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vaccinia virus-mediated intra-tumoral expression of matrix metalloproteinase 9 enhances oncolysis of pc-3 xenograft tumors.oncolytic viruses, including vaccinia virus (vacv), are a promising alternative to classical mono-cancer treatment methods such as surgery, chemo- or radiotherapy. however, combined therapeutic modalities may be more effective than mono-therapies. in this study, we enhanced the effectiveness of oncolytic virotherapy by matrix metalloproteinase (mmp-9)-mediated degradation of proteins of the tumoral extracellular matrix (ecm), leading to increased viral distribution within the tumors.201222917220
requirement of cd4 help for induction of cd8 t cell response specific for virally derived h60.cd40-cd40l-mediated help from cd4 t cells is essential to induce primary cd8 t cell responses specific to the non-inflammatory cell-based antigen h60. in this study, using h60 as a model antigen, we generated recombinant vaccinia viruses (rvvs) expressing the h60 cd8 epitope and investigated whether cd4 help was required to activate the cd8 t cell response specific to the virally expressed h60. the immune response after infection with rvvs expressing h60 was similar to that after immunization wi ...201222916048
imaging characteristics, tissue distribution, and spread of a novel oncolytic vaccinia virus carrying the human sodium iodide symporter.oncolytic viruses show promise for treating cancer. however, to assess therapy and potential toxicity, a noninvasive imaging modality is needed. this study aims to determine the in vivo biodistribution, and imaging and timing characteristics of a vaccinia virus, glv-1h153, encoding the human sodium iodide symporter (hnis.201222912675
detection of vaccinia virus in blood and faeces of experimentally infected cows.bovine vaccinia (bv), a zoonosis caused by vaccinia virus (vacv), affects dairy cattle and milkers, causing economic, veterinary and human health impacts. despite such impacts, there are no experimental studies about the pathogenesis of bv in cows to assess whether there is a systemic spread of the virus and whether there are different ways of vacv shedding. trying to answer some of these questions, a study was proposed using experimental inoculation of vacv in cows. all experimentally infected ...201322909142
oncolytic vaccinia virus glv-1h68 strain shows enhanced replication in human breast cancer stem-like cells in comparison to breast cancer cells.recent data suggest that cancer stem cells (cscs) play an important role in cancer, as these cells possess enhanced tumor-forming capabilities and are responsible for relapses after apparently curative therapies have been undertaken. hence, novel cancer therapies will be needed to test for both tumor regression and csc targeting. the use of oncolytic vaccinia virus (vacv) represents an attractive anti-tumor approach and is currently under evaluation in clinical trials. the purpose of this study ...201222901246
vaccinia virus virion membrane biogenesis protein a11 associates with viral membranes in a manner that requires the expression of another membrane biogenesis protein, a6.a group of vaccinia virus (vacv) proteins, including a11, l2, and a6, are required for biogenesis of the primary envelope of vacv, specifically, for the acquisition of viral membrane precursors. however, the interconnection among these proteins is unknown and, with the exception of l2, the connection of these proteins with membranes is also unknown. in this study, prompted by the findings that a6 coprecipitated a11 and that the cellular distribution of a11 was dramatically altered by repression ...201222875972
vaccinia virus glv-1h153 is effective in treating and preventing metastatic triple-negative breast cancer.this study aimed to investigate the therapeutic impact of a new oncolytic vaccinia virus in a triple-negative breast cancer (tnbc) murine model and its potential for treating distant metastatic disease.201222868370
synthesis and antiviral activities of hexadecyloxypropyl prodrugs of acyclic nucleoside phosphonates containing guanine or hypoxanthine and a (s)-hpmp or pee acyclic moiety.hexadecyloxypropyl esters of acyclic nucleoside phosphonates containing guanine (g) or hypoxanthine (hx) and a (s)-[3-hydroxy-2-(phosphonomethoxy)propyl] [(s)-hpmp] or 2-(2-phosphonoethoxy)ethyl (pee) acyclic moiety have been prepared. the activity of the prodrugs was evaluated in vitro against different virus families. whereas ester derivatives of peehx and (s)-hpmphx were antivirally inactive, monoesters of peeg, and mono- and diesters of (s)-hpmpg showed pronounced antiviral activity against ...201222858222
pervasive initiation and 3'-end formation of poxvirus postreplicative rnas.poxviruses are large dna viruses that replicate within the cytoplasm and encode a complete transcription system, including a multisubunit rna polymerase, stage-specific transcription factors, capping and methylating enzymes, and a poly(a) polymerase. expression of the more than 200 open reading frames by vaccinia virus, the prototype poxvirus, is temporally regulated: early mrnas are synthesized immediately after infection, whereas intermediate and late mrnas are synthesized following genome rep ...201222829601
cd8 t cells are essential for recovery from a respiratory vaccinia virus infection.the precise immune components required for protection against a respiratory orthopoxvirus infection, such as human smallpox or monkeypox, remain to be fully identified. in this study, we used the virulent western reserve strain of vaccinia virus (vacv-wr) to model a primary respiratory orthopoxvirus infection. naive mice infected with vacv-wr mounted an early cd8 t cell response directed against dominant and subdominant vacv-wr ags, followed by a cd4 t cell and ig response. in contrast to other ...201222826318
inactivation of vaccinia virus by natural sunlight and by artificial uvb radiation.this study determined the sensitivity of vaccinia virus, an orthopox virus commonly used as a surrogate for variola virus (etiological agent of smallpox), exposed to uvb radiation emitted by a solar simulator, or to direct natural sunlight. the data obtained indicate that: (1) the virucidal effect of natural sunlight can be mimicked adequately by an artificial light source with similar spectral characteristics in the uvb, (2) viral sensitivity to uvb or to solar radiation can be correlated with ...201322816993
airway cd8(+) t cells induced by pulmonary dna immunization mediate protective anti-viral immunity.vaccination strategies for protection against a number of respiratory pathogens must induce t-cell populations in both the pulmonary airways and peripheral lymphoid organs. in this study, we show that pulmonary immunization using plasmid dna formulated with the polymer polyethyleneimine (pei-dna) induced antigen-specific cd8(+) t cells in the airways that persisted long after antigen local clearance. the persistence of the cells was not mediated by local lymphocyte proliferation or persistent an ...201322806099
nk cell response to vaccinia virus is regulated by myeloid-derived suppressor cells.nk cells are critical for the innate immune control of poxviral infections. previous studies have shown that nk cells are efficiently activated in response to infection with vaccinia virus (vv), the most studied member of the poxvirus family. however, it remains unknown whether the activation of nk cells in response to vv infection is tightly regulated. in this study, we showed that myeloid-derived suppressor cells (mdscs) rapidly accumulated at the site of vv infection. in vivo depletion of mds ...201222798671
vaccinia virus protein c4 inhibits nf-κb activation and promotes virus virulence.vaccinia virus (vacv) strain western reserve protein c4 has been characterized and its function and contribution to virus virulence assessed. bioinformatic analysis showed that c4 is conserved in six orthopoxvirus species and shares 43 % amino acid identity with vacv protein c16, a known virulence factor. a recombinant vacv expressing a c-terminally tagged version of c4 showed that, like c16, this 37 kda protein is expressed early during infection and localizes to both the cytoplasm and the nucl ...201222791606
sub-viral imaging of vaccinia virus using super-resolution microscopy.the study of host-pathogen interactions over past decades has benefited from advances in microscopy and fluorescent imaging techniques. a particularly powerful model in this field is vaccinia virus (vacv), which due to its amenability to genetic manipulation has been a productive model in advancing the understanding of the transport of subcellular cargoes. conventional light microscopy imposes an upper limit of resolution of ~250nm, hence knowledge of events occurring at the sub-viral resolution ...201222776111
commensal bacteria lipoteichoic acid increases skin mast cell antimicrobial activity against vaccinia viruses.mast cells (mcs) are considered sentinels in the skin and mucosa. their ability to release antimicrobial peptides, such as cathelicidin, protects against bacterial infections when the epithelial barrier is breached. we recently described that mcs defend against bacterial and viral infections through the release of cathelicidin during degranulation. in this study, we hypothesize that cathelicidin expression is induced in mcs by the activation of tlr2 from bacterial products (lipoteichoic acid) pr ...201222772452
construction and evaluation of a new triple-gene expression cassette vaccinia virus shuttle vector.a vaccinia virus shuttle vector pstke with a triple-gene expression cassette was designed, and the derived recombinant virus could express at least three different target genes. a vaccinia virus and its mutant as the original viruses and egfp as the reporter gene were used to verify the three expression cassettes. two recombinant viruses containing egfp were obtained by homologous recombination and plaque screening. the expression and genetic stability of the recombinant virus and foreign genes ...201222766182
poxvirus cell entry: how many proteins does it take?for many viruses, one or two proteins enable cell binding, membrane fusion and entry. the large number of proteins employed by poxviruses is unprecedented and may be related to their ability to infect a wide range of cells. there are two main infectious forms of vaccinia virus, the prototype poxvirus: the mature virion (mv), which has a single membrane, and the extracellular enveloped virion (ev), which has an additional outer membrane that is disrupted prior to fusion. four viral proteins assoc ...201222754644
reverse genetics analysis of poxvirus intermediate transcription factors.vaccinia virus transcription is regulated in three stages. an intermediate transcription factor, comprised of virus-encoded polypeptides a8 and a23, was previously identified by in vitro analyses. to investigate its role, we engineered cells that stably expressed both subunits and complemented the replication of a8 and a23 deletion mutant viruses. without a8 or a23, viral early gene expression and dna replication occurred but intermediate and late gene expression and resolution of genome concate ...201222740406
immunization with wt1-derived peptides by tattooing inhibits the growth of tramp-c2 prostate tumor in mice.the expression of the transcription factor encoded by the wilms tumor gene 1 (wt1) is associated with a variety of human cancers. wt1 protein has been reported to serve as a target antigen for tumor-specific immune responses. we observed that the immunization of mice with peptide vaccines derived from wt1 in a mixture with the cpg adjuvant (odn 1826) by tattoo administration was superior to subcutaneous delivery of the peptides in combination with cpg formulated with the mineral oil adjuvant or ...201222735806
oncolytic vaccinia virus safely and effectively treats skin tumors in mouse models of xeroderma pigmentosum.xeroderma pigmentosum (xp) is an orphan autosomal recessive disorder of dna repair. when exposed to genotoxic stress, xp patients have reduced capacity to remove bulky adducts by nucleotide excision repair and are thus greatly predisposed to cancer. unfortunately, given the nature of their underlying genetic defect, tumor-bearing xp patients cannot be treated with conventional dna damaging therapies. engineered strains of the poxvirus vaccinia have been shown to cure cancer in numerous preclinic ...201322733395
species selectivity in poxviral complement regulators is dictated by the charge reversal in the central complement control protein modules.variola and vaccinia viruses, the two most important members of the family poxviridae, are known to encode homologs of the human complement regulators named smallpox inhibitor of complement enzymes (spice) and vaccinia virus complement control protein (vcp), respectively, to subvert the host complement system. intriguingly, consistent with the host tropism of these viruses, spice has been shown to be more human complement-specific than vcp, and in this study we show that vcp is more bovine compl ...201222732591
response surface methodology to determine optimal measles-specific cytokine responses in human peripheral blood mononuclear cells.limitations of assay variability, labor costs, and availability of cells can affect the conduct of large population-based studies. the ability to determine optimal conditions for laboratory assessment of immune outcomes, including measurement of cytokines, can reduce the number of peripheral blood mononuclear cells (pbmcs) needed, reduce the labor costs involved, and the variability in secreted cytokine response by pooling cytokines from the same cell culture supernatant. previously, we used res ...201222705088
[oncolytic poxviruses].the latest data on selection and construction of poxviruses capable of specifically lysing tumor cells of different genesis, inducing antitumor immunity and apoptosis of malignant cells are discussed. the review concerns several directions: virus attenuation, insertion of immunomodulatory protein genes, and anti-tumor protein genes. thymidine kinase and viral growth factor genes make the greatest contribution to the virus attenuation as their inactivation results in the virus inability to replic ...201222702138
real-time imaging of tumors using replication-competent light-emitting microorganisms.early detection of cancer and metastases is pivotal to the success of subsequent treatment intervention. in recent years, the use of live microorganisms, such as viruses and bacteria, has gained substantial research and clinical interest in both detection and therapy of cancer. many of these live microorganisms have shown remarkable tumor-specific replication following systemic delivery. with the aid of modern molecular technologies, modified live microorganisms can be engineered to carry additi ...201222700410
central nervous system distribution of the poxviral proteins after intranasal administration of proteins and titering of vaccinia virus in the brain after intracranial administration.poxviral proteins are known to interact with the immune system of the host. some of them interact with the transcription factors of the host, whereas others interact with the components of the immune system. vaccinia virus secretes a 28.8-kda complement control protein (vcp), which is known to regulate the complement system. this protein helps the virus to evade the immune response of the host. such viral proteins might also prove beneficial in the treatment and prevention of the progression of ...201222688775
application of quartz crystal microbalance with dissipation monitoring technology for studying interactions of poxviral proteins with their ligands.poxviruses are one of the most complex of animal viruses and encode for over 150 proteins. the interactions of many of the poxviral-encoded proteins with host proteins, as well as with other proteins, such as transcription complexes, have been well characterized at the qualitative level. some have also been characterized quantitatively by two hybrid systems and surface plasmon resonance approaches. presented here is an alternative approach that can enable the understanding of complex interaction ...201222688774
generation and characterization of monoclonal antibodies specific for vaccinia virus.monoclonal antibodies to specific vaccinia virus (vacv) proteins are valuable reagents in studies of vacv. in this chapter, we describe methods of generating a panel of monoclonal antibodies that recognize a variety of vacv proteins in their native conformation in infected cells. the antibodies thus generated recognize mostly vacv proteins that are involved in virion assembly or/and are major antigens in smallpox vaccine. these antibodies are useful for tracking distinct steps in virion assembly ...201222688770
analyzing cd8 t cells in mouse models of poxvirus infection.mouse models of immunology are frequently used to study host responses to poxviruses or poxvirus-based recombinant vaccines. in this context, the magnitude of cd8(+) t cell responses is often of interest. methods to evaluate cd8(+) t cell responses extend from those that rely on indirect measurement of effector function only, such as cytotoxicity assays, to those that only measure antiviral cd8(+) t cell numbers and not function, like peptide mhc tetramers. in this chapter, five methods are prov ...201222688769
measurements of vaccinia virus dissemination using whole body imaging: approaches for predicting of lethality in challenge models and testing of vaccines and antiviral treatments.preclinical evaluation of novel anti-smallpox vaccines and antiviral treatments often rely on mouse -challenge models using pathogenic vaccinia virus, such as western reserve (wr) strain or other orthopoxviruses. traditionally, efficacy of treatment is evaluated using various readouts, such as lethality (rare), measurements of body weight loss, pox lesion scoring, and determination of viral loads in internal organs by enumerating plaques in sensitive cell lines. these methodologies provide valua ...201222688767
an intradermal model for vaccinia virus pathogenesis in mice.intradermal injection of vaccinia virus in the ear pinnae of mice provides a model of dermal infection and vaccination. the key features of this model are the appearance of a lesion on the surface of the ear that can be measured as a clinical sign of disease and substantial growth of virus in the infected skin in the absence of systemic spread. in addition, infected ears can be easily removed to allow virological, histological, and cellular analyses. finally, evaluation of the roles of virus (an ...201222688766
imaging of vaccinia virus entry into hela cells.the recently developed technique of live cell imaging has found numerous applications, including the detection of virus movements in living cells. to monitor virus motility, viruses or cellular proteins are fused with fluorescence markers and then detected by time-lapse fluorescence microscopy. these techniques allow kinetic analyses of individual virus particles in motion during the virus entry process as well as monitoring of dynamic interactions between viruses and cellular structures in real ...201222688764
screening for vaccinia virus egress inhibitors: separation of imv, iev, and eev.concerns about the possible use of variola virus as a biological weapon as well as the need for therapeutics for the treatment or prevention of naturally acquired poxvirus infections or vaccination complications have led to the search for small molecule inhibitors of poxvirus replication. one unique and attractive target for antiviral development is viral egress. part of understanding the mechanism of action of viral egress inhibitors involves determining which virion form is being made. this ca ...201222688763
genetic manipulation of poxviruses using bacterial artificial chromosome recombineering.traditional methods for genetic manipulation of poxviruses rely on low-frequency natural recombination in virus-infected cells. although these powerful systems represent the technical foundation of current knowledge and applications of poxviruses, they require long (≥ 500 bp) flanking sequences for homologous recombination, an efficient viral selection method, and burdensome, time-consuming plaque purification. the beginning of the twenty-first century has seen the application of bacterial artif ...201222688760
working safely with vaccinia virus: laboratory technique and review of published cases of accidental laboratory infections.vaccinia virus (vacv), the prototype orthopoxvirus, is widely used in the laboratory as a model system to study various aspects of viral biology and virus-host interactions, as a protein expression system, as a vaccine vector, and as an oncolytic agent. the ubiquitous use of vacvs in the laboratory raises certain safety concerns because the virus can be a pathogen in individuals with immunological and dermatological abnormalities, and on occasion can cause serious problems in normal hosts. this ...201222688758
vaccinia virus infection suppresses the cell microrna machinery.micrornas are key players in the regulation of gene expression by posttranscriptional suppression. they are involved in physiological processes, and thus their deregulation may contribute to the development of diseases and progression of cancer. virus-encoded micrornas and micrornas of host origin play an important role in controlling the virus life cycle and immunity. the aim of this study was to determine the effect of vaccinia virus (vacv) infection on the expression of host-encoded micrornas ...201222674341
novel amphiphilic compounds effectively inactivate the vaccinia virus.recent studies demonstrated the ability of artificial ribonucleases (arnases, small organic rna cleaving compounds) to inactivate rna-viruses via the synergetic effect of viral rna cleavage and disruption of viral envelope [1,2]. herein, we describe the antiviral activity of arnases against dna-containing vaccinia virus: screening of arnases of various structures revealed that amphiphilic compounds built of positively charged 1,4-diazabicyclo[2.2.2] octane substituted at the bridge nitrogen atom ...201222673577
genome-wide genetic associations with ifnγ response to smallpox vaccine.smallpox is a deadly and debilitating disease that killed hundreds of millions of people in the past century alone. the use of vaccinia virus-based smallpox vaccines led to the eradication of smallpox. these vaccines are remarkably effective, inducing the characteristic pustule or "take" at the vaccine site in >97 % of recipients, and inducing a wide spectrum of long-lasting humoral and cellular immune responses. the mechanisms behind inter-individual vaccine-response variability are likely to i ...201222661280
designing around patents with an immunotherapy case: a take-home message of a full court decision by the us federal circuit.in tivo inc. v. echostar corp case (2010), all judges of the us court of appeals for the federal circuit (cafc) reemphasized that legitimate design around a competitor's patents is always encouraged as a route of innovation. the modified elements of the design-around must be evaluated against the asserted claim(s) to ensure that each limitation is met before concluding that the modification is not substantially different from the previously adjudged infringed product. regarding the significance ...201222634445
structural and biochemical characterization of the vaccinia virus envelope protein d8 and its recognition by the antibody la5.smallpox vaccine is considered a gold standard of vaccines, as it is the only one that has led to the complete eradication of an infectious disease from the human population. b cell responses are critical for the protective immunity induced by the vaccine, yet their targeted epitopes recognized in humans remain poorly described. here we describe the biochemical and structural characterization of one of the immunodominant vaccinia virus (vacv) antigens, d8, and its binding to the monoclonal antib ...201222623786
increased interaction between vaccinia virus proteins a33 and b5 is detrimental to infectious extracellular enveloped virion production.two mechanisms exist for the incorporation of b5 into extracellular virions, one of which is dependent on a33. in the companion to this paper (w. m. chan and b. m. ward, j. virol. 86:8210-8220, 2012), we show that the lumenal domain of a33 is sufficient for interaction with the coiled-coil domain of b5 and capable of directing b5-green fluorescent protein (gfp) into extracellular virions. here, we have created a panel of charge-to-alanine mutations in the lumenal domain of a33 to map the b5 inte ...201222623782
protein b5 is required on extracellular enveloped vaccinia virus for repulsion of superinfecting virions.vaccinia virus (vacv) spreads across cell monolayers fourfold faster than predicted from its replication kinetics. early after infection, infected cells repulse some superinfecting extracellular enveloped virus (eev) particles by the formation of actin tails from the cell surface, thereby causing accelerated spread to uninfected cells. this strategy requires the expression of two viral proteins, a33 and a36, on the surface of infected cells and upon contact with eev this complex induces actin po ...201222622330
preclinical evaluation of oncolytic vaccinia virus for therapy of canine soft tissue sarcoma.virotherapy using oncolytic vaccinia virus (vacv) strains is one promising new strategy for canine cancer therapy. in this study we describe the establishment of an in vivo model of canine soft tissue sarcoma (csts) using the new isolated cell line stsa-1 and the analysis of the virus-mediated oncolytic and immunological effects of two different lister vacv livp1.1.1 and glv-1h68 strains against csts. cell culture data demonstrated that both tested vacv strains efficiently infected and destroyed ...201222615950
genome-wide analysis of polymorphisms associated with cytokine responses in smallpox vaccine recipients.the role that genetics play in response to infection or disease is becoming increasingly clear as we learn more about immunogenetics and host-pathogen interactions. here we report a genome-wide analysis of the effects of host genetic variation on cytokine responses to vaccinia virus stimulation in smallpox vaccine recipients. our data show that vaccinia stimulation of immune individuals results in secretion of inflammatory and th1 cytokines. we identified multiple snps significantly associated w ...201222610502
position on donors and smallpox vaccine: a committee opinion.although there is presently no definitive evidence linking vaccinia virus transmission through reproductive cells, sart/asrm accordingly recommends that art practitioners consider deferring donors who have recently received smallpox vaccine or contracted symptomatic vaccinia virus infection through close contact with a vaccine recipient (until after the vaccine or infectious scab has spontaneously separated). good donor practice further suggests that donors who are not in good health, including ...201222537381
mhc class i antigen processing distinguishes endogenous antigens based on their translation from cellular vs. viral mrna.to better understand the generation of mhc class i-associated peptides, we used a model antigenic protein whose proteasome-mediated degradation is rapidly and reversibly controlled by shield-1, a cell-permeant drug. when expressed from a stably transfected gene, the efficiency of antigen presentation is ~2%, that is, one cell-surface mhc class i-peptide complex is generated for every 50 folded source proteins degraded upon shield-1 withdrawal. by contrast, when the same protein is expressed by v ...201222509014
integrin β1 mediates vaccinia virus entry through activation of pi3k/akt signaling.vaccinia virus has a broad range of infectivity in many cell lines and animals. although it is known that the vaccinia mature virus binds to cell surface glycosaminoglycans and extracellular matrix proteins, whether additional cellular receptors are required for virus entry remains unclear. our previous studies showed that the vaccinia mature virus enters through lipid rafts, suggesting the involvement of raft-associated cellular proteins. here we demonstrate that one lipid raft-associated prote ...201222496232
treating tumors with a vaccinia virus expressing ifnβ illustrates the complex relationships between oncolytic ability and immunogenicity.since previous work using a nonreplicating adenovirus-expressing mouse interferon-β (ad.mifnβ) showed promising preclinical activity, we postulated that a vector-expressing ifnβ at high levels that could also replicate would be even more beneficial. accordingly a replication competent, recombinant vaccinia viral vector-expressing mifnβ (vv.mifnβ) was tested. vv.mifnβ-induced antitumor responses in two syngeneic mouse flank models of lung cancer. although vv.mifnβ had equivalent in vivo efficacy ...201228160613
a novel high-throughput vaccinia virus neutralization assay and preexisting immunity in populations from different geographic regions in china.pre-existing immunity to vaccinia tian tan virus (vtt) resulting from a large vaccination campaign against smallpox prior to the early 1980s in china, has been a major issue for application of vtt-vector based vaccines. it is essential to establish a sensitive and high-throughput neutralization assay to understand the epidemiology of vaccinia-specific immunity in current populations in china.201222438922
molecular genetic and biochemical characterization of the vaccinia virus i3 protein, the replicative single-stranded dna binding protein.vaccinia virus, the prototypic poxvirus, efficiently and faithfully replicates its ∼200-kb dna genome within the cytoplasm of infected cells. this intracellular localization dictates that vaccinia virus encodes most, if not all, of its own dna replication machinery. included in the repertoire of viral replication proteins is the i3 protein, which binds to single-stranded dna (ssdna) with great specificity and stability and has been presumed to be the replicative ssdna binding protein (ssb). we s ...201222438556
cd27 stimulation promotes the frequency of il-7 receptor-expressing memory precursors and prevents il-12-mediated loss of cd8(+) t cell memory in the absence of cd4(+) t cell help.fully functional cd8(+) t cell memory is highly dependent upon cd4(+) t cell support. cd4(+) t cells play a critical role in inducing the expression of cd70, the ligand for cd27, on dendritic cells. in this study, we demonstrate that cd27 stimulation during primary cd8(+) t cell responses regulates the ability to mount secondary cd8(+) t cell responses. cd27 stimulation during vaccinia and dendritic cell immunization controls the expression of the il-7r (cd127), which has been shown to be necess ...201222422886
the amino terminus of the vaccinia virus e3 protein is necessary to inhibit the interferon response.vaccinia virus (vacv) encodes a multifunctional protein, e3l, that is necessary for interferon (ifn) resistance in cells in culture. interferon resistance has been mapped to the well-characterized carboxy terminus of e3l, which contains a conserved double-stranded rna binding domain. the amino terminus of e3l has a z-form nucleic acid binding domain, which has been shown to be dispensable for replication and ifn resistance in hela and rk13 cells; however, a virus expressing e3l deleted of the am ...201222419806
orthopoxvirus targets for the development of new antiviral agents.investments in the development of new drugs for orthopoxvirus infections have fostered new avenues of research, provided an improved understanding of orthopoxvirus biology and yielded new therapies that are currently progressing through clinical trials. these broad-based efforts have also resulted in the identification of new inhibitors of orthopoxvirus replication that target many different stages of viral replication cycle. this review will discuss progress in the development of new anti-poxvi ...201222406470
the myristate moiety and amino terminus of vaccinia virus l1 constitute a bipartite functional region needed for entry.vaccinia virus (vacv) l1 is a myristoylated envelope protein which is required for cell entry and the fusion of infected cells. l1 associates with members of the entry-fusion complex (efc), but its specific role in entry has not been delineated. we recently demonstrated (foo ch, et al., virology 385:368-382, 2009) that soluble l1 binds to cells and blocks entry, suggesting that l1 serves as the receptor-binding protein for entry. our goal is to identify the structural domains of l1 which are ess ...201222398293
vaccinia virus a6 is essential for virion membrane biogenesis and localization of virion membrane proteins to sites of virion assembly.poxvirus acquires its primary envelope through a process that is distinct from those of other enveloped viruses. the molecular mechanism of this process is poorly understood, but several poxvirus proteins essential for the process have been identified in studies of vaccinia virus (vacv), the prototypical poxvirus. previously, we identified vacv a6 as an essential factor for virion morphogenesis by studying a temperature-sensitive mutant with a lesion in a6. here, we further studied a6 by constru ...201222398288
skin infection generates non-migratory memory cd8+ t(rm) cells providing global skin immunity.protective t-cell memory has long been thought to reside in blood and lymph nodes, but recently the concept of immune memory in peripheral tissues mediated by resident memory t (t(rm)) cells has been proposed. here we show in mice that localized vaccinia virus (vacv) skin infection generates long-lived non-recirculating cd8(+) skin t(rm) cells that reside within the entire skin. these skin t(rm) cells are potent effector cells, and are superior to circulating central memory t (t(cm)) cells at pr ...201222388819
preferential replication of systemically delivered oncolytic vaccinia virus in focally irradiated glioma xenografts.radiotherapy is part of the standard of care in high-grade gliomas but its outcomes remain poor. integrating oncolytic viruses with standard anticancer therapies is an area of active investigation. the aim of this study was to determine how tumor-targeted ionizing radiation (ir) could be combined with systemically delivered oncolytic vaccinia virus.201222379115
validation of an immunoperoxidase monolayer assay for total anti-vaccinia virus antibody titration.vaccinia virus (vacv) has been associated with zoonotic exanthemic outbreaks affecting bovids and human beings, with significant public health and economic impacts. rapid and reliable diagnostic methods are needed to detect and epidemiologically monitor antibodies to vacv. the current study describes the development of an immunoperoxidase monolayer assay (ipma) for detection of total vacv antibodies in bovine serum. the assay was validated by comparison with a plaque reduction neutralization tes ...201222379052
the lipid raft-associated protein cd98 is required for vaccinia virus endocytosis.mature vaccinia virus (vaccinia mv) infects a broad range of animals in vivo and cell cultures in vitro; however, the cellular receptors that determine vaccinia mv tropism and entry pathways are poorly characterized. here, we performed quantitative proteomic analyses of lipid raft-associated proteins upon vaccinia mv entry into hela cells. we found that a type ii membrane glycoprotein, cd98, is enriched in lipid rafts upon vaccinia mv infection compared to mock-infected hela cells. the knockdown ...201222345471
electrochemical differentiation of epitope-specific aptamers.dna aptamers are promising immunoshielding agents that could protect oncolytic viruses (ovs) from neutralizing antibodies (nabs) and increase the efficiency of cancer treatment. in the present article, we introduce a novel technology for electrochemical differentiation of epitope-specific aptamers (edea) without selecting aptamers against individual antigenic determinants. for this purpose, we selected dna aptamers that can bind noncovalently to an intact oncolytic virus, vaccinia virus (vacv), ...201222324738
disruption of tnf-α/tnfr1 function in resident skin cells impairs host immune response against cutaneous vaccinia virus infection.one strategy adopted by vaccinia virus (vv) to evade the host immune system is to encode homologs of tnf receptors (tnfrs) that block tnf-α function. the response to vv skin infection under conditions of tnf-α deficiency, however, has not been reported. we found that tnfr1-/- mice developed larger primary lesions, numerous satellite lesions, and higher skin virus levels after vv scarification. following their recovery, vv-scarified tnfr1-/- mice were fully protected against challenge with a leth ...201222318381
oncolytic virus and anti-4-1bb combination therapy elicits strong antitumor immunity against established cancer.oncolytic virotherapy using vaccinia virus (vv) has shown some encouraging antitumor responses in mouse models and patients, but the breadth of efficacy in clinical trials has been somewhat limited. given that antitumor effects have correlated with increased host immune responses, we hypothesized that improved therapeutic outcomes may be achieved by using oncolytic virus (ov) in combination with a potent immune agonist reagent. in this study, we carried out a preclinical evaluation of a genetica ...201222315352
viral infection triggers rapid differentiation of human blood monocytes into dendritic cells.surprisingly little is known about the interaction of human blood mononuclear cells with viruses. here, we show that monocytes are the predominant cell type infected when peripheral blood mononuclear cells are exposed to viruses ex vivo. remarkably, infection with vesicular stomatitis virus, vaccinia virus, and a variety of influenza a viruses (including circulating swine-origin virus) induces monocytes to differentiate within 18 hours into cd16(-)cd83(+) mature dendritic cells with enhanced cap ...201222310910
aptamer-based viability impedimetric sensor for viruses.the development of aptamer-based viability impedimetric sensor for viruses (aptavisens-v) is presented. highly specific dna aptamers to intact vaccinia virus were selected using cell-selex technique and integrated into impedimetric sensors via self-assembly onto a gold microelectrode. remarkably, this aptasensor is highly selective and can successfully detect viable vaccinia virus particles (down to 60 virions in a microliter) and distinguish them from nonviable viruses in a label-free electroch ...201222303883
role of metalloproteases in vaccinia virus epitope processing for transporter associated with antigen processing (tap)-independent human leukocyte antigen (hla)-b7 class i antigen presentation.the transporter associated with antigen processing (tap) translocates the viral proteolytic peptides generated by the proteasome and other proteases in the cytosol to the endoplasmic reticulum lumen. there, they complex with nascent human leukocyte antigen (hla) class i molecules, which are subsequently recognized by the cd8(+) lymphocyte cellular response. however, individuals with nonfunctional tap complexes or tumor or infected cells with blocked tap molecules are able to present hla class i ...201222298786
eczema vaccinatum.eczema vaccinatum (ev) is a complication of smallpox vaccination that can occur in persons with eczema/atopic dermatitis (ad), in which vaccinia virus disseminates to cause an extensive rash and systemic illness. because persons with eczema are deferred from vaccination, only a single, accidentally transmitted case of ev has been described in the medical literature since military vaccination was resumed in the united states in 2002. to enhance understanding of ev, we review its history during th ...201222291103
susceptibility to vaccinia virus infection and spread in mice is determined by age at infection, allergen sensitization and mast cell status.patients, especially young children, with atopic dermatitis are at an increased risk of developing eczema vaccinatum, a severe reaction to the smallpox vaccine, either through direct vaccination or indirect contact with a person recently vaccinated.201222286752
recruitment of host translation initiation factor eif4g by the vaccinia virus ssdna-binding protein i3.poxviruses are large double-stranded dna viruses that replicate exclusively in the cytoplasm of infected cells within discrete compartments termed viral factories. recent work has shown that the prototypical poxvirus, vaccinia virus (vacv) sequesters components of the eukaryotic translation initiation complex eif4f within viral factories while also stimulating formation of eif4f complexes. however, the forces that govern these events remain unknown. here, we show that maximal eif4f formation req ...201222280895
glomulin: a permissivity factor for vaccinia virus infection.in earlier studies we provided evidence that vaccinia virus (vacv) phosphorylation-activation of host cell signaling effectors is critical for subsequent viral replication. in this report, using mass spectrometry-based proteomics, we have identified 387 host cell proteins that co-immunoprecipitate with vacv in infected, permissive pm1.ccr5 human t cells. among these, glomulin was distinguishable based on its known interaction with a tyrosine kinase receptor, c-met, its ability to become tyrosine ...201222280104
vaccinia mature virus fusion regulator a26 protein binds to a16 and g9 proteins of the viral entry fusion complex and dissociates from mature virions at low ph.vaccinia mature virus enters cells through either endocytosis or plasma membrane fusion, depending on virus strain and cell type. our previous results showed that vaccinia virus mature virions containing viral a26 protein enter hela cells preferentially through endocytosis, whereas mature virions lacking a26 protein enter through plasma membrane fusion, leading us to propose that a26 acts as an acid-sensitive fusion suppressor for mature virus (s. j. chang, y. x. chang, r. izmailyan r, y. l. tan ...201222278246
ox40 ligand and programmed cell death 1 ligand 2 expression on inflammatory dendritic cells regulates cd4 t cell cytokine production in the lung during viral disease.cd4 th differentiation is influenced by costimulatory molecules expressed on conventional dendritic cells (dcs) in regional lymph nodes and results in specific patterns of cytokine production. however, the function of costimulatory molecules on inflammatory (cd11b(+)) dcs in the lung during recall responses is not fully understood, but it is important for development of novel interventions to limit immunopathological responses to infection. using a mouse model in which vaccination with vaccinia ...201222266281
vaccinia virus zoonotic infection, são paulo state, brazil. 201222260819
chemotherapy enhances cd8(+) t cell-mediated antitumor immunity induced by vaccination with vaccinia virus.the use of immunotherapy or chemotherapy alone is generally ineffective against well-established tumors. to overcome this intrinsic resistance against therapy for tumors, we have attempted to combine immunotherapy with chemotherapy. in this study, we tried to induce a rapid antitumor effect via chemoimmunotherapy using a vaccinia viral vaccine as an immunotherapeutic agent with anticancer agents including epigallocatechin-3-gallate (egcg) and conventional anticancer drugs. although a combination ...200728182877
effect of serum type and concentration on the expression ofβ-galactosidase in recombinant vaccinia virus infected hela s3 cells.the effect of serum type and concentration on recombinant protein expression in vaccinia virus infected hela s3 cells was studied in both static and suspension culture. a model heterologous protein,β-galactosidase (β-gal), was used. calf and horse sera in the range of 0.5-10%(v/v) were investigated. in static culture, the calf serum concentration did not show any significant influence on the β-gal production which was almost completed within 24h postinfection (pi). higher horse serum concentrati ...199522359015
vaccinia virus expression vector: a new tool for immunologists.advances in genetic engineering have made it possible to use animal viruses as vectors for expression of unrelatedgenes(1). small dna viruses, such as sv40 and adenovirus, provide powerful tools for molecular biologists interested in studying the regulation of gene expression in eukaryotic cells. the more recent development of large dna viruses, such as vaccinia virus(2-4) and herpes simplex virus(5), as vectors may prove equally valuablefor immunological studies. these large viruses can express ...198525290368
[effect of antibiotic virusin 1609 on vaccinia virus and taylor's virus]. 201424544539
vaccination, vaccinia virus and vaccine lymph. 195024538092
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