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combination of fractionated irradiation with anti-vegf expressing vaccinia virus therapy enhances tumor control by simultaneous radiosensitization of tumor associated endothelium.oncolytic viruses are currently in clinical trials for a variety of tumors, including high grade gliomas. a characteristic feature of high grade gliomas is their high vascularity and treatment approaches targeting tumor endothelium are under investigation, including bevacizumab. the aim of this study was to improve oncolytic viral therapy by combining it with ionizing radiation and to radiosensitize tumor vasculature through a viral encoded anti-angiogenic payload. here, we show how vaccinia vir ...201323729266
c3a receptor promotes viral containment in mice inoculated with vaccinia virus at sites of allergic skin inflammation. 201323684067
analysis of the role of vaccinia virus h7 in virion membrane biogenesis with an h7-deletion mutant.essential vaccinia virus genes are often studied with conditional-lethal inducible mutants. here, we constructed a deletion mutant lacking the essential h7r gene (the δh7 mutant) with an h7-expressing cell line. compared to an inducible h7 mutant, the δh7 mutant showed a defect at an earlier step of virion membrane biogenesis, before the development of short crescent-shaped precursors of the viral envelope. our studies refine the role of h7 in virion membrane biogenesis and highlight the values ...201323678177
association of the vaccinia virus a11 protein with the endoplasmic reticulum and crescent precursors of immature virions.the apparent de novo formation of viral membranes within cytoplasmic factories is a mysterious, poorly understood first step in poxvirus morphogenesis. genetic studies identified several viral proteins essential for membrane formation and the assembly of immature virus particles. their repression results in abortive replication with the accumulation of dense masses of viroplasm. in the present study, we further characterized one of these proteins, a11, and investigated its association with cellu ...201323864611
phylogenetic and histological variation in avipoxviruses isolated in south africa.thirteen novel avipoxviruses were isolated from birds from different regions of south africa. these viruses could be divided into six groups, according to gross pathology and pock appearance on chick chorioallantoic membranes (cams). histopathology revealed distinct differences in epidermal and mesodermal cell proliferation, as well as immune cell infiltration, caused by the different avipoxviruses, even within groups of viruses causing similar cam gross pathology. in order to determine the gene ...201323860490
[analysis on status and characteristics of laboratory-acquired vaccinia virus infections cases].by analyzing the status and characteristics of vaccinia virus laboratory-acquired infections in the bibliographical information, this paper provides relevant recommendations and measures for prevention and control of vaccinia virus laboratory-acquired infections in china.201323855138
enveloped virus labeling via both intrinsic biosynthesis and metabolic incorporation of phospholipids in host cells.an alternative method for labeling fully replicative enveloped viruses was developed, in which both the biosynthesis and metabolic incorporation of phospholipids in host cells were simultaneously utilized to introduce an azide group to the envelope of the vaccinia virus by taking advantage of the host-derived lipid membrane formation mechanism. such an azide group could be subsequently used to fluorescently label the envelope of the virus via a bioorthogonal reaction. furthermore, simultaneous d ...201323600895
anatomically restricted synergistic antiviral activities of innate and adaptive immune cells in the skin.despite extensive ex vivo investigation, the spatiotemporal organization of immune cells interacting with virus-infected cells in tissues remains uncertain. to address this, we used intravital multiphoton microscopy to visualize immune cell interactions with virus-infected cells following epicutaneous vaccinia virus (vv) infection of mice. vv infects keratinocytes in epidermal foci and numerous migratory dermal inflammatory monocytes that outlie the foci. we observed ly6g(+) innate immune cells ...201323414756
getting in front and behind the enemy lines to counter virus infection.how immune cells collaborate to clear a virus from the skin is not well understood. in this issue of cell host & microbe,hickman et al. (2013) show that spatially segregated ly6g(+) monocytes and cd8(+) t cells act synergistically to clear vaccinia virus from a primary skin infection.201323414751
vaccinia virus-mediated melanin production allows mr and optoacoustic deep tissue imaging and laser-induced thermotherapy of cancer.we reported earlier the delivery of antiangiogenic single chain antibodies by using oncolytic vaccinia virus strains to enhance their therapeutic efficacy. here, we provide evidence that gene-evoked production of melanin can be used as a therapeutic and diagnostic mediator, as exemplified by insertion of only one or two genes into the genome of an oncolytic vaccinia virus strain. we found that produced melanin is an excellent reporter for optical imaging without addition of substrate. melanin pr ...201323401518
oncolytic and immunotherapeutic vaccinia induces antibody-mediated complement-dependent cancer cell lysis in humans.oncolytic viruses cause direct cytolysis and cancer-specific immunity in preclinical models. the goal of this study was to demonstrate induction of functional anticancer immunity that can lyse target cancer cells in humans. pexa-vec (pexastimogene devacirepvec; jx-594) is a targeted oncolytic and immunotherapeutic vaccinia virus engineered to express human granulocyte-macrophage colony-stimulating factor (gm-csf). pexa-vec demonstrated replication, gm-csf expression, and tumor responses in previ ...201323677592
cd4+ t cells provide intermolecular help to generate robust antibody responses in vaccinia virus-vaccinated humans.immunization with vaccinia virus elicits a protective ab response that is almost completely cd4(+) t cell dependent. a recent study in a rodent model observed a deterministic linkage between ab and cd4(+) t cell responses to particular vaccinia virus proteins suggesting that cd4(+) t cell help is preferentially provided to b cells with the same protein specificity (sette et al. 2008. immunity 28: 847-858). however, a causal linkage between ab and cd4(+) t cell responses to vaccinia or any other ...201323667112
high viral burden restricts short-lived effector cell number at late times postinfection through increased natural regulatory t cell expansion.generating and maintaining a robust cd8(+) t cell response in the face of high viral burden is vital for host survival. further, balancing the differentiation of effectors along the memory precursor effector cell pathway versus the short-lived effector cell (slec) pathway may be critical in controlling the outcome of virus infection with regard to clearance and establishing protection. although recent studies have identified several factors that have the capacity to regulate effector cd8(+) t ce ...201323589620
a rationally designed a34r mutant oncolytic poxvirus: improved efficacy in peritoneal carcinomatosis.oncolytic poxviruses have demonstrated initial promising results in patients with cancer in clinical trials, yet further improvements are needed. it has been shown that a single point mutation in the a34r gene resulted in the production of more total progeny virus and more extracellular enveloped virus (eev), a form that can be immune-evasive and with enhanced spread. we have genetically engineered a new oncolytic poxvirus (designated va34r) by incorporating this mutated a34r gene into a viral b ...201323439499
immunotherapy: oncolytic vaccinia virus shows promise in liver cancer. 201323438758
small cell ovarian carcinoma: genomic stability and responsiveness to therapeutics.the biology of small cell ovarian carcinoma of the hypercalcemic type (sccoht), which is a rare and aggressive form of ovarian cancer, is poorly understood. tumourigenicity, in vitro growth characteristics, genetic and genomic anomalies, and sensitivity to standard and novel chemotherapeutic treatments were investigated in the unique sccoht cell line, bin-67, to provide further insight in the biology of this rare type of ovarian cancer.201323433318
reflections on the early development of poxvirus vectors.poxvirus expression vectors were described in 1982 and quickly became widely used for vaccine development as well as research in numerous fields. advantages of the vectors include simple construction, ability to accommodate large amounts of foreign dna and high expression levels. numerous poxvirus-based veterinary vaccines are currently in use and many others are in human clinical trials. the early reports of poxvirus vectors paved the way for and stimulated the development of other viral vector ...201323583893
extracts from rabbit skin inflamed by the vaccinia virus attenuate bupivacaine-induced spinal neurotoxicity in pregnant rats.extracts from rabbit skin inflamed by the vaccinia virus can relieve pain and promote repair of nerve injury. the present study intraperitoneally injected extracts from rabbit skin inflamed by the vaccinia virus for 3 and 4 days prior to and following intrathecal injection of bupivacaine into pregnant rats. the pain threshold test after bupivacaine injection showed that the maximum possible effect of tail-flick latency peaked 1 day after intrathecal injection of bupivacaine in the extract-pretre ...201325206391
vaccinia virus protein k7 is a virulence factor that alters the acute immune response to infection.vaccinia virus (vacv) encodes many proteins that antagonize the innate immune system including a family of intracellular proteins with a b-cell lymphoma (bcl)-2-like structure. one of these bcl-2 proteins called k7 binds toll-like receptor-adaptor proteins and the dead-box rna helicase ddx3 and thereby inhibits the activation of nf-κb and interferon regulatory factor 3. however, the contribution of k7 to virus virulence is not known. here a vacv lacking the k7r gene (vδk7) was constructed and co ...201323580427
unintentional transfer of vaccinia virus associated with smallpox vaccines: acam2000(®) compared with dryvax(®).routine vaccination against smallpox (variola) ceased in the us in 1976. however, in 2002 limited coverage for military personnel and some healthcare workers was reinstituted. in march 2008, acam2000® replaced dryvax® as the vaccine used in the united states against smallpox. unintentional transfer of vaccinia virus from a vaccination site by autoinoculation or contact transmission, can have significant public health implications. we summarize unintentional virus transfer aes associated with aca ...201323571177
a36-dependent actin filament nucleation promotes release of vaccinia virus.cell-to-cell transmission of vaccinia virus can be mediated by enveloped virions that remain attached to the outer surface of the cell or those released into the medium. during egress, the outer membrane of the double-enveloped virus fuses with the plasma membrane leaving extracellular virus attached to the cell surface via viral envelope proteins. here we report that f-actin nucleation by the viral protein a36 promotes the disengagement of virus attachment and release of enveloped virus. cells ...201323555252
rational engineering of recombinant picornavirus capsids to produce safe, protective vaccine antigen.foot-and-mouth disease remains a major plague of livestock and outbreaks are often economically catastrophic. current inactivated virus vaccines require expensive high containment facilities for their production and maintenance of a cold-chain for their activity. we have addressed both of these major drawbacks. firstly we have developed methods to efficiently express recombinant empty capsids. expression constructs aimed at lowering the levels and activity of the viral protease required for the ...201323544011
discovering naturally processed antigenic determinants that confer protective t cell immunity.cd8+ t cells (tcd8) confer protective immunity against many infectious diseases, suggesting that microbial tcd8 determinants are promising vaccine targets. nevertheless, current t cell antigen identification approaches do not discern which epitopes drive protective immunity during active infection - information that is critical for the rational design of tcd8-targeted vaccines. we employed a proteomics-based approach for large-scale discovery of naturally processed determinants derived from a co ...201323543059
design of potent poxvirus inhibitors of the heterodimeric processivity factor required for viral replication.smallpox constitutes a major bioterrorism threat, which underscores the need to develop antiviral drugs for rapid response in the event of an attack. viral processivity factors are attractive drug targets in being both specific and essential for their cognate dna polymerases to synthesize extended strands of dna. an in silico model of the vacinnia virus processivity factor, comprised of the a20 and d4 heterocomplex, was constructed and used for lead optimization of an indole-based scaffold ident ...201323527789
crystallization and preliminary x-ray diffraction analysis of three recombinant mutants of vaccinia virus uracil dna glycosylase.amino-acid residues located at a highly flexible area in the uracil dna glycosylase of vaccinia virus were mutated. in the crystal structure of wild-type d4 these residues lie at the dimer interface. specifically, three mutants were generated: (i) residue arg167 was replaced with an alanine (r167ad4), (ii) residues glu171, ser172 and pro173 were substituted with three glycine residues (3gd4) and (iii) residues glu171 and ser172 were deleted (δ171-172d4). mutant proteins were expressed, purified ...201323519808
domain-level rocking motion within a polymerase that translocates on single-stranded nucleic acid.vaccinia virus poly(a) polymerase (vp55) is the only known polymerase that can translocate independently with respect to single-stranded nucleic acid (ssna). previously, its structure has only been solved in the context of the vp39 processivity factor. here, a crystal structure of unliganded monomeric vp55 has been solved to 2.86 å resolution, showing the first backbone structural isoforms among either vp55 or its processivity factor (vp39). backbone differences between the two molecules of vp55 ...201323519670
protective effect of surfactant protein d in pulmonary vaccinia virus infection: implication of a27 viral protein.vaccinia virus (vacv) was used as a surrogate of variola virus (varv) (genus orthopoxvirus), the causative agent of smallpox, to study orthopoxvirus infection. varv is principally transmitted between humans by aerosol droplets. once inhaled, varv first infects the respiratory tract where it could encounter surfactant components, such as soluble pattern recognition receptors. surfactant protein d (sp-d), constitutively present in the lining fluids of the respiratory tract, plays important roles i ...201323518578
targeting cxcl12/cxcr4 signaling with oncolytic virotherapy disrupts tumor vasculature and inhibits breast cancer metastases.oncolytic viruses hold promise for the treatment of cancer, but their interaction with the tumor microenvironment needs to be elucidated for optimal tumor cell killing. because the cxcr4 receptor for the stromal cell-derived factor-1 (sdf-1/cxcl12) chemokine is one of the key stimuli involved in signaling interactions between tumor cells and their stromal microenvironment, we used oncolytic virotherapy with a cxcr4 antagonist to target the cxcl12/cxcr4 signaling axis in a triple-negative 4t1 bre ...201323509246
vaccinia virus glv-1h153 is a novel agent for detection and effective local control of positive surgical margins for breast cancer.surgery is currently the definitive treatment for early-stage breast cancer. however, the rate of positive surgical margins remains unacceptably high. the human sodium iodide symporter (hnis) is a naturally occurring protein in human thyroid tissue, which enables cells to concentrate radionuclides. the hnis has been exploited to image and treat thyroid cancer. we therefore investigated the potential of a novel oncolytic vaccinia virus glv1h-153 engineered to express the hnis gene for identifying ...201323506710
biochemical and biophysical properties of a putative hub protein expressed by vaccinia virus.h5 is a constitutively expressed, phosphorylated vaccinia virus protein that has been implicated in viral dna replication, post-replicative gene expression, and virus assembly. for the purpose of understanding the role of h5 in vaccinia biology, we have characterized its biochemical and biophysical properties. previously, we have demonstrated that h5 is associated with an endoribonucleolytic activity. in this study, we have shown that this cleavage results in a 3'-oh end suitable for polyadenyla ...201323476017
effects of postchallenge administration of st-246 on dissemination of ihd-j-luc vaccinia virus in normal mice and in immune-deficient mice reconstituted with t cells.whole-body bioimaging was used to study dissemination of vaccinia virus (vacv) in normal and in immune deficient (nu(-)/nu(-)) mice protected from lethality by postchallenge administration of st-246. total fluxes were recorded in the liver, spleen, lungs, and nasal cavities of live mice after intranasal infection with a recombinant ihd-j-luc vacv expressing luciferase. areas under the flux curve were calculated for individual mice to assess viral loads. treatment for 2 to 5 days of normal balb/c ...201323468500
emergence of cowpox: study of the virulence of clinical strains and evaluation of antivirals.the last years, cowpox infections are being increasingly reported through eurasia. cowpox viruses (cpxvs) have been reported to have different genotypes and may be subdivided in at least five genetically distinct monophyletic clusters. however, little is known about their in vitro and in vivo features. in this report, five genetically diverse cpxvs, including one reference strain (cpxv strain brighton) and four clinical isolates from human and animal cases, were compared with regard to growth in ...201323457480
secondary and tertiary transmission of vaccinia virus after sexual contact with a smallpox vaccinee--san diego, california, 2012.on june 24, 2012, cdc notified public health services, county of san diego health and human services agency, of a suspected case of vaccinia virus infection transmitted by sexual contact. the case had been reported to cdc by an infectious disease specialist who had requested vaccinia immune globulin intravenous (vigiv) (cangene corporation, berwyn, pennsylvania) for a patient with lesions suspicious for vaccinia. the patient reported two recent sexual contacts: one with a partner who recently ha ...201323446513
imaging of intratumoral inflammation during oncolytic virotherapy of tumors by 19f-magnetic resonance imaging (mri).oncolytic virotherapy of tumors is an up-coming, promising therapeutic modality of cancer therapy. unfortunately, non-invasive techniques to evaluate the inflammatory host response to treatment are rare. here, we evaluate (19)f magnetic resonance imaging (mri) which enables the non-invasive visualization of inflammatory processes in pathological conditions by the use of perfluorocarbon nanoemulsions (pfc) for monitoring of oncolytic virotherapy.201323441176
randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia jx-594 in liver cancer.oncolytic viruses and active immunotherapeutics have complementary mechanisms of action (moa) that are both self amplifying in tumors, yet the impact of dose on subject outcome is unclear. jx-594 (pexa-vec) is an oncolytic and immunotherapeutic vaccinia virus. to determine the optimal jx-594 dose in subjects with advanced hepatocellular carcinoma (hcc), we conducted a randomized phase 2 dose-finding trial (n=30). radiologists infused low- or high-dose jx-594 into liver tumors (days 1, 15 and 29) ...201323396206
oncolytic vaccinia virus disrupts tumor-associated vasculature in humans.efforts to selectively target and disrupt established tumor vasculature have largely failed to date. we hypothesized that a vaccinia virus engineered to target cells with activation of the ras/mapk signaling pathway (jx-594) could specifically infect and express transgenes (hgm-csf, β-galactosidase) in tumor-associated vascular endothelial cells in humans. efficient replication and transgene expression in normal human endothelial cells in vitro required either vegf or fgf-2 stimulation. intraven ...201323393196
deletion of immunomodulator c6 from vaccinia virus strain western reserve enhances virus immunogenicity and vaccine efficacy.vectors based on vaccinia virus (vacv), the vaccine used to eradicate smallpox, are currently popular candidates for the vaccination against numerous infectious diseases including malaria and aids. although vacv induces robust cellular and humoral responses, enhancing the safety and efficacy of these vectors remains an important area of research. here, we describe the enhanced immunogenicity of a recombinant vacv western reserve (wr) strain lacking the immunomodulatory protein c6 (vδc6). intrade ...201323288427
[oncolytic properties of some orthopoxviruses, adenoviruses and parvoviruses in human glioma cells].currently one of the most promising approaches in development of cancer virotherapy is based on the ability of oncolytic viruses to selective infection and lysis of tumor cells.201324741936
cd4 and cd8 t cells participate in the immune memory response against vaccinia virus after a previous natural infection.the present study evaluates the immune response of memory cd4(+) and cd8(+) t cells from patients following a natural vaccinia virus (vacv) infection. a total of 42 individuals were involved in the study being: 22 previously infected individuals (vaccinated or not against smallpox) and 20 non-infected individuals (vaccinated or not). a short-term in vitro stimulation with uv-inactivated vacv of whole blood cells was performed. our study showed that previously infected individuals have a lower pe ...201324600565
transport and stability of the vaccinia virus a34 protein is affected by the a33 protein.vaccinia virus (vacv) has two infectious forms called intracellular mature virus and extracellular enveloped virus (eev). two of the seven viral proteins in the eev outer envelope, a33 and a34, are type ii membrane glycoproteins that each interact with another eev protein called b5; however, evidence for direct a33-a34 interaction is lacking. the localization and stability of a34 is affected by b5 and here data are presented showing that a34 is also affected by a33. in the absence of a33, just a ...201323255618
the effects of post-exposure smallpox vaccination on clinical disease presentation: addressing the data gaps between historical epidemiology and modern surrogate model data.decades after public health interventions - including pre- and post-exposure vaccination - were used to eradicate smallpox, zoonotic orthopoxvirus outbreaks and the potential threat of a release of variola virus remain public health concerns. routine prophylactic smallpox vaccination of the public ceased worldwide in 1980, and the adverse event rate associated with the currently licensed live vaccinia virus vaccine makes reinstatement of policies recommending routine pre-exposure vaccination unl ...201323994378
crystal structure of vaccinia viral a27 protein reveals a novel structure critical for its function and complex formation with a26 protein.vaccinia virus envelope protein a27 has multiple functions and is conserved in the orthopoxvirus genus of the poxvirus family. a27 protein binds to cell surface heparan sulfate, provides an anchor for a26 protein packaging into mature virions, and is essential for egress of mature virus (mv) from infected cells. here, we crystallized and determined the structure of a truncated form of a27 containing amino acids 21-84, c71/72a (ta27) at 2.2 å resolution. ta27 protein uses the n-terminal region in ...201323990784
cascade regulation of vaccinia virus gene expression is modulated by multistage promoters.vaccinia virus contains ~200 genes classified temporally as early, intermediate or late. we analyzed 53 intermediate promoters to determine whether any have dual late promoter activity. our strategy involved (i) construction of a cell line that stably expressed the three late transcription factors, (ii) infection with a vaccinia virus mutant that expresses rna polymerase but neither intermediate nor late transcription factors, and (iii) transfection with plasmids containing a luciferase reporter ...201324210117
forensic proteomics of poxvirus production.the field of microbial forensics has recently sought to develop methods to discern biological signatures to indicate production methods for biological agents. viral agents have received less attention to date. their obligate propagation in living cells makes purification from cellular material a challenge. this leads to potential carryover of protein-rich signatures of their production system. here we have explored a proteomic analysis of vaccinia virus as a model poxvirus system in which to com ...201323979794
vaccinia virus immune evasion: mechanisms, virulence and immunogenicity.virus infection of mammalian cells is sensed by pattern recognition receptors and leads to an innate immune response that restricts virus replication and induces adaptive immunity. in response, viruses have evolved many countermeasures that enable them to replicate and be transmitted to new hosts, despite the host innate immune response. poxviruses, such as vaccinia virus (vacv), have large dna genomes and encode many proteins that are dedicated to host immune evasion. some of these proteins are ...201323999164
new vaccinia virus promoter as a potential candidate for future vaccines.here we describe the design and strength of a new synthetic late-early optimized (leo) vaccinia virus (vacv) promoter used as a transcriptional regulator of gfp expression during modified vaccinia ankara infection. in contrast to the described synthetic vacv promoter (ps), leo induced significantly higher levels of gfp expression in vitro within the first hour after infection, which correlated with an enhancement in the gfp-specific cd8 t-cell response detected in vivo, demonstrating its potenti ...201324077296
the formin fhod1 and the small gtpase rac1 promote vaccinia virus actin-based motility.vaccinia virus dissemination relies on the n-wasp-arp2/3 pathway, which mediates actin tail formation underneath cell-associated extracellular viruses (cevs). here, we uncover a previously unappreciated role for the formin fhod1 and the small gtpase rac1 in vaccinia actin tail formation. fhod1 depletion decreased the number of cevs forming actin tails and impaired the elongation rate of the formed actin tails. recruitment of fhod1 to actin tails relied on its gtpase binding domain in addition to ...201324062339
silver nanoparticles inhibit vaccinia virus infection by preventing viral entry through a macropinocytosis-dependent mechanism.silver nanoparticles have been shown to inhibit viruses. however, very little is known about the mechanism of antiviral activity. this study tested the hypothesis that 25-nm silver nanoparticles inhibited vaccinia virus replication by preventing viral entry. plaque reduction, confocal microscopy, and beta-galactosidase reporter gene assays were used to examine viral attachment and entry in the presence and absence of silver nanoparticles. to explore the mechanism of inhibition, viral entry exper ...201323980510
barrier to autointegration factor (baf) inhibits vaccinia virus intermediate transcription in the absence of the viral b1 kinase.barrier to autointegration factor (baf/banf1) is a cellular dna-binding protein found in the nucleus and cytoplasm. cytoplasmic baf binds to foreign dna and can act as a defense against vaccinia dna replication. to evade baf, vaccinia expresses the b1 kinase, which phosphorylates baf and blocks its ability to bind dna. interestingly, b1 is also needed for viral intermediate gene expression via an unknown mechanism. therefore, we evaluated the impact of b1-baf signaling on vaccinia transcription. ...201323891157
vaccinia virus entry is followed by core activation and proteasome-mediated release of the immunomodulatory effector vh1 from lateral bodies.host cell entry of vaccinia virus, the prototypic poxvirus, involves a membrane fusion event delivering the viral core and two proteinaceous lateral bodies (lbs) into the cytosol. uncoating of viral cores is poorly characterized, and the composition and function of lbs remains enigmatic. we found that cytosolic cores rapidly dissociated from lbs and expanded in volume, which coincided with reduction of disulfide-bonded core proteins. we identified the abundant phosphoprotein f17, the dual-specif ...201323891003
optical detection and virotherapy of live metastatic tumor cells in body fluids with vaccinia strains.metastatic tumor cells in body fluids are important targets for treatment, and critical surrogate markers for evaluating cancer prognosis and therapeutic response. here we report, for the first time, that live metastatic tumor cells in blood samples from mice bearing human tumor xenografts and in blood and cerebrospinal fluid samples from patients with cancer were successfully detected using a tumor cell-specific recombinant vaccinia virus (vacv). in contrast to the fda-approved cellsearch syste ...201324019862
cd8 t cell memory to a viral pathogen requires trans cosignaling between hvem and btla.defining the molecular interactions required to program activated cd8 t cells to survive and become memory cells may allow us to understand how to augment anti-viral immunity. hvem (herpes virus entry mediator) is a member of the tumor necrosis factor receptor (tnfr) family that interacts with ligands in the tnf family, light and lymphotoxin-α, and in the ig family, b and t lymphocyte attenuator (btla) and cd160. the ig family members initiate inhibitory signaling when engaged with hvem, but may ...201324205056
direct formation of vaccinia virus membranes from the endoplasmic reticulum in the absence of the newly characterized l2-interacting protein a30.5.crescents consisting of a single lipoprotein membrane with an external protein scaffold comprise the initial structural elements of poxvirus morphogenesis. crescents enlarge to form spherical immature virions, which enclose viroplasm consisting of proteins destined to form the cores of mature virions. previous studies suggest that the l2 protein participates in the recruitment of endoplasmic reticulum (er)-derived membranes to form immature virions within assembly sites of cytoplasmic factories. ...201324027302
poxviral protein a52 stimulates p38 mitogen-activated protein kinase (mapk) activation by causing tumor necrosis factor receptor-associated factor 6 (traf6) self-association leading to transforming growth factor β-activated kinase 1 (tak1) recruitment.vaccinia virus encodes a number of proteins that inhibit and manipulate innate immune signaling pathways that also have a role in virulence. these include a52, a protein shown to inhibit il-1- and toll-like receptor-stimulated nfκb activation, via interaction with interleukin-1 receptor-associated kinase 2 (irak2). interestingly, a52 was also found to activate p38 mapk and thus enhance toll-like receptor-dependent il-10 induction, which was traf6-dependent, but the manner in which a52 manipulate ...201324114841
vaccinia virus in household environment during bovine vaccinia outbreak, brazil. 201324274787
reemergence of vaccinia virus during zoonotic outbreak, pará state, brazil.in 2010, vaccinia virus caused an outbreak of bovine vaccinia that affected dairy cattle and rural workers in pará state, brazil. genetic analyses identified the virus as distinct from bean58058 vaccinia virus (identified in 1960s) and from smallpox vaccine virus strains. these findings suggest spread of autochthonous group 1 vaccinia virus in this region.201324274374
proteomic, cellular, and network analyses reveal new dusp3 interactions with nucleolar proteins in hela cells.dusp3 (or vaccinia virus phosphatase vh1-related; vhr) is a small dual-specificity phosphatase known to dephosphorylate c-jun n-terminal kinases and extracellular signal-regulated kinases. in human cervical cancer cells, dusp3 is overexpressed, localizes preferentially to the nucleus, and plays a key role in cellular proliferation and senescence triggering. other dusp3 functions are still unknown, as illustrated by recent and unpublished results from our group showing that this enzyme mediates d ...201324245651
tracking viral genomes in host cells at single-molecule resolution.viral dna trafficking in cells has large impacts on physiology and disease development. current methods lack the resolution and accuracy to visualize and quantify viral dna trafficking at single-molecule resolution. we developed a noninvasive protocol for accurate quantification of viral dna-genome (vdna) trafficking in single cells. ethynyl-modified nucleosides were used to metabolically label newly synthesized adenovirus, herpes virus, and vaccinia virus vdna, without affecting infectivity. su ...201324139403
reliefseq: a gene-wise adaptive-k nearest-neighbor feature selection tool for finding gene-gene interactions and main effects in mrna-seq gene expression data.relief-f is a nonparametric, nearest-neighbor machine learning method that has been successfully used to identify relevant variables that may interact in complex multivariate models to explain phenotypic variation. while several tools have been developed for assessing differential expression in sequence-based transcriptomics, the detection of statistical interactions between transcripts has received less attention in the area of rna-seq analysis. we describe a new extension and assessment of rel ...201324339943
combination of virotherapy and t-cell therapy: arming oncolytic virus with t-cell engagers.while cure rates for several cancers have significantly improved, the outcome for patients with advanced solid tumors remains grimly unchanged over the last decades. thus, there is a need for new therapies that could improve outcome for patients who fail current therapies. oncolytic vaccinia virus (vv) would be an appealing addition to the current therapies of cancers because of its ability to infect, replicate in, and lyse tumor cells, and spread to other tumor cells in successive rounds of rep ...201324333405
transmission of vaccinia virus, possibly through sexual contact, to a woman at high risk for adverse complications.severe adverse events, including eczema vaccinatum (ev), can result after smallpox vaccination. persons at risk for ev include those with underlying dermatologic conditions, such as atopic dermatitis. we investigated a case of vaccinia infection, possibly acquired during sexual contact with a recently vaccinated military service member, in a female maryland resident with atopic dermatitis. the u.s. department of defense's vaccine healthcare centers network (vhcn) and the centers for disease cont ...201324306023
preventing postoperative metastatic disease by inhibiting surgery-induced dysfunction in natural killer cells.natural killer (nk) cell clearance of tumor cell emboli following surgery is thought to be vital in preventing postoperative metastases. using a mouse model of surgical stress, we transferred surgically stressed nk cells into nk-deficient mice and observed enhanced lung metastases in tumor-bearing mice as compared with mice that received untreated nk cells. these results establish that nk cells play a crucial role in mediating tumor clearance following surgery. surgery markedly reduced nk cell t ...201323090117
bovine vaccinia, a systemic infection: evidence of fecal shedding, viremia and detection in lymphoid organs.bovine vaccinia (bv) is a zoonosis caused by vaccinia virus (vacv) that affects dairy cattle and milkers, causing economic losses and impacting animal and human health. based on the clinical presentation, bv appears to be a localized disease, with lesions restricted to the skin of affected individuals. however, there are no studies on the pathogenesis of the disease in cows to determine if there is a systemic spread of the virus and if there are different ways of vacv shedding. the objective of ...201323021861
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
oncolytic vaccinia virus and radiotherapy in head and neck cancer.oncolytic forms of attenuated vaccinia virus are now in clinical development, assessing the compatibility of this novel treatment with radiotherapy may reveal exploitable synergistic relationships.201322925693
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
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
epitope mapping by random peptide phage display reveals essential residues for vaccinia extracellular enveloped virion spread.a33 is a type ii integral membrane protein expressed on the extracellular enveloped form of vaccinia virus (vacv). passive transfer of a33-directed monoclonal antibodies or vaccination with an a33 subunit vaccine confers protection against lethal poxvirus challenge in animal models. homologs of a33 are highly conserved among members of the orthopoxvirus genus and are potential candidates for inclusion in vaccines or assays targeting extracellular enveloped virus activity. one monoclonal antibody ...201223006741
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
characterization of an attenuated te3l-deficient vaccinia virus tian tan strain.an attenuated vaccinia virus (vacv), te3l(-)vtt, was evaluated for virulence and safety to determine its potential use as a vaccine or as a recombinant virus vector to express foreign genes. the virulence of te3l(-)vtt was compared with that of the wild-type vtt both in vivo and in vitro. the humoral and cellular immune responses were detected in a mouse model to test the vaccine efficacy of the te3l mutant. the results suggested that deletion of the te3l gene decreased the virulence and neurovi ...201223084929
dna-pk is a dna sensor for irf-3-dependent innate immunity.innate immunity is the first immunological defence against pathogens. during virus infection detection of nucleic acids is crucial for the inflammatory response. here we identify dna-dependent protein kinase (dna-pk) as a dna sensor that activates innate immunity. we show that dna-pk acts as a pattern recognition receptor, binding cytoplasmic dna and triggering the transcription of type i interferon (ifn), cytokine and chemokine genes in a manner dependent on ifn regulatory factor 3 (irf-3), tan ...201223251783
evaluation of normalization strategies for qpcr quantitation of intracellular viral dna: the example of vaccinia virus.quantitation of intracellular viral genomes is critical in both clinical and fundamental virology. quantitative real time pcr (qpcr) is currently the gold standard to detect and monitor virus infections, due to its high sensitivity and reproducibility. the reliability of qpcr data depends primarily on the technical process. normalization, which corrects inter-sample variations related to both pre-analytical and qpcr steps, is a key point of an accurate quantitation. total dna input and qpcr-meas ...201222981457
clathrin potentiates vaccinia-induced actin polymerization to facilitate viral spread.during their egress, newly assembled vaccinia virus particles fuse with the plasma membrane and enhance their spread by inducing arp2/3-dependent actin polymerization. investigating the events surrounding vaccinia virus fusion, we discovered that vaccinia transiently recruits clathrin in a manner dependent on the clathrin adaptor ap-2. the recruitment of clathrin to vaccinia dramatically enhances the ability of the virus to induce actin-based motility. we demonstrate that clathrin promotes clust ...201222980331
vaccinia virus egress: actin out with clathrin.to ensure spread from one cell to another, exocytosed vaccinia virions recruit cellular actin polymerization machinery to blast off from the cell surface on actin tails. humphries et al. (2012) now show that the virus exploits clathrin to organize viral factors into a launch pad that facilitates efficient actin tail formation.201222980323
a novel hla-b18 restricted cd8+ t cell epitope is efficiently cross-presented by dendritic cells from soluble tumor antigen.ny-eso-1 has been a major target of many immunotherapy trials because it is expressed by various cancers and is highly immunogenic. in this study, we have identified a novel hla-b*1801-restricted cd8(+) t cell epitope, ny-eso-1(88-96) (lefylampf) and compared its direct- and cross-presentation to that of the reported ny-eso-1(157-165) epitope restricted to hla-a*0201. although both epitopes were readily cross-presented by dcs exposed to various forms of full-length ny-eso-1 antigen, remarkably n ...201222970293
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
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
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
rnai screening reveals proteasome- and cullin3-dependent stages in vaccinia virus infection.a two-step, automated, high-throughput rnai silencing screen was used to identify host cell factors required during vaccinia virus infection. validation and analysis of clustered hits revealed previously unknown processes during virus entry, including a mechanism for genome uncoating. viral core proteins were found to be already ubiquitinated during virus assembly. after entering the cytosol of an uninfected cell, the viral dna was released from the core through the activity of the cell's protea ...201223084750
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
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
preferential colonization of metastases by oncolytic vaccinia virus strain glv-1h68 in a human pc-3 prostate cancer model in nude mice.recently, we showed that the oncolytic vaccinia virus glv-1h68 has a significant therapeutic potential in treating lymph node metastases of human pc-3 prostate carcinoma in tumor xenografts. in this study, underlying mechanisms of the virus-mediated metastases reduction were analyzed. immunohistochemistry demonstrated that virus-treatment resulted in a drastically decrease of blood and lymph vessels, representing essential routes for pc-3 cell migration, in both tumors and metastases. thus, glv- ...201223049897
characterization of a new vaccinia virus isolate reveals the c23l gene as a putative genetic marker for autochthonous group 1 brazilian vaccinia virus.since 1999, several vaccinia virus (vacv) isolates, the etiological agents of bovine vaccinia (bv), have been frequently isolated and characterized with various biological and molecular methods. the results from these approaches have grouped these vacv isolates into two different clusters. this dichotomy has elicited debates surrounding the origin of the brazilian vacv and its epidemiological significance. to ascertain vital information to settle these debates, we and other research groups have ...201223189200
correlates between host and viral transcriptional program associated with different oncolytic vaccinia virus isolates.vaccinia virus (vacv) has emerged as an attractive tool in oncolytic virotherapy. vacv replication efficiency plays a crucial role in the therapeutic outcome. however, little is known about the influence of host factors on viral replication efficiency and permissiveness of a host cell line to infection and oncolysis. in this study, replication of the attenuated vacv glv-1h68 strain and three wild-type vacv isolates was determined in two autologous human melanoma cell lines (888-mel and 1936-mel) ...201223131031
cd69 does not affect the extent of t cell priming.cd69 is rapidly upregulated on t cells upon activation. in this work we show that this is also the case for cd69 expression on dendritic cells (dc). thus, the expression kinetics of cd69 on both cell types is reminiscent of the one of costimulatory molecules. using mouse models of transgenic t cells, we aimed at evaluating the effect of monoclonal antibody (mab)-based targeting and gene deficiency of cd69 expressed by either dc or t cells on the extent of antigen (ag)-specific t cell priming, wh ...201223119065
protection of rabbits and immunodeficient mice against lethal poxvirus infections by human monoclonal antibodies.smallpox (variola virus) is a bioweapon concern. monkeypox is a growing zoonotic poxvirus threat. these problems have resulted in extensive efforts to develop potential therapeutics that can prevent or treat potentially lethal poxvirus infections in humans. monoclonal antibodies (mabs) against smallpox are a conservative approach to this problem, as the licensed human smallpox vaccine (vaccinia virus, vacv) primarily works on the basis of protective antibody responses against smallpox. fully hum ...201223133652
targeting 4-1bb (cd137) to enhance cd8 t cell responses with poxviruses and viral antigens.attenuated vaccinia virus (vacv) vectors are considered prime vaccine candidates for use in immunotherapy of infectious disease. in spite of this, recent data show that the level of attenuation may hamper the efficient generation of protective cd8 t cells. this suggests that additional adjuvant-like activities may need to be combined with attenuated vacv for optimal vaccination. stimulatory reagents to the tnfr family molecule 4-1bb (cd137) may represent such an adjuvant for vaccination. previou ...201223162550
group 2 vaccinia virus, brazil.in 2011, vaccinia virus caused an outbreak of bovine vaccinia, affecting dairy cattle and dairy workers in brazil. genetic and phenotypic analyses identified this isolate as distinct from others recently identified, thereby reinforcing the hypothesis that different vaccinia virus strains co-circulate in brazil.201223171598
virotherapy of canine tumors with oncolytic vaccinia virus glv-1h109 expressing an anti-vegf single-chain antibody.virotherapy using oncolytic vaccinia virus (vacv) strains is one promising new strategy for cancer therapy. we have previously reported that oncolytic vaccinia virus strains expressing an anti-vegf (vascular endothelial growth factor) single-chain antibody (scab) glaf-1 exhibited significant therapeutic efficacy for treatment of human tumor xenografts. here, we describe the use of oncolytic vaccinia virus glv-1h109 encoding glaf-1 for canine cancer therapy. in this study we analyzed the virus-me ...201223091626
[effect of neurotropin on chronic headaches in children].we report the cases of 2 girls, aged 13 and 15 years, who experienced exacerbation of migraine at 2-3 years after its onset. the chronic headaches were refractory to various anti-migraine and analgesic agents, persisted for 3-6 months in each patient, and rendered them unable to attend school. these headaches commonly manifested with symptoms of orthostatic dysregulation and paroxysmal back/limb pain. in addition, t2-weighted magnetic resonance images showed dots of highly intense signals in the ...201223240530
a novel therapeutic regimen to eradicate established solid tumors with an effective induction of tumor-specific immunity.the efficacy of oncolytic viruses depends on multiple actions including direct tumor lysis, modulation of tumor perfusion, and stimulation of tumor-directed immune responses. in this study, we investigated whether a sequential combination of immunologically distinct viruses might enhance antitumor efficacy through the induction of tumor-specific immunity and circumvention or mitigation of antiviral immune responses.201223091113
a vaccinia virus encoding the human sodium iodide symporter facilitates long-term image monitoring of virotherapy and targeted radiotherapy of pancreatic cancer.to assess therapeutic response and potential toxicity of oncolytic virotherapy, a noninvasive, deep-tissue imaging modality is needed. this study aimed to assess the feasibility, parameters, and determining factors of serial imaging and long-term monitoring of virotherapy and the therapeutic response of pancreatic cancer xenografts treated with a vaccinia virus carrying the human sodium iodide symporter glv-1h153.201223139088
cd8 marks a subpopulation of lung-derived dendritic cells with differential responsiveness to viral infection and toll-like receptor stimulation.an increasing number of studies suggest that individual subsets of dendritic cells (dc) exhibit distinct capabilities with regard to the generation of the adaptive immune response. in this study, we evaluated the properties of a relatively unexplored dc subset present in the lung-draining mediastinal lymph node. this subset expresses the airway dendritic cell marker cd103 together with cd8. these dc were of interest given that our previous studies using a model of respiratory infection with vacc ...201222811544
innate immune response of human plasmacytoid dendritic cells to poxvirus infection is subverted by vaccinia e3 via its z-dna/rna binding domain.plasmacytoid dendritic cells (pdcs) play important roles in antiviral innate immunity by producing type i interferon (ifn). in this study, we assess the immune responses of primary human pdcs to two poxviruses, vaccinia and myxoma virus. vaccinia, an orthopoxvirus, was used for immunization against smallpox, a contagious human disease with high mortality. myxoma virus, a leporipoxvirus, causes lethal disease in rabbits, but is non-pathogenic in humans. we report that myxoma virus infection of hu ...201222606294
modulation of the myxoma virus plaque phenotype by vaccinia virus protein f11.vaccinia virus (vacv) produces large plaques consisting of a rapidly expanding ring of infected cells surrounding a lytic core, whereas myxoma virus (myxv) produces small plaques that resemble a focus of transformed cells. this is odd, because bioinformatics suggests that myxv carries homologs of nearly all of the genes regulating orthopoxvirus attachment, entry, and exit. so why does myxv produce foci? one notable difference is that myxv-infected cells produce few of the actin microfilaments th ...201222514354
targeting pediatric cancer stem cells with oncolytic virotherapy.cancer stem cells (cscs), also termed "cancer-initiating cells" or "cancer progenitor cells," which have the ability to self-renew, proliferate, and maintain the neoplastic clone, have recently been discovered in a wide variety of pediatric tumors. these cscs are thought to be responsible for tumorigenesis and tumor maintenance, aggressiveness, and recurrence due to inherent resistance to current treatment modalities such as chemotherapy and radiation. oncolytic virotherapy offers a novel, targe ...201222430386
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