fusion (f) glycoprotein and is clearly cytopathic, but other aspects of rsv infection may also contribute to cytopathology. to investigate this possibility, we generated an rsv replicon that lacks all three of its glycoprotein genes and so cannot cause cell-cell fusion or virus spread. this replicon includes a green fluorescent protein gene and an antibiotic res ...201121389127
assembly of alphavirus replication complexes from rna and protein components in a novel trans-replication system in mammalian cells.for positive-strand rna viruses, the viral genomic rna also acts as an mrna directing the translation of the replicase proteins of the virus. replication takes place in association with cytoplasmic membranes, which are heavily modified to create specific replication compartments. here we have expressed by plasmid dna transfection the large replicase polyprotein of semliki forest virus (sfv) in mammalian cells from a nonreplicating mrna and provided a separate rna containing the replication signa ...201121389137
structure and functional relevance of a transcription-regulating sequence involved in coronavirus discontinuous rna synthesis.transmissible gastroenteritis coronavirus (tgev) genomic rna transcription generates 5'- and 3'-coterminal subgenomic mrnas. this process involves a discontinuous step during the synthesis of minus-sense rna that is modulated by transcription-regulating sequences located at the 3' end of the leader (trs-l) and also preceding each viral gene (trs-bs). trss include a highly conserved core sequence (cs) (5'-cuaaac-3') and variable flanking sequences. it has been previously proposed that trs-bs act ...201121389138
genomic and phylogenetic characterization of leanyer virus, a novel orthobunyavirus isolated in northern australia.leanyer virus (leav), currently classified as a member of the genus orthobunyavirus, in the family bunyaviridae, was originally isolated from a pool of anopheles meraukensis mosquitoes, collected at leanyer, northern territory, australia in 1974. when it failed to react in serological tests with antisera from other known viruses, full-length genomic sequencing was pursued to determine the relationship of leav to other orthobunyavirus species. genetic and serological characterization confirmed it ...201121402599
a protective role for complement c3 protein during pandemic 2009 h1n1 and h5n1 influenza a virus infection.highly pathogenic h5n1 influenza infections are associated with enhanced inflammatory and cytokine responses, severe lung damage, and an overall dysregulation of innate immunity. c3, a member of the complement system of serum proteins, is a major component of the innate immune and inflammatory responses. however, the role of this protein in the pathogenesis of h5n1 infection is unknown. here we demonstrate that h5n1 influenza virus infected mice had increased levels of c5a and c3 activation bypr ...201121408070
saliva proteins of vector culicoides modify structure and infectivity of bluetongue virus particles.bluetongue virus (btv) and epizootic haemorrhagic disease virus (ehdv) are related orbiviruses, transmitted between their ruminant hosts primarily by certain haematophagous midge vectors (culicoides spp.). the larger of the btv outer-capsid proteins, 'vp2', can be cleaved by proteases (including trypsin or chymotrypsin), forming infectious subviral particles (isvp) which have enhanced infectivity for adult culicoides, or kc cells (a cell-line derived from c. sonorensis). we demonstrate that vp2 ...201121423801
n-linked glycosylation of dengue virus ns1 protein modulates secretion, cell-surface expression, hexamer stability, and interactions with human complement.dengue virus (denv) ns1 is a versatile non-structural glycoprotein that is secreted as a hexamer, binds to the cell surface of infected and uninfected cells, and has immune evasive functions. denv ns1 displays two conserved n-linked glycans at n130 and n207. in this study, we examined the role of these two n-linked glycans on ns1 secretion, stability, and function. because some groups have reported reduced yields of infectious denv when n130 and n207 are changed, we analyzed glycosylation-defici ...201121429549
identification and characterization of a ross river virus variant that grows persistently in macrophages, shows altered disease kinetics in a mouse model, and exhibits resistance to type i interferon.alphaviruses, such as chikungunya virus, o'nyong-nyong virus, and ross river virus (rrv), cause outbreaks of human rheumatic disease worldwide. rrv is a positive-sense single-stranded rna virus endemic to australia and papua new guinea. in this study, we sought to establish an in vitro model of rrv evolution in response to cellular antiviral defense mechanisms. rrv was able to establish persistent infection in activated macrophages, and a small-plaque variant (rrv(pers)) was isolated after sever ...201121430046
activation of the alphavirus spike protein is suppressed by bound e3.alphaviruses are taken up into the endosome of the cell, where acidic conditions activate the spikes for membrane fusion. this involves dissociation of the three e2-e1 heterodimers of the spike and e1 interaction with the target membrane as a homotrimer. the biosynthesis of the heterodimer as a ph-resistant p62-e1 precursor appeared to solve the problem of premature activation in the late and acidic parts of the biosynthetic transport pathway in the cell. however, p62 cleavage into e2 and e3 by ...201121430054
broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis.compound a3 was identified in a high-throughput screen for inhibitors of influenza virus replication. it displays broad-spectrum antiviral activity, and at noncytotoxic concentrations it is shown to inhibit the replication of negative-sense rna viruses (influenza viruses a and b, newcastle disease virus, and vesicular stomatitis virus), positive-sense rna viruses (sindbis virus, hepatitis c virus, west nile virus, and dengue virus), dna viruses (vaccinia virus and human adenovirus), and retrovir ...201121436031
replicase-based plasmid dna shows anti-tumor activity.double stranded rna (dsrna) has multiple anti-tumor mechanisms. over the past several decades, there have been numerous attempts to utilize synthetic dsrna to control tumor growth in animal models and clinical trials. recently, it became clear that intracellular dsrna is more effective than extracellular dsrna on promoting apoptosis and orchestrating adaptive immune responses. to overcome the difficulty in delivering a large dose of synthetic dsrna into tumors, we propose to deliver a rna replic ...201121443770
activation of interferon signaling pathways in spinal cord astrocytes from an als mouse model.amyotrophic lateral sclerosis (als) is a progressive neurodegenerative disorder affecting predominantly motor neurons. recent studies suggest that the disease progression of als is non-cell-autonomous, although the interaction between neurons and glial cells in different disease stages is not entirely clear. here, we demonstrate that the interferon (ifn) signaling pathway is activated in human sod1(g93a) transgenic mice, a rodent model of als. ifn-stimulated genes (isgs) increased in the spinal ...201121446050
mosquito rnai is the major innate immune pathway controlling arbovirus infection and transmission.mosquito-borne arboviruses cause serious diseases in humans that are increasingly becoming public health problems, yet arbovirus infections cause minimal pathology in the mosquito vector, allowing persistent infections and lifelong virus transmission. the principal mosquito innate immune response to virus infections, rnai, differs substantially from the human immune response and this difference could be the basis for the disparate outcomes of infection in the two hosts. understanding the mosquit ...201121449839
a trimeric, v2-deleted hiv-1 envelope glycoprotein vaccine elicits potent neutralizing antibodies but limited breadth of neutralization in human volunteers.a key missing element in the development of a successful human immunodeficiency virus (hiv) vaccine is an immunogen that can generate broadly cross-neutralizing antibodies against primary isolates of the virus.201121451004
sensory maps in the olfactory cortex defined by long-range viral tracing of single neurons.sensory information may be represented in the brain by stereotyped mapping of axonal inputs or by patterning that varies between individuals. in olfaction, a stereotyped map is evident in the first sensory processing centre, the olfactory bulb (ob), where different odours elicit activity in unique combinatorial patterns of spatially invariant glomeruli. activation of each glomerulus is relayed to higher cortical processing centres by a set of ~20-50 'homotypic' mitral and tufted (mt) neurons. in ...201121451523
distinct representations of olfactory information in different cortical centres.sensory information is transmitted to the brain where it must be processed to translate stimulus features into appropriate behavioural output. in the olfactory system, distributed neural activity in the nose is converted into a segregated map in the olfactory bulb. here we investigate how this ordered representation is transformed in higher olfactory centres in mice. we have developed a tracing strategy to define the neural circuits that convey information from individual glomeruli in the olfact ...201121451525
patterns of axonal collateralization of single layer v cortical projection neurons in the rat presubiculum.the presubiculum is one of the important regions of the parahippocampal area known to be responsible for processing and integrating spatial representation information. to understand better the functional roles played by the presubiculum, it is essential to elucidate how output signals from the presubiculum distribute to its target regions. in the present study, the axonal branching patterns of single pyramidal neurons in layer v of the rat presubiculum were investigated by using in vivo injectio ...201121452203
pseudotyping lentiviral vectors with aura virus envelope glycoproteins for dc-sign-mediated transduction of dendritic cells.abstract lentiviral vectors (lvs) pseudotyped with envelope proteins of alphaviruses have recently attracted considerable interest for their potential as gene delivery tools. we report the production of human immunodeficiency virus type 1 (hiv-1)-derived lvs pseudotyped with envelope glycoproteins derived from the aura virus (aura). we found that the aura-glycoprotein-pseudotyped lvs use c-type lectins (dc-sign and l-sign) as attachment factors. these interactions with dc-sign are specific as de ...201121452926
larval environmental temperature and insecticide exposure alter aedes aegypti competence for arboviruses.abstract temperature is a key factor influencing mosquito growth and development and is also known to affect insecticide efficacy. we evaluated the effects of larval rearing temperature and exposure to insecticides on adult mosquito fitness and competence for arboviral infection using sindbis virus (sinv). we exposed newly hatched larvae of aedes aegypti to an environmentally realistic level of insecticide malathion at 20°c and 30°c and allowed the resulting adults to feed on sinv-infected blood ...201121453010
structure-dependent impairment of intracellular apolipoprotein e4 trafficking and its detrimental effects are rescued by small-molecule structure correctors.apolipoprotein (apo) e4 is the major genetic risk factor for alzheimer disease (ad) and likely contributes to neuropathology through various pathways. here we report that the intracellular trafficking of apoe4 is impaired in neuro-2a cells and primary neurons, as shown by measuring fluorescence recovery after photobleaching. in neuro-2a cells, more apoe4 than apoe3 molecules remained immobilized in the endoplasmic reticulum (er) and the golgi apparatus, and the lateral motility of apoe4 was sign ...201121454574
measles virus neurovirulence and host immunity.measles virus is highly neuroinvasive, yet host immune responses are highly effective at limiting neurovirulence in humans. we know that neurons are an important target of infection and that both ifn-? and -ß expression are observed in the measles virus-infected human brain. rodent models can be used to understand how this response is orchestrated. constitutive expression of the major inducible 70-kda heat-shock protein is a feature of primate tissues that is lacking in mice. this article examin ...201121461314
the contribution of molecular epidemiology to the understanding and control of viral diseases of salmonid aquaculture.abstract: molecular epidemiology is a science which utilizes molecular biology to define the distribution of disease in a population (descriptive epidemiology) and relies heavily on integration of traditional (or analytical) epidemiological approaches to identify the etiological determinants of this distribution. the study of viral pathogens of aquaculture has provided many exciting opportunities to apply such tools. this review considers the extent to which molecular epidemiological studies hav ...201121466673
interferon alpha regulates mapk and stat1 pathways in human hepatoma cells.signaling events triggered by interferon (ifn) account for the molecular mechanisms of antiviral effect. jak-stat pathway plays a critical role in ifn signaling, and other pathways are also implicated in ifn-mediated antiviral effect. changes in mitogen-activated protein kinase (mapk) and stat1 pathways were evaluated in human hepatoma cells huh7 and hepg2 upon ifn alpha treatment.201121466707
rescue of infectious particles from preassembled alphavirus nucleocapsid cores.alphaviruses are small, spherical, enveloped, positive-sense, single-stranded, rna viruses responsible for considerable human and animal disease. using microinjection of preassembled cores as a tool, a system has been established to study the assembly and budding process of sindbis virus, the type member of the alphaviruses. we demonstrate the release of infectious virus-like particles from cells expressing sindbis virus envelope glycoproteins following microinjection of sindbis virus nucleocaps ...201121471237
a diverse range of gene products are effectors of the type i interferon antiviral response.the type i interferon response protects cells against invading viral pathogens. the cellular factors that mediate this defence are the products of interferon-stimulated genes (isgs). although hundreds of isgs have been identified since their discovery more than 25 years ago, only a few have been characterized with respect to antiviral activity. for most isg products, little is known about their antiviral potential, their target specificity and their mechanisms of action. using an overexpression ...201121478870
can pesticides and larval competition alter susceptibility of aedes mosquitoes (diptera: culicidae) to arbovirus infection?density-dependent processes such as larval competition may be important regulatory factors among some mosquito species. the application of pesticides used for control may alter these density-dependent interactions with consequences for the number of survivors and associated sublethal and chronic effects on these individuals. we examined how intraspecific competition among larvae and low concentrations of malathion alter aedes aegypti l. and aedes albopictus skuse adult life history traits and co ...201121485385
treatment of mice with human monoclonal antibody 24h after lethal aerosol challenge with virulent venezuelan equine encephalitis virus prevents disease but not infection.we recently described a venezuelan equine encephalitis virus (veev)-specific human monoclonal antibody (mab), f5 nigg, that recognizes a new neutralization epitope on the veev e2 envelope glycoprotein. in this study, we investigated the ability of f5 nigg given prophylactically or therapeutically to protect mice from subcutaneous or aerosolized veev infection. f5 nigg had potent ability to protect mice from infection by either route when administered 24h before exposure; however, mice treated 24 ...201121489591
a role for endosomal proteins in alphavirus dissemination in mosquitoes.little is known about endosomal pathway proteins involved in arthropod-borne virus (arbovirus) assembly and cell-to-cell spread in vector mosquitoes. unc93a and synaptic vesicle-2 (sv2) proteins are involved in intracellular transport in mammals. they show amino acid sequence conservation from mosquitoes to humans, and their transcripts are highly enriched in aedes aegypti during arbovirus infection. transient gene silencing of sv2 or unc93a in mosquitoes infected with the recombinant alphavirus ...201121496127
a 5'-proximal stem-loop structure of 5' untranslated region of porcine reproductive and respiratory syndrome virus genome is key for virus replication.abstract:201121496223
the soluble serum protein gas6 bridges virion envelope phosphatidylserine to the tam receptor tyrosine kinase axl to mediate viral entry.virus entry into cells is typically initiated by binding of virally encoded envelope proteins to specific cell surface receptors. studying infectivity of lentivirus pseudotypes lacking envelope binding, we still observed high infectivity for some cell types. on further investigation, we discovered that this infectivity is conferred by the soluble bovine protein s in fetal calf serum, or gas6, its human homolog. gas6 enhances native infectivity of pseudotypes of multiple viral envelope proteins. ...201121501828
cxcr3 dependent plasma blast migration to the central nervous system during viral encephalomyelitis.immunoglobulin in cerebral spinal fluid and antibody secreting cells (asc) within the central nervous system (cns) parenchyma are common hallmarks of microbial infections and autoimmune disorders. however, the signals directing asc migration into the inflamed cns are poorly characterized. this study demonstrates that cxcr3 mediates cns accumulation of asc during neurotropic coronavirus induced encephalomyelitis. expansion of cxcr3 expressing asc in draining lymph nodes prior to accumulation with ...201121507985
viral-mediated expression of a constitutively active form of creb in the dentate gyrus does not induce abnormally enduring fear memory.increasing creb-dependent transcription in dentate gyrus (dg) granule cells in vivo using viral-mediated expression of a constitutively active form of creb (crebca) is sufficient to enhance contextual fear memory but whether this treatment renders memory abnormally enduring is unknown. here we confirm that over-expressing crebca in the dg increases retention of contextual fear conditioning (cfc) and show that this memory decays normally. specifically, the retention scores of crebca mice are sign ...201121510980
stimulation of stop codon readthrough: frequent presence of an extended 3' rna structural element.in sindbis, venezuelan equine encephalitis and related alphaviruses, the polymerase is translated as a fusion with other non-structural proteins via readthrough of a uga stop codon. surprisingly, earlier work reported that the signal for efficient readthrough comprises a single cytidine residue 3'-adjacent to the uga. however, analysis of variability at synonymous sites revealed strikingly enhanced conservation within the ∼150 nt 3'-adjacent to the uga, and rna folding algorithms revealed the po ...201121525127
probable non-vector-borne transmission of zika virus, colorado, usa.clinical and serologic evidence indicate that 2 american scientists contracted zika virus infections while working in senegal in 2008. one of the scientists transmitted this arbovirus to his wife after his return home. direct contact is implicated as the transmission route, most likely as a sexually transmitted infection.201121529401
fatal human case of western equine encephalitis, uruguay.to the editor: the genus alphavirus (family togaviridae) comprises 29 viral species (1), grouped in at least 7 antigenic complexes by their serologic cross-reactivity (2). they are maintained in nature through enzootic cycles involving arthropods as vectors with subsequent amplification in small mammals or birds, and epizootic cycles between mosquitoes and large mammals such as horses or humans.201121529429
bordetella pertussis infection exacerbates influenza virus infection through pertussis toxin-mediated suppression of innate immunity.pertussis (whooping cough) is frequently complicated by concomitant infections with respiratory viruses. here we report the effect of bordetella pertussis infection on subsequent influenza virus (pr8) infection in mouse models and the role of pertussis toxin (pt) in this effect. balb/c mice infected with a wild-type strain of b. pertussis (wt) and subsequently (up to 14 days later) infected with pr8 had significantly increased pulmonary viral titers, lung pathology and mortality compared to mice ...201121533103
pathogenesis of japanese encephalitis virus infection in a golden hamster model and evaluation of flavivirus cross-protective immunity.abstract. japanese encephalitis virus (jev) is a mosquito-borne flavivirus endemic to southeast asia and surrounding pacific islands, and it has most recently emerged in northern australia. jev is closely related to west nile virus (wnv) and st. louis encephalitis virus (slev), both endemic to the united states. in the event that jev is introduced into the americas, it will be important to determine whether immunity to wnv or slev might afford protection from infection and development of viremia ...201121540381
distribution of mosquitoes and mosquito-borne arboviruses in yunnan province near the china-myanmar-laos border.abstract. economic development and increased tourism in the southern region of yunnan province in china, adjacent to several countries in southeast asia, has increased the likelihood of import and export of vectors and vector-borne diseases. we report the results of surveillance of mosquitoes and mosquito-borne arboviruses along the border of china-myanmar-laos in 2005 and 2006, and information associating several arboviruses with infections and possibly disease in local human populations. seven ...201121540383
structure of the autocatalytic cysteine protease domain of potyvirus helper-component proteinase.the helper-component proteinase (hc-pro) of potyvirus is involved in polyprotein processing, aphid transmission and suppression of antiviral rna silencing. there is no high-resolution structure reported for any part of hc-pro, hindering mechanistic understanding of its multiple functions. we have determined the crystal structure of the cysteine protease domain of hc-pro from turnip mosaic virus at 2.0 å resolution. as a protease, hc-pro only cleaves a gly-gly dipeptide at its own c-terminus. the ...201121543324
interferon-{beta} controls west nile virus infection and pathogenesis in mice.studies with mice lacking the common plasma membrane receptor for type i interferon (ifnαβr(-/-)) have revealed that ifn signaling restricts tropism, dissemination, and lethality after infection with west nile virus (wnv) or several other pathogenic viruses. however, the specific functions of individual ifn subtypes remain uncertain. here, using ifn-β(-/-) mice, we defined the antiviral and immunomodulatory function of this ifn subtype in restricting viral infection. ifn-β(-/-) mice were more vu ...201121543483
the domain i-domain iii linker plays an important role in the fusogenic conformational change of the alphavirus membrane fusion protein.the alphavirus semliki forest virus (sfv) infects cells through a low-ph dependent membrane fusion reaction mediated by the virus fusion protein e1. acidic ph initiates a series of e1 conformational changes that culminate in membrane fusion and include dissociation of the e1/e2 heterodimer, insertion of the e1 fusion loop into the target membrane, and refolding of e1 to a stable trimeric hairpin conformation. a highly conserved histidine (h3) on the e1 protein was previously shown to promote low ...201121543498
design of chimeric alphaviruses with a programmed, attenuated, cell type-restricted phenotype.the alphavirus genus in the togaviridae family contains a number of human and animal pathogens. the importance of alphaviruses has been strongly underappreciated; however, epidemics of chikungunya virus (chikv), causing millions of cases of severe and often persistent arthritis in the indian subcontinent, have raised their profile in recent years. in spite of a continuous public health threat, to date no licensed vaccines have been developed for alphavirus infections. in this study, we have appl ...201121345954
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