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oncolytic poxviruses.current standard treatments of cancer can prolong survival of many cancer patients but usually do not effectively cure the disease. oncolytic virotherapy is an emerging therapeutic for the treatment of cancer that exploits replication-competent viruses to selectively infect and destroy cancerous cells while sparing normal cells and tissues. clinical and/or preclinical studies on oncolytic viruses have revealed that the candidate viruses being tested in trials are remarkably safe and offer potent ...201425839047
the avian cell line age1.cr.pix characterized by metabolic flux analysis.in human vaccine manufacturing some pathogens such as modified vaccinia virus ankara, measles, mumps virus as well as influenza viruses are still produced on primary material derived from embryonated chicken eggs. processes depending on primary cell culture, however, are difficult to adapt to modern vaccine production. therefore, we derived previously a continuous suspension cell line, age1.cr.pix, from muscovy duck and established chemically-defined media for virus propagation.201425077436
raccoonpoxvirus safety in immunocompromised and pregnant mouse models.numerous poxviruses infect humans and animal hosts, and a poxvirus vaccine with an improved safety profile is needed as the current vaccinia virus vaccine is contraindicated in individuals that have a history of eczema or heart disease, or are immunocompromised or pregnant. in addition, poxviruses make excellent vaccine vectors for other infectious diseases and cancer. raccoonpoxvirus is a naturally occurring attenuated north american poxvirus, and thus it is of interest as a vaccine vector plat ...201424837508
differential induction of apoptosis, interferon signaling, and phagocytosis in macrophages infected with a panel of attenuated and nonattenuated poxviruses.due to the essential role macrophages play in antiviral immunity, it is important to understand the intracellular and molecular processes that occur in macrophages following infection with various strains of vaccinia virus, particularly those used as vaccine vectors. similarities as well as differences were found in macrophages infected with different poxvirus strains, particularly at the level of virus-induced apoptosis and the expression of immunomodulatory genes, as determined by microarray a ...201424599993
local control of repeated-dose rectal challenges in dna/mva-vaccinated macaques protected against a first series of simian immunodeficiency virus challenges.here, we report the results of a late boost and three additional series of simian immunodeficiency virus (siv) challenges in seven dna/modified vaccinia virus ankara (mva)-vaccinated rhesus macaques who resisted a first series of rectal challenges. during 29 additional challenges delivered over 2.3 years, all animals became infected. however, 13 blips of virus in six macaques and anamnestic env-specific rectal iga responses in three of the six suggested that local control of infections was occur ...201424574408
resistance to infection, early and persistent suppression of simian immunodeficiency virus sivmac251 viremia, and significant reduction of tissue viral burden after mucosal vaccination in female rhesus macaques.the efficacy of oral, intestinal, nasal, and vaginal vaccinations with dna simian immunodeficiency virus (siv)/interleukin-2 (il-2)/il-15, siv gag/pol/env recombinant modified vaccinia virus ankara (rmva), and at-2 sivmac239 inactivated particles was compared in rhesus macaques after low-dose vaginal challenge with sivmac251. intestinal immunization provided better protection from infection, as a significantly greater median number of challenges was necessary in this group than in the others. or ...201424155376
adaptive gene amplification as an intermediate step in the expansion of virus host range.the majority of recently emerging infectious diseases in humans is due to cross-species pathogen transmissions from animals. to establish a productive infection in new host species, viruses must overcome barriers to replication mediated by diverse and rapidly evolving host restriction factors such as protein kinase r (pkr). many viral antagonists of these restriction factors are species specific. for example, the rhesus cytomegalovirus pkr antagonist, rhtrs1, inhibits pkr in some african green m ...201424626510
a novel target and approach for identifying antivirals against molluscum contagiosum virus.the dermatological disease molluscum contagiosum (mc) presents as lesions restricted solely to the skin. the poxvirus molluscum contagiosum virus (mcv) is responsible for this skin disease that is easily transmitted through casual contact among all populations, with greater frequency in children and immunosuppressed individuals. in addition, sexual transmission of mcv in adolescents and adults is a health concern. although the skin lesions ultimately resolve in immunocompetent individuals, they ...201425267668
electron tomography and simulation of baculovirus actin comet tails support a tethered filament model of pathogen propulsion.several pathogens induce propulsive actin comet tails in cells they invade to disseminate their infection. they achieve this by recruiting factors for actin nucleation, the arp2/3 complex, and polymerization regulators from the host cytoplasm. owing to limited information on the structural organization of actin comets and in particular the spatial arrangement of filaments engaged in propulsion, the underlying mechanism of pathogen movement is currently speculative and controversial. using electr ...201424453943
surface-dried viruses can resist glucoprotamin-based disinfection.touching of contaminated objects and surfaces is a well-known method of virus transmission. once they are attached to the hands, viruses can easily get adsorbed and initiate infection. hence, disinfection of frequently touched surfaces is of major importance to prevent virus spreading. here we studied the antiviral activity of a glucoprotamin-containing disinfectant against influenza a virus and the model virus vaccinia virus (vacv) dried on inanimate surfaces. the efficacy of the surface disinf ...201425217017
the pulmonary localization of virus-specific t lymphocytes is governed by the tissue tropism of infection.the migration of pathogen-specific t cells into nonlymphoid tissues, such as the lung, is critical to control peripheral infections. use of in vivo intravascular labeling of leukocytes has allowed for improved discrimination between cells located in the blood from cells present within peripheral tissues, such as the lung. this is particularly important in the lung, which is comprised of an intricate network of blood vessels that harbors a large proportion of the total blood volume at any given t ...201424899187
combined cytolytic effects of a vaccinia virus encoding a single chain trimer of mhc-i with a tax-epitope and tax-specific ctls on htlv-i-infected cells in a rat model.adult t cell leukemia (atl) is a malignant lymphoproliferative disease caused by human t cell leukemia virus type i (htlv-i). to develop an effective therapy against the disease, we have examined the oncolytic ability of an attenuated vaccinia virus (vv), lc16m8δ (m8δ), and an htlv-i tax-specific cytotoxic t lymphocyte (ctl) line, 4o1/c8, against an htlv-i-infected rat t cell line, fpm1. our results demonstrated that m8δ was able to replicate in and lyse tumorigenic fpm1 cells but was incompeten ...201424791004
immune therapy for human papillomaviruses-related cancers.human papillomaviruses (hpvs) are a large family of double strand dna viruses comprising more than 180 types. infection with hpv is very common and it is associated with benign and malignant proliferation of skin and squamous mucosae. many hpvs, considered low-risk such as hpv 6 and 11, produce warts; while high-risk viruses, such as hpvs 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, and 58, induce tumors. about 5% of all cancers in men and women are associated with hpv infection. because there are no ...201425493236
regression of human papillomavirus intraepithelial lesions is induced by mva e2 therapeutic vaccine.human papilloma viruses can induce warts, condylomas, and other intraepithelial cervical lesions that can progress to cancer. cervical cancer is a serious problem in developing countries because early detection is difficult, and thus proper early treatment is many times missing. in this phase iii clinical trial, we evaluated the potential use of mva e2 recombinant vaccinia virus to treat intraepithelial lesions associated with papillomavirus infection. a total of 1176 female and 180 male patient ...201425275724
antitumor activity and immunogenicity of recombinant vaccinia virus expressing hpv 16 e7 protein sige7lamp is enhanced by high-level coexpression of igfbp-3.we constructed recombinant vaccinia viruses (vacvs) coexpressing the insulin-like growth factor-binding protein-3 (igfbp-3) gene and the fusion gene encoding the sige7lamp antigen. the expression of the igfbp-3 transgene was regulated either by the early h5 promoter or by the synthetic early/late (e/l) promoter. we have shown that igfbp-3 expression regulated by the h5 promoter yielded higher amount of igfbp-3 protein when compared with the e/l promoter. the immunization with p13-sige7lamp-h5-ig ...201424556712
development of cmx001 (brincidofovir) for the treatment of serious diseases or conditions caused by dsdna viruses.cmx001 (hexadecyloxypropyl-cidofovir, brincidofovir) is a broad spectrum, lipid conjugate of cidofovir that is converted intracellularly into the active antiviral, cidofovir diphosphate. the lipid conjugation results in oral bioavailability, higher intracellular concentrations of active drug, lower plasma concentrations of cidofovir and increased antiviral potency against dsdna viruses.201425120093
augmented replicative capacity of the boosting antigen improves the protective efficacy of heterologous prime-boost vaccine regimens.prime-boost immunization regimens have proven efficacious at generating robust immune responses. however, whether the level of replication of the boosting antigen impacts the magnitude and protective efficacy of vaccine-elicited immune responses remains unclear. to evaluate this, we primed mice with replication-defective adenovirus vectors expressing the lymphocytic choriomeningitis virus (lcmv) glycoprotein (gp), followed by boosting with either lcmv armstrong, which is rapidly controlled, or l ...201424648461
the use of directed evolution to create a stable and immunogenic recombinant bcg expressing a modified hiv-1 gag antigen.numerous features make mycobacterium bovis bcg an attractive vaccine vector for hiv. it has a good safety profile, it elicits long-lasting cellular immune responses and in addition manufacturing costs are affordable. despite these advantages it is often difficult to express viral antigens in bcg, which results in genetic instability and low immunogenicity. the aim of this study was to generate stable recombinant bcg (rbcg) that express high levels of hiv antigens, by modification of the hiv gene ...201425061753
cd40l-adjuvanted dna/modified vaccinia virus ankara simian immunodeficiency virus siv239 vaccine enhances siv-specific humoral and cellular immunity and improves protection against a heterologous sive660 mucosal challenge.it remains a challenge to develop a successful human immunodeficiency virus (hiv) vaccine that is capable of preventing infection. here, we utilized the benefits of cd40l, a costimulatory molecule that can stimulate both dendritic cells (dcs) and b cells, as an adjuvant for our simian immunodeficiency virus (siv) dna vaccine in rhesus macaques. we coexpressed the cd40l with our dna/siv vaccine such that the cd40l is anchored on the membrane of siv virus-like particle (vlp). these cd40l containin ...201424920805
use of an in vivo fta assay to assess the magnitude, functional avidity and epitope variant cross-reactivity of t cell responses following hiv-1 recombinant poxvirus vaccination.qualitative characteristics of cytotoxic cd8+ t cells (ctls) are important in measuring the effectiveness of ctls in controlling hiv-1 infections. indeed, in recent studies patients who are naturally resistant to hiv-1 infections have been shown to possess ctls that are of high functional avidity and have a high capacity to recognize hiv epitope variants, when compared to hiv-1 infection progressors. when developing efficacious vaccines, assays that can effectively measure ctl quality specifical ...201425170620
recombinant mycobacterium bovis bacillus calmette-guérin vectors prime for strong cellular responses to simian immunodeficiency virus gag in rhesus macaques.live attenuated nonpathogenic mycobacterium bovis bacillus calmette-guérin (bcg) mediates long-lasting immune responses, has been safely administered as a tuberculosis vaccine to billions of humans, and is affordable to produce as a vaccine vector. these characteristics make it very attractive as a human immunodeficiency virus (hiv) vaccine vector candidate. here, we assessed the immunogenicity of recombinant bcg (rbcg) constructs with different simian immunodeficiency virus (siv)gag expression ...201425080550
[a novel immunization strategy to induce strong humoral responses against hiv-1 using combined dna, recombinant vaccinia virus and protein vaccines].to optimize the immunization strategy against hiv-1, a dna vaccine was combined with a recombinant vaccinia virus (rtv) vaccine and a protein vaccine. immune responses against hiv-1 were detected in 30 female guinea pigs divided into six groups. three groups of guinea pigs were primed with hiv-1 dna vaccine three times, boosted with rtv at week 14, and then boosted with gp140 protein at intervals of 4, 8 or 12 weeks. simultaneously, the other three groups of animals were primed with rtv vaccine ...201425868279
a recombinant modified vaccinia ankara vaccine encoding epstein-barr virus (ebv) target antigens: a phase i trial in uk patients with ebv-positive cancer.epstein-barr virus (ebv) is associated with several cancers in which the tumor cells express ebv antigens ebna1 and lmp2. a therapeutic vaccine comprising a recombinant vaccinia virus, mva-el, was designed to boost immunity to these tumor antigens. a phase i trial was conducted to demonstrate the safety and immunogenicity of mva-el across a range of doses.201425124688
engineering large viral dna genomes using the crispr-cas9 system.manipulation of viral genomes is essential for studying viral gene function and utilizing viruses for therapy. several techniques for viral genome engineering have been developed. homologous recombination in virus-infected cells has traditionally been used to edit viral genomes; however, the frequency of the expected recombination is quite low. alternatively, large viral genomes have been edited using a bacterial artificial chromosome (bac) plasmid system. however, cloning of large viral genomes ...201425040500
carbohydrate-based ice recrystallization inhibitors increase infectivity and thermostability of viral vectors.the inability of vaccines to retain sufficient thermostability has been an obstacle to global vaccination programs. to address this major limitation, we utilized carbohydrate-based ice recrystallization inhibitors (iris) to eliminate the cold chain and stabilize the potency of vaccinia virus (vv), vesicular stomatitis virus (vsv) and herpes virus-1 (hsv-1). the impact of these iris was tested on the potency of the viral vectors using a plaque forming unit assay following room temperature storage ...201425078058
synthesis and antiviral activity of new phenylimidazopyridines and n-benzylidenequinolinamines derived by molecular simplification of phenylimidazo[4,5-g]quinolines.continuing our program of research concerning the antiviral activity of a wide series of new angular and linear azolo bicyclic and tricyclic derivatives, now we have simplified and modified the 4-chloro-2-(4-nitrophenyl)-3h-imidazo[4,5-g]quinoline 1, which previously resulted the most active derivative, through either the elimination of the central ring or the opening of the imidazole ring, obtaining various imidazopyridines and n-benzylidenequinolinamines respectively. title compounds were test ...201425014745
exploring mucosal immunization with a recombinant influenza virus carrying an hiv-polyepitope in mice with pre-existing immunity to influenza.hiv-1 vaccines based on recombinant vectors have been developed to elicit immune responses; however, the failure of the step hiv-1 vaccine trial has caused concern regarding the impact on vaccine efficacy of pre-existing vector seropositivity in humans. by using a mouse model of infection, we evaluated the immune responses elicited by intranasal and vaginal immunization with the recombinant influenza virus wsn/ckg carrying the pclus3-p18 peptide and a gag epitope in its hemagglutinin, and the im ...201424662706
hiv-1 adenoviral vector vaccines expressing multi-trimeric baff and 4-1bbl enhance t cell mediated anti-viral immunity.adenoviral vectored vaccines have shown considerable promise but could be improved by molecular adjuvants. ligands in the tnf superfamily (tnfsf) are potential adjuvants for adenoviral vector (ad5) vaccines based on their central role in adaptive immunity. many tnfsf ligands require aggregation beyond the trimeric state (multi-trimerization) for optimal biological function. here we describe ad5 vaccines for hiv-1 gag antigen (ad5-gag) adjuvanted with the tnfsf ligands 4-1bbl, baff, gitrl and cd2 ...201424587225
the recombinant vaccinia virus gene product, b18r, neutralizes interferon alpha and alleviates histopathological complications in an hiv encephalitis mouse model.interferon-alpha (ifn-α) has been identified as a neurotoxin that plays a prominent role in human immunodeficiency virus (hiv)-associated neurocognitive disorders and hiv encephalitis (hive) pathology. ifn-α is associated with cognitive dysfunction in other inflammatory diseases where ifn-α is upregulated. trials of monoclonal anti-ifn-α antibodies have been generally disappointing possibly due to high specificity to limited ifn-α subtypes and low affinity. we investigated a novel ifn-α inhibito ...201424564363
vaccinia virus lc16m8∆ as a vaccine vector for clinical applications.the lc16m8 strain of vaccinia virus, the active ingredient in the japanese smallpox vaccine, was derived from the lister/elstree strain. lc16m8 is replication-competent and has been administered to over 100,000 infants and 3,000 adults with no serious adverse reactions. despite this outstanding safety profile, the occurrence of spontaneously-generated large plaque-forming virulent lc16m8 revertants following passage in cell culture is a major drawback. we identified the gene responsible for the ...201426344890
effects of different promoters on the virulence and immunogenicity of a hiv-1 env-expressing recombinant vaccinia vaccine.previously, we developed a vaccination regimen that involves priming with recombinant vaccinia virus lc16m8δ (rm8δ) strain followed by boosting with a sendai virus-containing vector. this protocol induced both humoral and cellular immune responses against the hiv-1 envelope protein. the current study aims to optimize this regimen by comparing the immunogenicity and safety of two rm8δ strains that express hiv-1 env under the control of a moderate promoter, p7.5, or a strong promoter, psfj1-10. m8 ...201424370703
progress toward a universal h5n1 vaccine: a recombinant modified vaccinia virus ankara-expressing trivalent hemagglutinin vaccine.the rapid evolution of new sublineages of h5n1 influenza poses the greatest challenge in control of h5n1 infection by currently existing vaccines. to overcome this, an mvator vector expressing three h5ha antigens a/vietnam/1203/04, a/indonesia/669/06 and a/anhui/01/05 (mvator-tri-ha vector) was developed to elicit broad cross-protection against diverse clades by covering amino acid variations in the major neutralizing epitopes of ha among h5n1 subtypes.201425229722
modified vaccinia virus ankara encoding influenza virus hemagglutinin induces heterosubtypic immunity in macaques.current influenza virus vaccines primarily aim to induce neutralizing antibodies (nabs). modified vaccinia virus ankara (mva) is a safe and well-characterized vector for inducing both antibody and cellular immunity. we evaluated the immunogenicity and protective efficacy of mva encoding influenza virus hemagglutinin (ha) and/or nucleoprotein (np) in cynomolgus macaques. animals were given 2 doses of mva-based vaccines 4 weeks apart and were challenged with a 2009 pandemic h1n1 isolate (h1n1pdm) ...201425210172
il-15 adjuvanted multivalent vaccinia-based universal influenza vaccine requires cd4+ t cells for heterosubtypic protection.current influenza vaccines are ineffective against novel viruses and the source or the strain of the next outbreak of influenza is unpredictable; therefore, establishing universal immunity by vaccination to limit the impact of influenza remains a high priority. to meet this challenge, a novel vaccine has been developed using the immunogenic live vaccinia virus as a vaccine vector, expressing multiple h5n1 viral proteins (ha, na, m1, m2, and np) together with il-15 as a molecular adjuvant. previo ...201424706798
homosubtypic and heterosubtypic antibodies against highly pathogenic avian influenza h5n1 recombinant proteins in h5n1 survivors and non-h5n1 subjects.six recombinant vaccinia viruses containing ha, na, np, m or ns gene insert derived from a highly pathogenic avian influenza h5n1 virus, and the recombinant vaccinia virus harboring plasmid backbone as the virus control were constructed. the recombinant proteins were characterized for their expression and subcellular locations in tk(-) cells. antibodies to the five recombinant proteins were detected in all 13 sequential serum samples collected from four h5n1 survivors during four years of follow ...201424725952
initial characterization of vaccinia virus b4 suggests a role in virus spread.currently, little is known about the ankyrin/f-box protein b4. here, we report that b4r-null viruses exhibited reduced plaque size in tissue culture, and decreased ability to spread, as assessed by multiple-step growth analysis. electron microscopy indicated that b4r-null viruses still formed mature and extracellular virions; however, there was a slight decrease of virions released into the media following deletion of b4r. deletion of b4r did not affect the ability of the virus to rearrange acti ...201424889230
vaccination directed against the human endogenous retrovirus-k (herv-k) gag protein slows herv-k gag expressing cell growth in a murine model system.human endogenous retroviruses (hervs) are remnants of ancestral infections and chromosomally integrated in all cells of an individual, are transmitted only vertically and are defective in viral replication. however enhanced expression of herv-k accompanied by the emergence of anti-herv-k-directed immune responses has been observed inter-alia in hiv-infected individuals and tumor patients. therefore herv-k might serve as a tumor-specific antigen or even as a constant target for the development of ...201424669861
bacterial expression of the hinab domain of ifi16: purification, characterization of dna binding activity, and co-crystallization with viral dsdna.interferon-inducible protein 16 (ifi16) is a multifunctional p200-family protein that plays pivotal roles in p53-mediated apoptosis, tumor suppression and dna damage response. recently, another function of ifi16 in innate immune sensing and response has been uncovered, in which ifi16 recognizes the exogenous dnas through cooperative binding of dnas via its two dna binding domains, hina and hinb. although the mechanism by which the hinb domain recognizes dnas has been elucidated, the molecular ba ...201425050461
construction of deletion-knockout mutant fowlpox virus (fwpv).the construction of deletion-knockout poxviruses is a useful approach to determining the function of specific virus genes. this protocol is an adaptation of the transient dominant knockout selection protocol published by falkner and moss (1990) for use with vaccinia virus. the protocol makes use of the dominant selectable marker escherichia coli guanine phosphoribosyltransferase (gpt) gene (mulligan and berg, 1981), under the control of an early/late poxvirus promoter. the deletion viruses that ...201427257612
analysis of sensitivity and rapid hybridization of a multiplexed microbial detection microarray.microarrays have proven to be useful in rapid detection of many viruses and bacteria. pathogen detection microarrays have been used to diagnose viral and bacterial infections in clinical samples and to evaluate the safety of biological drug materials. a multiplexed version of the lawrence livermore microbial detection array (llmda) was developed and evaluated with minimum detectable concentrations for pure unamplified dna viruses, along with mixtures of viral and bacterial dna subjected to diffe ...201424602557
novel hiv il-4r antagonist vaccine strategy can induce both high avidity cd8 t and b cell immunity with greater protective efficacy.we have established that the efficacy of a heterologous poxvirus vectored hiv vaccine, fowlpox virus (fpv)-hiv gag/pol prime followed by attenuated vaccinia virus (vv)-hiv gag/pol booster immunisation, is strongly influenced by the cytokine milieu at the priming vaccination site, with endogenous il-13 detrimental to the quality of the hiv specific cd8+ t cell response induced. we have now developed a novel hiv vaccine that co-expresses a c-terminal deletion mutant of the mouse il-4, deleted for ...201425151041
influence of sulphate on the composition and antibacterial and antiviral properties of the exopolysaccharide from porphyridium cruentum.the influence of two culture media and three different concentrations of sulphate in the medium on the growth of two strains of porphyridium cruentum and on the production, composition and viscoelastic characteristics, and antimicrobial properties of the sulphated exopolysaccharide (eps) were studied.201424582595
different hiv pox viral vector-based vaccines and adjuvants can induce unique antigen presenting cells that modulate cd8 t cell avidity.the lung-derived dendritic cell (ldc) recruitment following intranasal (i.n.) vaccination of different poxviral vector-based vaccines/adjuvants were evaluated to decipher how these factors influenced cd8(+) t cell avidity. compared to the standard i.n. recombinant fowlpox virus (fpv)-hiv vaccination, the fpv-hiv il-13rα2 or il-4rα antagonist adjuvanted vaccines that induced higher avidity cd8(+) t cells, also recruited significantly elevated mhcii(+) cd11c(+) cd11b(+) cd103(-) cd64(-) mar-1(-) c ...201425261870
immediate-early protein of equid herpesvirus type 1 as a target for cytotoxic t-lymphocytes in the thoroughbred horse.cytotoxic t-lymphocytes (ctls) are associated with protective immunity against disease caused by equid herpesvirus type 1 (ehv-1). however, the ehv-1 target proteins for ctls are poorly defined. this limits the development of vaccine candidates designed to stimulate strong ctl immunity. here, classical ctl assays using lymphocytes from horses of three defined mhc class i types that experienced natural infection with ehv-1 and a modified vaccinia virus construct containing an ehv-1 gene encoding ...201424836672
changes in the mitochondrial network during ectromelia virus infection of permissive l929 cells.mitochondria are extremely important organelles in the life of a cell. recent studies indicate that mitochondria also play a fundamental role in the cellular innate immune mechanisms against viral infections. moreover, mitochondria are able to alter their shape continuously through fusion and fission. these tightly regulated processes are activated or inhibited under physiological or pathological (e.g. viral infection) conditions to help restore homeostasis. however, many types of viruses, such ...201424660173
a plasmid-based reverse genetics system for mammalian orthoreoviruses driven by a plasmid-encoded t7 rna polymerase.mammalian orthoreoviruses (reoviruses) have served as highly useful models for studies of virus replication and pathogenesis. the development of a plasmid-based reverse genetics system represented a major breakthrough in reovirus research. the current reverse genetics systems for reoviruses rely on the expression of t7 rna polymerase within cells transfected with reovirus gene-segment cdna plasmids. in these systems, the t7 rna polymerase is provided by using a recombinant vaccinia virus express ...201424183920
expression of a non-coding rna in ectromelia virus is required for normal plaque formation.poxviruses are dsdna viruses with large genomes. many genes in the genome remain uncharacterized, and recent studies have demonstrated that the poxvirus transcriptome includes numerous so-called anomalous transcripts not associated with open reading frames. here, we characterize the expression and role of an apparently non-coding rna in orthopoxviruses, which we call viral hairpin rna (vhrna). using a bioinformatics approach, we predicted expression of a transcript not associated with an open re ...201424078045
development and evaluation of single domain antibodies for vaccinia and the l1 antigen.there is ongoing interest to develop high affinity, thermal stable recognition elements to replace conventional antibodies in biothreat detection assays. as part of this effort, single domain antibodies that target vaccinia virus were developed. two llamas were immunized with killed viral particles followed by boosts with the recombinant membrane protein, l1, to stimulate the immune response for envelope and membrane proteins of the virus. the variable domains of the induced heavy chain antibodi ...201425211488
identification of 10 cowpox virus proteins that are necessary for induction of hemorrhagic lesions (red pocks) on chorioallantoic membranes.cowpox viruses (cpxv) cause hemorrhagic lesions ("red pocks") on infected chorioallantoic membranes (cam) of embryonated chicken eggs, while most other members of the genus orthopoxvirus produce nonhemorrhagic lesions ("white pocks"). cytokine response modifier a (crma) of cpxv strain brighton red (br) is necessary but not sufficient for the induction of red pocks. to identify additional viral proteins involved in the induction of hemorrhagic lesions, a library of single-gene cpxv knockout mutan ...201424850732
genome sequence of wau86/88-1, a new variant of vaccinia virus lister strain from poland.the poxviruses warsaw agricultural university 86 (wau86) and 88-1 (wau88-1) were isolated in 1986 to 1988 from separate outbreaks in laboratory mice in poland and described as ectromelia virus isolates. the genome sequences of these poxviruses reveal that they are almost identical and represent a novel variant of the vaccinia virus lister strain.201424407630
crystal structure of the vaccinia virus dna polymerase holoenzyme subunit d4 in complex with the a20 n-terminal domain.vaccinia virus polymerase holoenzyme is composed of the dna polymerase e9, the uracil-dna glycosylase d4 and a20, a protein with no known enzymatic activity. the d4/a20 heterodimer is the dna polymerase co-factor whose function is essential for processive dna synthesis. genetic and biochemical data have established that residues located in the n-terminus of a20 are critical for binding to d4. however, no information regarding the residues of d4 involved in a20 binding is yet available. we expres ...201424603707
impact of distinct poxvirus infections on the specificities and functionalities of cd4+ t cell responses.the factors that determine cd4+ t cell (tcd4+) specificities, functional capacity, and memory persistence in response to complex pathogens remain unclear. we explored these parameters in the c57bl/6 mouse through comparison of two highly related (>92% homology) poxviruses: ectromelia virus (ectv), a natural mouse pathogen, and vaccinia virus (vacv), a heterologous virus that nevertheless elicits potent immune responses. in addition to elucidating several previously unidentified major histocompat ...201424965457
epithelial immunization induces polyfunctional cd8+ t cells and optimal mousepox protection.we assessed several routes of immunization with vaccinia virus (vacv) in protecting mice against ectromelia virus (ectv). by a wide margin, skin scarification provided the greatest protection. humoral immunity and resident-memory t cells notwithstanding, several approaches revealed that circulating, memory cd8(+) t cells primed via scarification were functionally superior and conferred enhanced virus control. immunization via the epithelial route warrants further investigation, as it may also pr ...201424899206
prediction of steps in the evolution of variola virus host range.variola virus, the agent of smallpox, has a severely restricted host range (humans) but a devastatingly high mortality rate. although smallpox has been eradicated by a world health organization vaccination program, knowledge of the evolutionary processes by which human super-pathogens such as variola virus arise is important. by analyzing the evolution of variola and other closely related poxviruses at the level of single nucleotide polymorphisms we detected a hotspot of genome variation within ...201424626337
the complete genome sequences of poxviruses isolated from a penguin and a pigeon in south africa and comparison to other sequenced avipoxviruses.two novel avipoxviruses from south africa have been sequenced, one from a feral pigeon (columba livia) (fep2) and the other from an african penguin (spheniscus demersus) (pepv). we present a purpose-designed bioinformatics pipeline for analysis of next generation sequence data of avian poxviruses and compare the different avipoxviruses sequenced to date with specific emphasis on their evolution and gene content.201424919868
the canarypox virus vector alvac induces distinct cytokine responses compared to the vaccinia virus-based vectors mva and nyvac in rhesus monkeys.despite the growing use of poxvirus vectors as vaccine candidates for multiple pathogens and cancers, their innate stimulatory properties remain poorly characterized. here we show that the canarypox virus-based vector alvac induced distinct systemic proinflammatory and antiviral cytokine and chemokine levels following the vaccination of rhesus monkeys compared to the vaccinia virus-based vectors mva and nyvac. these data suggest that there are substantial biological differences among leading pox ...201424257612
human memory t cells from the bone marrow are resting and maintain long-lasting systemic memory.in the bone marrow, a population of memory t cells has been described that promotes efficient secondary immune responses and has been considered to be preactivated, owing to its expression of cd69 and cd25. here we show that human bone marrow professional memory t cells are not activated but are resting in terms of proliferation, transcription, and mobility. they are in the g0 phase of the cell cycle, and their transcriptome is that of resting t cells. the repertoire of cd4(+) bone marrow memory ...201424927527
kay-2-41, a novel nucleoside analogue inhibitor of orthopoxviruses in vitro and in vivo.the availability of adequate treatments for poxvirus infections would be valuable not only for human use but also for veterinary use. in the search for novel antiviral agents, a 1'-methyl-substituted 4'-thiothymidine nucleoside, designated kay-2-41, emerged as an efficient inhibitor of poxviruses. in vitro, kay-2-41 was active in the micromolar range against orthopoxviruses (opvs) and against the parapoxvirus orf. the compound preserved its antiviral potency against opvs resistant to the referen ...201424126587
[apoptin enhances the oncolytic activity of vaccinia virus].chicken anemia virus gene encoding apoptin, a selective killer of cancer cells was synthesized and inserted into vaccinia virus (strain l-ivp) genome. the insertion has replaced major part of the viral c11r gene encoding viral growth factor (vgf), which is important for the virulence. the recombinant virus vvdgf-apos24/2 was obtained through the transient dominant selection technique with the use of puromycin resistance gene as the selective marker. the expression apoptin gene from a synthetic e ...201425509357
development of a novel, guinea pig-specific ifn-γ elispot assay and characterization of guinea pig cytomegalovirus gp83-specific cellular immune responses following immunization with a modified vaccinia virus ankara (mva)-vectored gp83 vaccine.the guinea pig (cavia porcellus) provides a useful animal model for studying the pathogenesis of many infectious diseases, and for preclinical evaluation of vaccines. however, guinea pig models are limited by the lack of immunological reagents required for characterization and quantification of antigen-specific t cell responses. to address this deficiency, an enzyme-linked immunospot (elispot) assay for guinea pig interferon (ifn)-γ was developed to measure antigen/epitope-specific t cell respon ...201424856783
mouse cmv infection delays antibody class switch upon an unrelated virus challenge.poor immune protection upon vaccination is a critical determinant of immunosenescence. latent cytomegalovirus (cmv) infection has been associated with poor antibody responses to vaccination, but a causative role for cmv in the poor immune response requires experimental evidence and thus could not be confirmed in clinical studies. to test the hypothesis that latent cmv infection causes poor antibody responses, we infected young or adult mice with mouse cmv and challenged them with vesicular stoma ...201424462805
generation of a complete single-gene knockout bacterial artificial chromosome library of cowpox virus and identification of its essential genes.cowpox virus (cpxv) belongs to the genus orthopoxvirus in the poxviridae family. it infects a broad range of vertebrates and can cause zoonotic infections. cpxv has the largest genome among the orthopoxviruses and is therefore considered to have the most complete set of genes of all members of the genus. since cpxv has also become a model for studying poxvirus genetics and pathogenesis, we created and characterized a complete set of single gene knockout bacterial artificial chromosome (bac) clon ...201424155400
identification and characterization of a phage display-derived peptide for orthopoxvirus detection.fast and reliable diagnostic assays are required for a resilient detection of clinical infections or biothreat-relevant pathogens. while pcr has proven to be the gold standard for nucleic acid detection, the identification of pathogen particles is still challenging and depends on the availability of well-characterized, chemically stable, and selective recognition molecules. here, we report the screening of a phage display random peptide library for vaccinia virus-binding peptides. the identified ...201425311190
presence of neutralizing antibodies to orthopoxvirus in capybaras (hydrochoerus hydrochaeris) in brazil.cantagalo virus is a strain of vaccinia virus (genus orthopoxvirus) and the etiological agent of an important vesicopustular disease that affects dairy cows and milkers in brazil. the reservoirs involved in the maintenance of this virus in nature are unknown. in the present work, the detection of neutralizing antibodies to orthopoxvirus in capybaras collected in são paulo state is reported. capybaras are the largest rodent species native to south america and have already been reported as putativ ...201425500667
myd88-dependent immunity to a natural model of vaccinia virus infection does not involve toll-like receptor 2.although the pattern recognition receptor toll-like receptor 2 (tlr2) is typically thought to recognize bacterial components, it has been described to alter the induction of both innate and adaptive immunity to a number of viruses, including vaccinia virus (vacv). however, many pathogens that reportedly encode tlr2 agonists may actually be artifactually contaminated during preparation, possibly with cellular debris or merely with molecules that sensitize cells to be activated by authentic tlr2 a ...201424403581
inactivation of bacterial and viral biothreat agents on metallic copper surfaces.in recent years several studies in laboratory settings and in hospital environments have demonstrated that surfaces of massive metallic copper have intrinsic antibacterial and antiviral properties. microbes are rapidly inactivated by a quick, sharp shock known as contact killing. the underlying mechanism is not yet fully understood; however, in this process the cytoplasmic membrane is severely damaged. pathogenic bacterial and viral high-consequence species able to evade the host immune system a ...201425100640
combination of biobarcode assay with on-chip capillary electrophoresis for ultrasensitive and multiplex biological agent detection.early diagnosis of biological agents is of paramount importance to prevent the casualties and fatal disease in human during bioterrorism or biological warfare. in this study, we reported an efficient and sensitive multiplex biological agent detection method based on the dna biobarcode assay and the micro-capillary electrophoresis (μce) technology. monoplex as well as multiplex pathogen identification was performed using five targets including bacillus anthracis, francisella tularensis, yersinia ...201424878840
genome segregation and packaging machinery in acanthamoeba polyphaga mimivirus is reminiscent of bacterial apparatus.genome packaging is a critical step in the virion assembly process. the putative atp-driven genome packaging motor of acanthamoeba polyphaga mimivirus (apmv) and other nucleocytoplasmic large dna viruses (ncldvs) is a distant ortholog of prokaryotic chromosome segregation motors, such as ftsk and hera, rather than other viral packaging motors, such as large terminase. intriguingly, apmv also encodes other components, i.e., three putative serine recombinases and a putative type ii topoisomerase, ...201424623441
laboratory-acquired buffalopox virus infection, india. 201424447599
relationship between poor immunogenicity of hla-a2-restricted peptide epitopes and paucity of naïve cd8(+) t-cell precursors in hla-a2-transgenic mice.we examined the immunogenicity of h-2 class i-restricted and hla-a2-restricted epitopes through peptide immunization of hla-a2-transgenic mice that also express mouse h-2 class i molecules. all four of the tested epitopes restricted by h-2 class i robustly elicited t-cell responses, but four of seven epitopes restricted by hla-a2 did not induce t-cell responses, showing that hla-a2-restricted peptide epitopes tend to be poorly immunogenic in hla-a2-transgenic mice. this finding was confirmed in ...201425177254
α4-integrins control viral meningoencephalitis through differential recruitment of t helper cell subsets.natalizumab blocks α4-integrins and is a prototypic agent for a series of anti-inflammatory drugs that impair trafficking of immune cells into the cns. however, modulation of the access of immune cells to the cns is associated with impaired immune surveillance and detrimental viral infections of the cns. here, we explored the potency of cellular immune responses within the cns to protect against viral encephalitis in mice with t cell conditional disruption of vla-4 integrin (α4β1) expression.201424606807
t cell antigen discovery using soluble vaccinia proteome reveals recognition of antigens with both virion and nonvirion association.vaccinia virus (vacv) is a useful model system for understanding the immune response to a complex pathogen. proteome-wide ab profiling studies reveal the humoral response to be strongly biased toward virion-associated ags, and several membrane proteins induce ab-mediated protection against vacv challenge in mice. some studies have indicated that the cd4 response is also skewed toward proteins with virion association, whereas the cd8 response is more biased toward proteins with early expression. ...201425024392
cellular sensing of viral dna and viral evasion mechanisms.mammalian cells detect foreign dna introduced as free dna or as a result of microbial infection, leading to the induction of innate immune responses that block microbial replication and the activation of mechanisms that epigenetically silence the genes encoded by the foreign dna. a number of dna sensors localized to a variety of sites within the cell have been identified, and this review focuses on the mechanisms that detect viral dna and how the resulting responses affect viral infections. viru ...201425002095
t-bet and eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow.trail(+)dx5(-)eomes(-) natural killer (nk) cells arise in the mouse fetal liver and persist in the adult liver. their relationships with trail(-)dx5(+) nk cells remain controversial. we generated a novel eomes-gfp reporter murine model to address this question. we found that eomes(-) nk cells are not precursors of classical eomes(+) nk cells but rather constitute a distinct lineage of innate lymphoid cells. eomes(-) nk cells are strictly dependent on both t-bet and il-15, similarly to nkt cells. ...201424516120
the escherichia coli effector espj blocks src kinase activity via amidation and adp ribosylation.the hallmark of enteropathogenic escherichia coli (epec) infection is the formation of actin-rich pedestal-like structures, which are generated following phosphorylation of the bacterial effector tir by cellular src and abl family tyrosine kinases. this leads to recruitment of the nck-wip-n-wasp complex that triggers arp2/3-dependent actin polymerization in the host cell. the same phosphorylation-mediated signalling network is also assembled downstream of the vaccinia virus protein a36 and the p ...201425523213
characterization of t-cell responses to conserved regions of the hiv-1 proteome in balb/c mice.a likely requirement for a protective vaccine against human immunodeficiency virus type 1 (hiv-1)/aids is, in addition to eliciting antibody responses, induction of effective t cells. to tackle hiv-1 diversity by t-cell vaccines, we designed an immunogen, hivconsv, derived from the most functionally conserved regions of the hiv-1 proteome and demonstrated its high immunogenicity in humans and rhesus macaques when delivered by regimens combining plasmid dna, nonreplicating simian (chimpanzee) ade ...201425230940
a novel mode of poxvirus superinfection exclusion that prevents fusion of the lipid bilayers of viral and cellular membranes.superinfection exclusion is a widespread phenomenon that prevents secondary infections by closely related viruses. the vaccinia virus a56 and k2 proteins in the cell membrane can prevent superinfection by interacting with the entry-fusion complex of subsequent viruses. here, we described another form of exclusion that is established earlier in infection and does not require the a56 or k2 protein. cells infected with one or more infectious virions excluded hundreds of superinfecting vaccinia viru ...201424920806
a loss of function analysis of host factors influencing vaccinia virus replication by rna interference.vaccinia virus (vacv) is a large, cytoplasmic, double-stranded dna virus that requires complex interactions with host proteins in order to replicate. to explore these interactions a functional high throughput small interfering rna (sirna) screen targeting 6719 druggable cellular genes was undertaken to identify host factors (hf) influencing the replication and spread of an egfp-tagged vacv. the experimental design incorporated a low multiplicity of infection, thereby enhancing detection of cellu ...201424901222
a single vertebrate dna virus protein disarms invertebrate immunity to rna virus infection.virus-host interactions drive a remarkable diversity of immune responses and countermeasures. we found that two rna viruses with broad host ranges, vesicular stomatitis virus (vsv) and sindbis virus (sinv), are completely restricted in their replication after entry into lepidopteran cells. this restriction is overcome when cells are co-infected with vaccinia virus (vacv), a vertebrate dna virus. using rnai screening, we show that lepidopteran rnai, nuclear factor-κb, and ubiquitin-proteasome pat ...201424966209
novel mode of isg15-mediated protection against influenza a virus and sendai virus in mice.isg15 is a diubiquitin-like modifier and one of the most rapidly induced genes upon type i interferon stimulation. hundreds of host proteins and a number of viral proteins have been shown to be isgylated, and understanding how these modifications affect the interferon response and virus replication has been of considerable interest. isg15(-/-) mice exhibit increased susceptibility to viral infection, and in the case of influenza b virus and vaccinia virus, isg15 conjugation has been shown to res ...201425320315
a small molecule inhibits virion attachment to heparan sulfate- or sialic acid-containing glycans.primary attachment to cellular glycans is a critical entry step for most human viruses. some viruses, such as herpes simplex virus type 1 (hsv-1) and hepatitis c virus (hcv), bind to heparan sulfate, whereas others, such as influenza a virus (iav), bind to sialic acid. receptor mimetics that interfere with these interactions are active against viruses that bind to either heparan sulfate or to sialic acid. however, no molecule that inhibits the attachment of viruses in both groups has yet been id ...201424789779
t-cell help dependence of memory cd8+ t-cell expansion upon vaccinia virus challenge relies on cd40 signaling.due to their capacity to differentiate into long-lived memory cells, cd8(+) t cells are able to resolve subsequent infections faster than during the primary response. among other factors, cd4(+) t cells play a crucial role during primary and secondary cd8(+) t-cell responses. however, the timing and mechanisms by which they influence cd8(+) t cells may differ in primary and secondary responses. here, we demonstrate that during both primary and secondary vaccinia virus infection, cd4(+) t cells a ...201424108445
cdc42 and the rho gef intersectin-1 collaborate with nck to promote n-wasp-dependent actin polymerisation.vaccinia virus enhances its cell-to-cell spread by inducing arp2/3-dependent actin polymerisation. this process is initiated by src- and abl-mediated phosphorylation of the viral transmembrane protein a36, leading to recruitment of a signalling network consisting of grb2, nck, wip and n-wasp. nck is a potent activator of n-wasp-arp2/3-dependent actin polymerisation. however, recent observations demonstrate that an interaction between nck and n-wasp is not required for vaccinia actin tail formati ...201424284073
immune control strategies for vaccinia virus-related laboratory-acquired infections.while presenting biological characteristics of vaccinia virus and laboratory-acquired infections during related research processes, this paper focuses on benefits and risks of vaccinia virus immunization in relation to laboratory-acquired infections, describes characteristics and the adaptation of vaccinia virus vaccine, analyses the role vaccinia virus immunization plays in the prevention and control of laboratory-acquired infections, and finally proposes solutions and countermeasures to furthe ...201424625408
the master regulator of the cellular stress response (hsf1) is critical for orthopoxvirus infection.the genus orthopoxviridae contains a diverse group of human pathogens including monkeypox, smallpox and vaccinia. these viruses are presumed to be less dependent on host functions than other dna viruses because they have large genomes and replicate in the cytoplasm, but a detailed understanding of the host factors required by orthopoxviruses is lacking. to address this topic, we performed an unbiased, genome-wide pooled rnai screen targeting over 17,000 human genes to identify the host factors t ...201424516381
critical role of endoplasmic reticulum aminopeptidase 1 in determining the length and sequence of peptides bound and presented by hla-b27.hla-b27 and endoplasmic reticulum aminopeptidase 1 (erap1) are the two strongest genetic factors predisposing to ankylosing spondylitis (as). a key aminopeptidase in class i major histocompatibility complex presentation, erap1 potentially contributes to the pathogenesis of as by altering hla-b27 peptide presentation. the aim of this study was to analyze the effects of erap1 on the hla-b27 peptide repertoire and peptide presentation to cytotoxic t lymphocytes (ctls).201424504800
vaccinia virus requires glutamine but not glucose for efficient replication.viruses require host cell metabolism to provide the necessary energy and biosynthetic precursors for successful viral replication. vaccinia virus (vacv) is a member of the poxviridae family, and its use as a vaccine enabled the eradication of variola virus, the etiologic agent of smallpox. a global metabolic screen of vacv-infected primary human foreskin fibroblasts suggested that glutamine metabolism is altered during infection. glutamine and glucose represent the two main carbon sources for ma ...201424501408
oncolytic vaccinia virus demonstrates antiangiogenic effects mediated by targeting of vegf.oncolytic vaccinia virus has been shown to induce a profound, rapid and tumor-specific vascular collapse in both preclinical models and clinical studies; however, a complete examination of the kinetics and levels of collapse and revascularization has not been described previously. contrast-enhanced ultrasound was used to follow tumor perfusion levels in mouse tumor models at times after vaccinia therapy. it was observed that revascularization after viral therapy was dramatically delayed and did ...201424474587
a novel oncolytic viral therapy and imaging technique for gastric cancer using a genetically engineered vaccinia virus carrying the human sodium iodide symporter.gastric cancers have poor overall survival despite recent advancements in early detection methods, endoscopic resection techniques, and chemotherapy treatments. vaccinia viral therapy has had promising therapeutic potential for various cancers and has a great safety profile. we investigated the therapeutic efficacy of a novel genetically-engineered vaccinia virus carrying the human sodium iodide symporter (hnis) gene, glv-1 h153, on gastric cancers and its potential utility for imaging with (99m ...201424383569
safety and biodistribution of a double-deleted oncolytic vaccinia virus encoding cd40 ligand in laboratory beagles.we evaluated adverse events, biodistribution and shedding of oncolytic vaccinia virus encoding cd40 ligand in two beagles, in preparation for a phase 1 trial in canine cancer patients. dog 1 received one dose of vaccinia virus and was euthanized 24 hours afterwards, while dog 2 received virus four times once weekly and was euthanized 7 days after that. dogs were monitored for adverse events and underwent a detailed postmortem examination. blood, saliva, urine, feces, and organs were collected fo ...201427119092
vaccinia virus inhibits nf-κb-dependent gene expression downstream of p65 translocation.the transcription factor nuclear factor kappa light-chain enhancer of activated b cells (nf-κb) plays a critical role in host defense against viral infection by inducing the production of proinflammatory mediators and type i interferon. consequently, viruses have evolved many mechanisms to block its activation. the poxvirus vaccinia virus (vacv) encodes numerous inhibitors of nf-κb activation that target multiple points in the signaling pathway. a derivative of vacv strain copenhagen, called vv8 ...201424371075
characterization and structure of the vaccinia virus nf-κb antagonist a46.successful vaccinia virus (vacv) replication in the host requires expression of viral proteins that interfere with host immunity, such as antagonists of the activation of the proinflammatory transcription factor nf-κb. two such vacv proteins are a46 and a52. a46 interacts with the toll-like receptor/interleukin-1r (tir) domain of toll-like receptors and intracellular adaptors such as mal (myd88 adapter-like), tram (tir domain-containing adapter-inducing interferon-β (trif)-related adaptor molecu ...201424356965
development and comparison of a quantitative taqman-mgb real-time pcr assay to three other methods of quantifying vaccinia virions.plaque assays are a widely used method to quantify stocks of viruses. although this method is well established for titrating viral stocks, it is time consuming and can take several days to complete. in this study, the creation and validation of a quantitative real-time pcr (qpcr) assay for enumerating virions of vaccinia virus is reported. pcr primers and a minor groove-binding probe were designed to hybridize to the dna polymerase gene (e9l) from a number of different orthopoxviruses. the numbe ...201424211297
virus-encoded ectopic cd74 enhances poxvirus vaccine efficacy.vaccinia virus (vv) has been used globally as a vaccine to eradicate smallpox. widespread use of this viral vaccine has been tempered in recent years because of its immuno-evasive properties, with restrictions prohibiting vv inoculation of individuals with immune deficiencies or atopic skin diseases. vv infection is known to perturb several pathways for immune recognition including mhc class ii (mhcii) and cd1d-restricted antigen presentation. mhcii and cd1d molecules associate with a conserved ...201424205828
vaccinia virus glv-1h153 in combination with 131i shows increased efficiency in treating triple-negative breast cancer.we investigated the therapeutic efficacy of a replication-competent oncolytic vaccinia virus, glv-1h153, carrying human sodium iodide symporter (hnis), in combination with radioiodine in an orthotopic triple-negative breast cancer (tnbc) murine model. in vitro viral infection was confirmed by immunoblotting and radioiodine uptake assays. orthotopic xenografts (mda-mb-231 cells) received intratumoral injection of glv-1h153 or pbs. one week after viral injection, xenografts were randomized into 4 ...201424186964
il-18 expression results in a recombinant vaccinia virus that is highly attenuated and immunogenic.interferon-γ (ifn-γ) is an attenuating factor for vaccinia virus (vacv), decreasing its virulence in vivo by more than a million fold. it is also a highly effective adjuvant when administered at the time of immunization with protein antigens. however, recombinant vacv (rvacv) vaccines expressing ifn-γ do not induce enhanced immune responses. it is possible that the ifn-γ expressed by rvacvs induces both an antiviral state and increased immunological clearance, thus resulting in decreased levels ...201424168450
the d10 decapping enzyme of vaccinia virus contributes to decay of cellular and viral mrnas and to virulence in mice.posttranscriptional mechanisms are important for regulation of cellular and viral gene expression. the presence of the 5' cap structure m(7)g(5')ppp(5')nm is a general feature of mrnas that provides protection from exoribonuclease digestion and enhances translation. vaccinia virus and other poxviruses encode enzymes for both cap synthesis and decapping. decapping is mediated by two related enzymes, d9 and d10, which are synthesized before and after viral dna replication, respectively. the timing ...201424155373
t-cell engager-armed oncolytic vaccinia virus significantly enhances antitumor therapy.oncolytic vaccinia virus (vv) therapy has shown promise in preclinical models and in clinical studies. however, complete responses have rarely been observed. this lack of efficacy is most likely due to suboptimal virus spread through the tumor resulting in limited tumor cell destruction. we reasoned that redirecting t cells to the tumor has the potential to improve the antitumor activity of oncolytic vvs. we, therefore, constructed a vv encoding a secretory bispecific t-cell engager consisting o ...201424135899
langerin+ dermal dc, but not langerhans cells, are required for effective cd8-mediated immune responses after skin scarification with vaccinia virus.skin scarification (s.s.) with vaccinia virus (vacv) is essential for generation of an optimal protective t-cell memory immune response. dendritic cells (dcs), which are professional antigen-presenting cells, are required for naive t-cell priming and activation. at least three subsets of skin-resident dc have been identified: langerhans cells (lcs), dermal langerin+ dc (lang+ ddc), and dermal langerin- dc (lang- ddc). using langerin-diphtheria toxin receptor mice and established mouse model of v ...201424126845
preventing the return of smallpox: molecular modeling studies on thymidylate kinase from variola virus.smallpox was one of the most devastating diseases in the human history and still represents a serious menace today due to its potential use by bioterrorists. considering this threat and the non-existence of effective chemotherapy, we propose the enzyme thymidylate kinase from variola virus (vartmpk) as a potential target to the drug design against smallpox. we first built a homology model for vartmpk and performed molecular docking studies on it in order to investigate the interactions with inhi ...201423998201
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