Publications

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antiviral activities and phosphorylation of 5-halo-2'-deoxyuridines and n-methanocarbathymidine in cells infected with vaccinia virus.the antipoxviral activities and phosphorylation of n-methanocarbathymidine ([n]-mct) and four 5-halo-2'-deoxyuridines, namely 5-fluoro-(fdu), 5-chloro-(cldu), 5-bromo-(brdu), and 5-iodo-(idu) derivatives, were explored.200818610554
reduced protection from simian immunodeficiency virus sivmac251 infection afforded by memory cd8+ t cells induced by vaccination during cd4+ t-cell deficiency.adaptive cd4(+) and cd8(+) t-cell responses have been associated with control of human immunodeficiency virus/simian immunodeficiency virus (hiv/siv) replication. here, we have designed a study with indian rhesus macaques to more directly assess the role of cd8 siv-specific responses in control of viral replication. macaques were immunized with a dna prime-modified vaccinia virus ankara (mva)-siv boost regimen under normal conditions or under conditions of antibody-induced cd4(+) t-cell deficien ...200818667509
boosting bcg vaccination with mva85a down-regulates the immunoregulatory cytokine tgf-beta1.in clinical trials recombinant-modified vaccinia virus ankara expressing the mycobacterium tuberculosis antigen 85a (mva85a) induces approximately 10 times more effector t cells than any other recombinant mva vaccine. we have found that in bcg primed subjects mva85a vaccination reduces transforming growth factor beta 1 (tgf-beta1) mrna in peripheral blood lymphocytes and reduces tgf-beta1 protein in the serum, but increases ifn-gamma elispot responses to the recall antigen sk/sd. tgf-beta1 is es ...200818682270
viral targeting of dead box protein 3 reveals its role in tbk1/ikkepsilon-mediated irf activation.viruses are detected by different classes of pattern recognition receptors (prrs), such as toll-like receptors and rig-like helicases. engagement of prrs leads to activation of interferon (ifn)-regulatory factor 3 (irf3) and irf7 through ikkepsilon and tbk1 and consequently ifn-beta induction. vaccinia virus (vacv) encodes proteins that manipulate host signalling, sometimes by targeting uncharacterised proteins. here, we describe a novel vacv protein, k7, which can inhibit prr-induced ifn-beta i ...200818636090
vaccinia virus wr53.5/f14.5 protein is a new component of intracellular mature virus and is important for calcium-independent cell adhesion and vaccinia virus virulence in mice.the vaccinia virus wr53.5l/f14.5l gene encodes a small conserved protein that was not detected previously. however, additional proteomic analyses of different vaccinia virus isolates and strains revealed that the wr53.5 protein was incorporated into intracellular mature virus (imv). the wr53.5 protein contains a putative n-terminal transmembrane region and a short c-terminal region. protease digestion removed the c terminus of wr53.5 protein from imv particles, suggesting a similar topology to t ...200818684811
dose-dependent lymphocyte apoptosis following respiratory infection with vaccinia virus.recently there has been renewed interest in poxvirus pathogenesis, especially with regard to infection via the respiratory route. members of this family are known to produce a number of proteins that have the potential to negatively regulate the immune response. vaccinia virus (vacv) has been used for a number of years as a model for the study of poxvirus infection. we have previously reported a dose-dependent decrease in virus-specific cd8(+) t cells following respiratory infection with vacv. i ...200818692098
oncolytic vaccinia virotherapy of anaplastic thyroid cancer in vivo.anaplastic thyroid carcinoma (atc) is a fatal disease with a median survival of only 6 months. novel therapies are needed to improve dismal outcomes.200818697871
safety and immunologic response of a viral vaccine to prostate-specific antigen in combination with radiation therapy when metronomic-dose interleukin 2 is used as an adjuvant.we have previously reported on the safety and immunologic response of a poxvirus-based vaccine encoding prostate-specific antigen (psa) used in combination with radiation therapy in patients with localized prostate cancer. we hypothesized that a "metronomic" dose of interleukin 2 (il-2) as a biological adjuvant would cause less toxicity while maintaining immunologic response.200818698048
the vaccinia virus gene i2l encodes a membrane protein with an essential role in virion entry.the previously unstudied vaccinia virus gene i2l is conserved in all orthopoxviruses. we show here that the 8-kda i2 protein is expressed at late times of infection, is tightly associated with membranes, and is encapsidated in mature virions. we have generated a recombinant virus in which i2 expression is dependent upon the inclusion of tetracycline in the culture medium. in the absence of i2, the biochemical events of the viral life cycle progress normally, and virion morphogenesis culminates i ...200818701587
vaccinia virus encodes i5, a small hydrophobic virion membrane protein that enhances replication and virulence in mice.the vaccinia virus i5l open reading frame encodes a 79-amino-acid protein, with two predicted transmembrane domains, that is conserved among all sequenced members of the chordopoxvirus subfamily. no nonpoxvirus homologs or functional motifs have been recognized, and the role of the i5 protein remains unknown. we found that synthesis of i5 was dependent on viral dna replication and occurred exclusively at late times, consistent with a consensus late promoter motif adjacent to the start of the ope ...200818701595
vaccinia virus proteins a52 and b14 share a bcl-2-like fold but have evolved to inhibit nf-kappab rather than apoptosis.vaccinia virus (vacv), the prototype poxvirus, encodes numerous proteins that modulate the host response to infection. two such proteins, b14 and a52, act inside infected cells to inhibit activation of nf-kappab, thereby blocking the production of pro-inflammatory cytokines. we have solved the crystal structures of a52 and b14 at 1.9 a and 2.7 a resolution, respectively. strikingly, both these proteins adopt a bcl-2-like fold despite sharing no significant sequence similarity with other viral or ...200818704168
immunogenic properties of plant-derived recombinant smallpox vaccine candidate pb5.the extracellular virion membrane protein b5 is a potent inducer of immune responses capable of protecting mice and primates against poxvirus infections. here, we examined the antibody response induced in mice immunized intramuscularly (i.m.) or intranasally (i.n.) with plant-derived b5 (pb5) accompanied or not with plant total soluble protein (tsp) at various concentrations. increasing amounts of tsp inhibited the pb5-specific response in both i.m.- and i.n.-immunized mice, with more dramatic e ...200818706953
the profilin:actin complex localizes to sites of dynamic actin polymerization at the leading edge of migrating cells and pathogen-induced actin tails.a unique set of affinity-purified anti-profilin and anti-actin antibodies generated against a covalently coupled version of the profilin:actin complex was used to assess the distribution of profilin and non-filamentous actin in mouse melanoma cells. in agreement with the profilin:actin complex being the principal source of actin for filament formation, we observed extensive co-distribution of both antibody preparations with vasodilator-stimulated phosphoprotein (vasp) and the p34 subunit of the ...200818707793
the antiallodynic effect of neurotropin is mediated via activation of descending pain inhibitory systems in rats with spinal nerve ligation.neurotropin, a nonprotein extract isolated from inflamed skin of rabbits inoculated with vaccinia virus, is widely used in japan to treat chronic pain such as neuropathic pain. although some studies have been conducted on the mechanism of the antiallodynic action of neurotropin, this mechanism has yet to be adequately clarified.200818713930
optimization of plasmid-only rescue of highly attenuated and temperature-sensitive respiratory syncytial virus (rsv) vaccine candidates for human trials.respiratory syncytial virus (rsv) is the most common cause of severe bronchiolitis in infants and young children in the u.s. no licensed rsv vaccines are currently available. established techniques for recovering rsv from cdna utilize mammalian cells, such as hep-2 or bsr t7/5, that are not currently suitable for vaccine manufacture. when using hep-2 cells, co-infection with an attenuated vaccinia virus that expresses t7 rna polymerase is also required. for human clinical trials, processes that ...200818722472
[construction and biological characteristic for the recombinant modified vaccinia virus ankara co-expressing modified gp5 and m protein of porcine reproductive and respiratory syndrome virus].modified orf5 (morf5) and orf6 gene of prrsv were cloned into two multiple cloning sites of mva transfer vector plr-gpt to construct the recombinant plasmid plr-morf5/orf6. homologous recombination between plr-morf5/orf6 and the wtmva on bhk-21 cell line was mediated with liposome by infecting the cell with 0.01 moi wtmva two hours before transfecting the recombinant plasmid into the cell. when the cytopathic effect (cpe) was obvious, virus was collected from the cell plate and the recombinant v ...200818724695
vrk1 phosphorylates creb and mediates ccnd1 expression.vaccinia virus b1 kinase plays a key role in viral dna replication. the homologous mammalian vaccinia-related kinases (vrks) are also implicated in the regulation of dna replication, although direct evidence remains elusive. here we show that vrk1 regulates cell cycle progression in the dna replication period by inducing cyclin d1 (ccnd1) expression. furthermore, depletion of vrk1 in human cancer cells reduces the fraction of cells in s phase at a given time. vrk1 specifically enhances activity ...200818713830
vaccinia virus subverts a mitochondrial antiviral signaling protein-dependent innate immune response in keratinocytes through its double-stranded rna binding protein, e3.skin keratinocytes provide a first line of defense against invading microorganisms in two ways: (i) by acting as a physical barrier to pathogen entry and (ii) by initiating a vigorous innate immune response upon sensing danger signals. how keratinocytes detect virus infections and generate antiviral immune responses is not well understood. orthopoxviruses are dermatotropic dna viruses that cause lethal disease in humans. virulence in animal models depends on the virus-encoded bifunctional z-dna/ ...200818715932
viral complement regulators: the expert mimicking swindlers.the complement system is a principal bastion of innate immunity designed to combat a myriad of existing as well as newly emerging pathogens. since viruses are obligatory intracellular parasites, they are continuously exposed to host complement assault and, therefore, have imbibed various strategies to subvert it. one of them is molecular mimicry of the host complement regulators. large dna viruses such as pox and herpesviruses encode proteins that are structurally and functionally similar to hum ...200718341208
activity of the anti-orthopoxvirus compound st-246 against vaccinia, cowpox and camelpox viruses in cell monolayers and organotypic raft cultures.the potential use of variola virus as a biological weapon has renewed efforts in the development of antiviral agents against orthopoxviruses. st-246 [4-trifluoromethyl-n-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-di oxo-4,6-ethenocycloprop [f]isoindol-2(1 h)-yl)-benzamide] is an anti-orthopoxvirus compound active against several orthopoxviruses including vaccinia virus (vv), cowpox virus (cpv), camelpox virus (cmlv), ectromelia virus (ectv) and variola virus in cell culture. the compound has been shown ...200718240860
[screening and application of enhancer-like sequences from vaccinia virus].to screen enhancer-like sequences from vaccinia virus genome, to construct an expression vector harboring prokaryotic enhancer-like sequence and study the effect of interferon gene expression.200718322583
antimicrobial peptides as new recognition molecules for screening challenging species.the goal of this study was to evaluate binding of four targets of biodefense interest to immobilized antimicrobial peptides (amps) in biosensor assays. polymyxins b and e, melittin, cecropins a, b, and p, parasin, bactenecin and magainin-1, as well as control antibodies, were used as capture molecules for detection of cy3-labeled venezuelan equine encephalitis virus (vee), vaccinia virus, c. burnetti and b. melitensis. although vee, vaccinia virus and c. burnetti did not show any binding activit ...200718231571
[effect of extracts from rabbit skin inflamed by vaccinia virus in the management of postherpetic neuralgia and on serum interleukin-6 level in aged patients].to observe the effect of the extracts from rabbit skin inflamed by vaccinia virus for injection, a commercially available agent (analgecine), in the treatment of postherpetic neuralgia (phn) in aged patients and its influence on serum interleukin-6 (il-6) level.200718159027
efficient development of plasmodium liver stage-specific memory cd8+ t cells during the course of blood-stage malarial infection.immunity to plasmodium liver stages in individuals in malaria-endemic areas is inextricably linked to concomitant blood-stage parasitemia. although plasmodium sporozoite infection induces measurable cd8+ t cell responses, the development of memory t cells during active erythrocytic infection remains uncharacterized. using transgenic t cells, we assessed antigen-specific effector cd8+ t cell responses induced by normal (norspz) and radiation-attenuated (irrspz) plasmodium yoelii sporozoites. the ...200718190264
targeting of interferon-beta to produce a specific, multi-mechanistic oncolytic vaccinia virus.oncolytic viruses hold much promise for clinical treatment of many cancers, but a lack of systemic delivery and insufficient tumor cell killing have limited their usefulness. we have previously demonstrated that vaccinia virus strains are capable of systemic delivery to tumors in mouse models, but infection of normal tissues remains an issue. we hypothesized that interferon-beta (ifn-beta) expression from an oncolytic vaccinia strain incapable of responding to this cytokine would have dual benef ...200718162040
brazilian vaccinia viruses and their origins.although the world health organization (who) declared global smallpox eradicated in 1980, concerns over emergent poxvirus infections have increased. most poxvirus infections are zoonotic; exploring their genetic diversity will illuminate the genetic and evolutionary aspects of poxvirus infections, ecology, and epidemiology. in recent decades, several strains of the orthopoxvirus vaccinia virus (vacv) have been isolated throughout brazil, including genetically distinct isolates within the same ou ...200718214166
alkyne-azide click chemistry mediated carbanucleosides synthesis.hitherto unknown 1,4-disubstituted-[1,2,3]-triazolo-4',4'-dihydroxymethyl-3'-deoxy carbanucleosides were synthesized based on a "click approach." various alkynes were introduced on a key azido intermediate by the "click" 1,3-dipolar huisgen cycloaddition. their antiviral activities and cellular toxicities were evaluated on vaccinia virus. none of the synthesized compounds exhibited a significant antiviral activity.200718066789
specific tumor cell targeting by a recombinant mva expressing a functional single chain antibody on the surface of intracellular mature virus (imv) particles.recombinant vaccinia virus with tumor cell specificity may provide a versatile tool either for direct lysis of cancer cells or for the targeted transfer of genes encoding immunomodulatory or toxic molecules. we report the expression of a tumor-specific single-chain antibody on the surface of intracellular mature vaccinia virus particles (imv). the wild-type p14 externally membrane-associated protein p14 (a27l gene), which is not required for viral binding and replication, was replaced by p14 fus ...200718158739
new analogs of acyclovir substituted at the side chain.a series of novel analogs of acyclovir, substituted with an alkyl (methyl, ethyl, n-butyl) or phenyl group at the positions 1', 4', and/or 5', has been obtained in a direct one-pot coupling reaction of guanosine and the respective 1,3-dioxolanes. the new acyclonucleosides were essentially inactive in antiviral (hsv, vv, vsv, hbv) evaluation in vitro.200718058508
mucosal priming with replicative tiantan vaccinia and systemic boosting with dna vaccine raised strong mucosal and systemic hiv-specific immune responses.an effective vaccine strategy for hiv-1 will probably require the induction and maintenance of both humoral and cellular immunity at mucosal and systemic sites. we tested a new prime-boost approach of intranasal priming with 3 x 10(6) pfu of replicative recombinant tiantan vaccinia virus (rttv) and intramuscular boosting with 100 microg dna plasmid expressing hiv-1 gag in balb/c mice along with other strategies. our data demonstrated that intranasal priming with replicative recombinant tiantan v ...200718061316
treatment of anaplastic thyroid carcinoma in vitro with a mutant vaccinia virus.anaplastic thyroid carcinoma (atc) is a fatal disease resistant to all conventional treatments. novel therapies are needed to improve dismal outcomes.200718063085
poxviral b1 kinase overcomes barrier to autointegration factor, a host defense against virus replication.barrier to autointegration factor (baf) is a dna-binding protein found in the nucleus and cytoplasm of eukaryotic cells that functions to establish nuclear architecture during mitosis. herein, we demonstrate a cytoplasmic role for baf in host defense during poxviral infections. vaccinia is the prototypic poxvirus, a family of dna viruses that replicate exclusively in the cytoplasm of infected cells. mutations in the vaccinia b1 kinase (b1) compromise viral dna replication, but the mechanism by w ...200718005698
new pseudonucleosides containing chiral oxazolidin-2-ones and cyclosulfamides as aglycones: synthesis and antiviral evaluation.a series of chiral cyclosulfamides and oxazolidinon-2-ones have been synthesized starting from aminoacids. regioselective substitution of these pseudopyrimidic heterocyles was carried out under mitsunobu conditions. best substitution results were obtained by preliminary deprotection of cyclosulfamides and their condensation with beta-d-ribofuranose. chiral oxazolidin-2-ones were coupled directly with d-ribofuranose. all compounds were tested against hsv-2, vv and sv viruses. two compounds 6b and ...200718066822
cd4 t cells are required for cd8 t cell survival during both primary and memory recall responses.the role of cd4 t cell help in primary and secondary cd8 t cell responses to infectious pathogens remains incompletely defined. the primary cd8 t response to infections was initially thought to be largely independent of cd4 t cells, but it is not clear why some primary, pathogen-specific cd8 t cell responses are cd4 t cell dependent. furthermore, although the generation of functional memory cd8 t cells is cd4 t cell help dependent, it remains controversial when the "help" is needed. in this stud ...200718056368
discovery of small molecule inhibitors of ubiquitin-like poxvirus proteinase i7l using homology modeling and covalent docking approaches.essential for viral replication and highly conserved among poxviridae, the vaccinia virus i7l ubiquitin-like proteinase (ulp) is an attractive target for development of smallpox antiviral drugs. at the same time, the i7l proteinase exemplifies several interesting challenges from the rational drug design perspective. in the absence of a published i7l x-ray structure, we have built a detailed 3d model of the i7l ligand binding site (s2-s2' pocket) based on exceptionally high structural conservatio ...200717960327
safety, immunogenicity and protective efficacy in mice of a new cell-cultured lister smallpox vaccine candidate.it is now difficult to manufacture the first-generation smallpox vaccine, as the process could not comply with current safety and manufacturing regulations. in this study, a candidate non-clonal second-generation smallpox vaccine developed by sanofi-pasteur from the lister strain has been assessed using a cowpox virus challenge in mice. we have observed similar safety, immunogenicity and protection (from disease and death) after a short or long interval following vaccination, as well as similar ...200717964011
clinical and immunologic responses to multiple doses of imvamune (modified vaccinia ankara) followed by dryvax challenge.smallpox vaccination with replication deficient vaccinia strains such as modified vaccinia ankara (mva) may induce protective immunity with improved safety and tolerability profiles compared with currently available smallpox vaccines. ninety subjects were randomized equally to six groups in a partially blinded, randomized, controlled clinical trial. imvamune (mva-bn, bavarian nordic a/s, kvistgård, denmark) vaccine or placebo was administered at study days 0 and 28 by subcutaneous or intramuscul ...200718036708
genomic differences of vaccinia virus clones from dryvax smallpox vaccine: the dryvax-like acam2000 and the mouse neurovirulent clone-3.conventional vaccines used for smallpox eradication were often denoted one or another strain of vaccinia virus (vacv), even though seed virus was sub-cultured multifariously, which rendered the virion population genetically heterogeneous. acam2000 cell culture vaccine, recently licensed in the u.s., consists of a biologically vaccine-like vacv homogeneous-sequence clone from the conventional smallpox vaccine dryvax, which we verified from dryvax sequence chromatograms is genetically heterogeneou ...200718037545
poxvirus-based vaccine therapy for patients with advanced pancreatic cancer.an open-label phase 1 study of recombinant prime-boost poxviruses targeting cea and muc-1 in patients with advanced pancreatic cancer was conducted to determine safety, tolerability and obtain preliminary data on immune response and survival.200718039393
baffled by poxviruses?successful viruses engage in a dynamic interplay with their hosts, where both utilize diverse strategies to impose their supremacy. in this issue of cell host & microbe, wiebe and traktman describe a novel interaction between vaccinia virus and mammalian cells. a host protein called baf can bind ectopic cytoplasmic dna and block viral dna replication, whereas vaccinia in turn counteracts this inhibition with a virus-encoded serine threonine kinase that inactivates baf.200718005693
colocalization of transcription and translation within cytoplasmic poxvirus factories coordinates viral expression and subjugates host functions.poxviruses are large dna viruses that include the causal agent of human smallpox and vaccinia virus. poxviruses replicate in cytoplasmic foci known as dna factories. here we show that a virus-encoded transcription factor, viral mrna, cellular rna-binding protein heterodimer g3bp/caprin-1 (p137), translation initiation factors eif4e and eif4g, and ribosomal proteins are concentrated in the same subdomains of cytoplasmic dna factories. furthermore, a cell coinfected with two recombinant vaccinia v ...200718005740
immunisation with bcg and recombinant mva85a induces long-lasting, polyfunctional mycobacterium tuberculosis-specific cd4+ memory t lymphocyte populations.in the search for effective vaccines against intracellular pathogens such as hiv, tuberculosis and malaria, recombinant viral vectors are increasingly being used to boost previously primed t cell responses. published data have shown prime-boost vaccination with bcg-mva85a (modified vaccinia virus ankara expressing antigen 85a) to be highly immunogenic in humans as measured by ex vivo ifn-gamma elispot. here, we used polychromatic flow cytometry to investigate the phenotypic and functional profil ...200717948267
f11l-mediated inhibition of rhoa-mdia signaling stimulates microtubule dynamics during vaccinia virus infection.microtubules play an important role in the transport of viral pathogens during the establishment of their infection cycles. the microtubule cytoskeleton also facilitates efficient release of newly assembled progeny at later stages of infection. however, the precise effects of viral infection on microtubule dynamics are not understood. using live-cell imaging, we show that vaccinia virus stimulates increases in peripheral microtubule dynamics at 8 hr postinfection. infection also increases the fr ...200718005700
the release of vaccinia virus from infected cells requires rhoa-mdia modulation of cortical actin.prior to being released from the infected cell, intracellular enveloped vaccinia virus particles are transported from their perinuclear assembly site to the plasma membrane along microtubules by the motor kinesin-1. after fusion with the plasma membrane, stimulation of actin tails beneath extracellular virus particles acts to enhance cell-to-cell virus spread. however, we lack molecular understanding of events that occur at the cell periphery just before and during the liberation of virus partic ...200718005701
comparison of a semipermeable dressing bonded to an absorbent pad and a semipermeable dressing over a separate gauze pad for containment of vaccinia virus at the vaccination site.to compare the ability of 2 types of dressings to contain vaccinia virus after smallpox vaccination.200717952843
genomic sequence of chorioallantois vaccinia virus ankara, the ancestor of modified vaccinia virus ankara.chorioallantois vaccinia virus ankara (cva) is the parental virus of modified vaccinia virus ankara (mva), which was derived from cva by more than 570 passages in chicken embryo fibroblasts (cef). mva became severely host-cell-restricted to avian cells and has strongly diminished virulence in mammalian hosts, while maintaining good immunogenicity. we determined the complete coding sequence of the parental cva and mapped the exact positions of the six major deletions that emerged in the mva genom ...200718024893
[expression of influenza a3 virus (h3n2) m2 gene in vaccinia virus tiantan strain].to construct a recombinant vaccinia virus rvj1175m2 expressing influenza a3 virus (h3n2) m2 gene, full length gene encoding influenza virus (h3n2) m2 protein was amplified with pcr and cloned into plasmid pjsc1175 which was used for homologous recombination with vaccinia virus tiantan strain. along with this, a recombinant vaccinia virus rvj1175m2 containing the m2 gene was subsequently constructed. it was identified by pcr that the gene of m2 protein was inserted into the tk locus of vaccinia v ...200717969855
mass spectrometry and peptide-based vaccine development.the development of new vaccines against pathogens is an important part of infectious disease control. in the last decade, a variety of proteins giving rise to naturally processed pathogen-derived antigenic peptides, representing b-cell and t-cell epitopes, have been characterized. numerous candidate vaccines consisting of synthetic peptides are being designed and evaluated, with encouraging results. in this context, the application of mass spectrometry based on the isolation and identification o ...200717971823
[a novel system for producing lentiviral vectors].the aim was to develop a cell culture system capable of producing high titer lentiviral vector stocks with recombinant vaccinia viruses as helpers. bhk21 was co-transfected by three main plasmids containing the transducing plasmid pvecrna, the packaging plasmid pgagpol and the envelop plasmid pvsvg, and thereafter infected with the vaccinia vtf-3 containing bacteriophage t7 rna polymerase gene using lipofectamine2000. after 4 days incubation, the culture supernatant of lentiviral vectors was col ...200718051882
characterization of dna-binding activity of z alpha domains from poxviruses and the importance of the beta-wing regions in converting b-dna to z-dna.the e3l gene is essential for pathogenesis in vaccinia virus. the e3l gene product consists of an n-terminal z alpha domain and a c-terminal double-stranded rna (dsrna) binding domain; the left-handed z-dna-binding activity of the z alpha domain of e3l is required for viral pathogenicity in mice. e3l is highly conserved among poxviruses, including the smallpox virus, and it is likely that the orthologous z alpha domains play similar roles. to better understand the biological function of e3l prot ...200717984076
prevention of vaccinia infection in a laboratory worker.because smallpox may be a weapon, immunization programs have been restarted and research continues with vaccinia (smallpox vaccine). ocular complications occur in 5 to 9% of those who contract smallpox and in 10 to 20 per million vaccinia recipients through self-inoculation or from contact with vaccinated individuals. both variola virus (smallpox) and vaccinia virus (smallpox vaccine) are orthopoxviruses that can cause conjunctival and eyelid infections, cornea ulceration, keratitis, iritis, opt ...200717985778
redirecting adaptive immunity against foreign antigens to tumors for cancer therapy.immunotherapy for cancer is often limited by weak immunogenicity of tumor antigens. however, immune systems are usually strong and effective against foreign invading antigens. to test whether the destructive effect of adaptive immunity against foreign antigens can be redirected to tumors for cancer therapy, we immunized mice with adenovector expressing lacz (ad/cmv-lacz). subcutaneous syngeneic tumors were then established in the immunized animals or in naïve animals. the immune response against ...200717986853
[design and construction of transfer vectors in order to obtain recombinant modified vaccinia virus ankara (mva)].modified vaccinia virus ankara (mva) constitutes a good candidate for the development of non-replicative expression viral vectors because it does not replicate in most of mammalian cells. it is essential, for the production of recombinant mva, the availability of transfer vectors which allow the introduction of desired genes into non-essential regions for in vitro viral replication, by homologous recombination with the viral genome. in the present work, the transfer vectors named vt-mha and vt-m ...200717987847
structural insights into the mechanism and evolution of the vaccinia virus mrna cap n7 methyl-transferase.the vaccinia virus mrna capping enzyme is a multifunctional heterodimeric protein associated with the viral polymerase that both catalyses the three steps of mrna capping and regulates gene transcription. the structure of a subcomplex comprising the c-terminal n7-methyl-transferase (mt) domain of the large d1 subunit, the stimulatory d12 subunit and bound s-adenosyl-homocysteine (adohcy) has been determined at 2.7 a resolution and reveals several novel features of the poxvirus capping enzyme. th ...200717989694
poxvirus dna primase.poxviruses are large enveloped viruses that replicate in the cytoplasm of vertebrate or invertebrate cells. at least six virus-encoded proteins are required for synthesis and processing of the double-stranded dna genome of vaccinia virus, the prototype member of the family. one of these proteins, d5, is an ntpase that contains an n-terminal archaeoeukaryotic primase domain and a c-terminal superfamily iii helicase domain. here we report that individual conserved aspartic acid residues in the pre ...200718000036
tail scarification with vaccinia virus lister as a model for evaluation of smallpox vaccine potency in mice.since smallpox eradication by the who during the 1980s, potency of new vaccines is compared to vaccines that were used during the eradication campaign. in this work we characterize the tail scarification technique in mice as a model for scarification in humans. similar to humans, mice develop "clinical take" which is dependent on the vaccination dose. appearance of anti-vaccinia igm is followed by igg antibodies 10 days post scarification and lasting more then 1(1/2) years. mice with "clinical t ...200717928110
detuning cd8 t cells: down-regulation of cd8 expression, tetramer binding, and response during ctl activation.cd8 is critical for t cell recognition of peptide/class i major histocompatability complex ligands, yet is down-regulated during activation of cd8 t cells. we report that loss of cd8 expression early during in vivo responses to vaccinia virus or listeria monocytogenes (lm) correlates with decreased t cell staining with specific class i/peptide tetramers and reduced cd8 t cell sensitivity for antigen. loss of cd8 cell surface expression occurs despite sustained mrna expression, and cd8 levels ret ...200717954566
adjuvanting a dna vaccine with a tlr9 ligand plus flt3 ligand results in enhanced cellular immunity against the simian immunodeficiency virus.dna vaccines offer promising strategies for immunization against infections. however, their clinical use requires improvements in immunogenicity. we explored the efficacy of toll-like receptor (tlr) ligands (tlr-ls) on augmenting the immunogenicity of a dna prime-modified vaccinia virus ankara (mva) boost vaccine against siv. rhesus macaques were injected with fms-like tyrosine kinase 3 (flt3)-ligand (fl) to expand dendritic cells (dcs) and were primed with a dna vaccine encoding immunodeficienc ...200717954572
boosting bcg with recombinant modified vaccinia ankara expressing antigen 85a: different boosting intervals and implications for efficacy trials.to investigate the safety and immunogenicity of boosting bcg with modified vaccinia ankara expressing antigen 85a (mva85a), shortly after bcg vaccination, and to compare this first with the immunogenicity of bcg vaccination alone and second with a previous clinical trial where mva85a was administered more than 10 years after bcg vaccination.200717957238
eradication of solid human breast tumors in nude mice with an intravenously injected light-emitting oncolytic vaccinia virus.previously, we reported that a recombinant vaccinia virus (vacv) carrying a light-emitting fusion gene enters, replicates in, and reveals the locations of tumors in mice. a new recombinant vacv, glv-1h68, as a simultaneous diagnostic and therapeutic agent, was constructed by inserting three expression cassettes (encoding renilla luciferase-aequorea green fluorescent protein fusion, beta-galactosidase, and beta-glucuronidase) into the f14.5l, j2r (encoding thymidine kinase) and a56r (encoding hem ...200717942938
[oncolytic virotherapy: new strategies in oncology].the introduction of new therapeutical approaches to the medical practice has never been an easy task. on the one hand, modern therapies have to fulfil the strict requirements of the industry, on the other, patients and therapists have usually high expectations towards them. thus, the public's initial euphoric emotions can quickly turn into pessimism following the experience of the first complications and difficulties of the new therapeutic method. regarding oncolytic virotherapy, the emerging tr ...200717947194
cognate memory cd4+ t cells generated with dendritic cell priming influence the expansion, trafficking, and differentiation of secondary cd8+ t cells and enhance tumor control.cd4(+) t cells are known to provide support for the activation and expansion of primary cd8(+) t cells, their subsequent differentiation, and ultimately their survival as memory cells. however, the importance of cognate memory cd4(+) t cells in the expansion of memory cd8(+) t cells after re-exposure to ag has been not been examined in detail. using bone marrow-derived dendritic cells pulsed with cognate or noncognate mhc class i- and class ii-restricted peptides, we examined whether the presenc ...200717947656
immune responses against hcv-ns3 after accidental infection with hcv-ns3 recombinant vaccinia virus. 200717927619
combination of intratumoral injections of vaccinia virus mva expressing gm-csf and immunization with dna vaccine prolongs the survival of mice bearing hpv16 induced tumors with downregulated expression of mhc class i molecules.downregulation of mhc class i molecules is believed to be often the cause of tumor immune escape and at the same time it is the major obstacle to t-cell based immunotherapy of tumors. in our experimental model, the c57bl/6 mice bearing tumors induced by tc-1/a9 cells characterized by expression of hpv16 oncogenes and downregulation of h-2b molecules were immunized with highly immunogenic e7ggg.gus dna vaccine expressing the fused gene of modified hpv16 e7 (e7ggg) with e.coli beta-glucuronidase ( ...200717822323
the 29-nucleotide deletion present in human but not in animal severe acute respiratory syndrome coronaviruses disrupts the functional expression of open reading frame 8.one of the most striking and dramatic genomic changes observed in the severe acute respiratory syndrome coronavirus (sars-cov) isolated from humans soon after its zoonotic transmission from palm civets was the acquisition of a characteristic 29-nucleotide deletion. this occurred in open reading frame 8 (orf8), one of the accessory genes unique to the sars-cov. the function of orf8 and the significance of the deletion are unknown. the intact orf8 present in animal and some early human isolates en ...200717928347
human cd4+ t cell epitopes from vaccinia virus induced by vaccination or infection.despite the importance of vaccinia virus in basic and applied immunology, our knowledge of the human immune response directed against this virus is very limited. cd4(+) t cell responses are an important component of immunity induced by current vaccinia-based vaccines, and likely will be required for new subunit vaccine approaches, but to date vaccinia-specific cd4(+) t cell responses have been poorly characterized, and cd4(+) t cell epitopes have been reported only recently. classical approaches ...200717937498
identification of novel antipoxviral agents: mitoxantrone inhibits vaccinia virus replication by blocking virion assembly.the bioterror threat of a smallpox outbreak in an unvaccinated population has mobilized efforts to develop new antipoxviral agents. by screening a library of known drugs, we identified 13 compounds that inhibited vaccinia virus replication at noncytotoxic doses. the anticancer drug mitoxantrone is unique among the inhibitors identified in that it has no apparent impact on viral gene expression. rather, it blocks processing of viral structural proteins and assembly of mature progeny virions. the ...200717928345
dna branch nuclease activity of vaccinia a22 resolvase.dna replication, recombination, and repair can result in formation of diverse branched dna structures. many large dna viruses are known to encode dna branch nucleases, but several of the expected activities have not previously been found among poxvirus enzymes. vaccinia encodes an enzyme, a22 resolvase, which is known to be active on four-stranded dna junctions (holliday junctions) or holliday junction-like structures containing three of the four strands. here we report that a22 resolvase in fac ...200717890227
co-expressing gp5 and m proteins under different promoters in recombinant modified vaccinia virus ankara (rmva)-based vaccine vector enhanced the humoral and cellular immune responses of porcine reproductive and respiratory syndrome virus (prrsv).the porcine reproductive and respiratory syndrome virus (prrsv) has three major structural proteins which designated as gp5, m, and n. protein gp5 and m have been considered very important to arouse the humoral and cellular immune responses against prrsv infection and proposed to be the excellent candidate proteins in the design of prrs bioengineering vaccine. there were some attempts on expressing gp5 or m in dna vaccine and adenovirus to arouse humoral and cellular immune responses, but few pa ...200717922181
neph1 cooperates with nephrin to transduce a signal that induces actin polymerization.while the mechanisms that regulate actin dynamics in cellular motility are intensively studied, relatively little is known about signaling events that transmit outside-in signals and direct assembly and regulation of actin polymerization complexes at the cell membrane. the kidney podocyte provides a unique model for investigating these mechanisms since deletion of nephrin or neph1, two interacting components of the specialized podocyte intercellular junction, results in abnormal podocyte morphog ...200717923684
understanding respiratory syncytial virus (rsv) vaccine-enhanced disease.respiratory syncytial virus (rsv) is the most common cause of lower respiratory tract infection in infants and children worldwide. in addition, rsv causes serious disease in elderly and immune compromised individuals. rsv infection of children previously immunized with a formalin-inactivated (fi)-rsv vaccine is associated with enhanced disease and pulmonary eosinophilia that is believed to be due to an exaggerated memory th2 response. as a consequence, there is currently no licensed rsv vaccine ...200717917067
[expression of recombinant spike protein of sars-coronavirus in vaccinia virus and analysis of its immunogenicity].a recombinant vaccinia virus (rwr-sars-s)expressing spike protein of severe acute respiratory syndrome coronavirus was constructed. the expression of full length recombinant sars spike protein (rss) in hela cells possessing specific reaction ability to chicken anti-sera was confirmed by sds-page and western-blot (190 kd). hela cells infected with rwr-sars-s also showed high sensitivity in detecting specific serum antibody by indirect immunofluoresence assay (ifa). the results above indicated tha ...200717894231
human neonatal dendritic cells are competent in mhc class i antigen processing and presentation.neonates are clearly more susceptible to severe disease following infection with a variety of pathogens than are adults. however, the causes for this are unclear and are often attributed to immunological immaturity. while several aspects of immunity differ between adults and neonates, the capacity of dendritic cells in neonates to process and present antigen to cd8+ t cells remains to be addressed. we used human cd8+ t cell clones to compare the ability of neonatal and adult monocyte-derived den ...200717895997
high level protein expression in mammalian cells using a safe viral vector: modified vaccinia virus ankara.vaccinia virus vectors are attractive tools to direct high level protein synthesis in mammalian cells. in one of the most efficient strategies developed so far, the gene to be expressed is positioned downstream of a bacteriophage t7 promoter within the vaccinia genome and transcribed by the t7 rna polymerase, also encoded by the vaccinia virus genome. tight regulation of transcription and efficient translation are ensured by control elements of the escherichia coli lactose operon and the encepha ...200717892951
granzyme b production distinguishes recently activated cd8(+) memory cells from resting memory cells.for immune diagnostic purposes it would be critical to be able to distinguish between ongoing immune processes, such as active infections, and long-term immune memory, for example imprinted by infections that have been cleared a long time ago or by vaccinations. we tested the hypothesis that the secretion of granzyme b, as detected in ex vivo elispot assays, permits this distinction. we studied ebv-, flu- and cmv-specific cd8(+) cells in healthy individuals, vaccinia virus-reactive cd8(+) cells ...200717825804
impaired immune response to vaccinia virus inoculated at the site of cutaneous allergic inflammation.patients with atopic dermatitis (ad) exposed to the vaccinia virus (vv) smallpox vaccine have an increased risk of developing eczema vaccinatum.200717889291
substrate specificity of homogeneous monkeypox virus uracil-dna glycosylase.weak or nonexistent smallpox immunity in today's human population raises concerns about the possibility of natural or provoked genetic modifications leading to re-emergence of variola virus and other poxviruses. thus, the development of new antiviral strategies aimed at poxvirus infections in humans is a high priority. the dna repair protein uracil-dna glycosylase (ung) is one of the viral enzymes important for poxvirus pathogenesis. consequently, the inhibition of ung is a rational therapeutic ...200717910420
different contribution of co-stimulatory molecules b7.1 and b7.2 to the immune response to recombinant modified vaccinia virus ankara vaccine expressing prm/e proteins of japanese encephalitis virus and two hepatitis b virus vaccines.this study clarifies the role of co-stimulatory molecules b7.1 and b7.2 in the immune response to 3 types of vaccines: a/ recombinant modified vaccinia virus ankara (mva) (vjh9) expressing prm/e proteins of japanese encephalitis virus (jev), b/ recombinant yeast-expressed hepatitis b virus (yhbv), c/ human plasma-derived hepatitis b virus (phbv). we constructed plasmids expressing b7.1 and b7.2 molecules and found that the expression level of b7.2 protein in transfected cho-k1 cells was higher t ...200717900219
cd8 t cells inhibit respiratory syncytial virus (rsv) vaccine-enhanced disease.vaccination of children with a formalin-inactivated (fi) respiratory syncytial virus (rsv) vaccine led to exacerbated disease including pulmonary eosinophilia following a natural rsv infection. immunization of balb/c mice with fi-rsv or a recombinant vaccinia virus (vv) expressing the rsv attachment (g) protein (vvg) results in a pulmonary th2 response and eosinophilia after rsv challenge that closely mimics the rsv vaccine-enhanced disease observed in humans. the underlying causes of rsv vaccin ...200717911628
effect of oral treatment with hexadecyloxypropyl-[(s)-9-(3-hydroxy-2- phosphonylmethoxypropyl)adenine] [(s)-hpmpa] or octadecyloxyethyl-(s)-hpmpa on cowpox or vaccinia virus infections in mice.we have previously reported that (s)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine, or (s)-hpmpa, is active in vitro against cowpox virus (cv) and vaccinia virus (vv) but is not active orally in animals. however, the ether lipid esters of (s)-hpmpa, hexadecyloxypropyl-[(s)-hpmpa] [hdp-(s)-hpmpa] and octadecyloxyethyl-[(s)-hpmpa] [ode-(s)-hpmpa], had significantly enhanced activity in vitro and are orally bioavailable in mice. in the current study, hdp-(s)-hpmpa and ode-(s)-hpmpa were prepared i ...200717846137
interactions between human immunodeficiency virus type 1 and vaccinia virus in human lymphoid tissue ex vivo.vaccinia virus (vacv) has been attracting attention recently not only as a vector for various vaccines but also as an immunization tool against smallpox because of its potential use as a bioterrorism agent. it has become evident that in spite of a long history of studies of vacv, its tissue pathogenesis remains to be fully understood. here, we investigated the pathogenesis of vacv and its interactions with human immunodeficiency virus type 1 (hiv-1) in the context of human lymphoid tissues. we f ...200717804502
myxoma virus and oncolytic virotherapy: a new biologic weapon in the war against cancer.oncolytic virotherapy is an innovative alternative to more conventional cancer therapies. the ability of some viruses to specifically target and kill malignant cancerous cells while leaving normal tissue unscathed has opened a large repertoire of new and selective cancer killing therapeutic candidates. poxviruses, such as vaccinia virus, have a long history of use in humans as live vaccines and have more recently been studied as potential platforms for delivery of immunotherapeutics and attenuat ...200717727330
recombinant sendai virus induces t cell immunity against respiratory syncytial virus that is protective in the absence of antibodies.respiratory syncytial virus (rsv) causes severe respiratory disease in infants and a vaccine is highly desirable. the fusion (f) protein of rsv is an important vaccine target, but the contribution of f-specific t cells to successful vaccination remains unclear. we studied the immune response to vaccination of mice with a recombinant sendai virus expressing rsv f (rsev f). rsev f induced protective neutralizing antibody and rsv f-specific ctl responses. t cell immunity was stronger than that indu ...200717904538
an accelerated vaccine schedule with a poly-antigenic hepatitis c virus mva-based candidate vaccine induces potent, long lasting and in vivo cross-reactive t cell responses.we designed and evaluated in hla-class i transgenic mouse models a hepatitis c virus (hcv) t cell-based mva vectored vaccine expressing three viral antigens known to be targets of potent cd8+- and cd4+-mediated responses. an accelerated (3 week-based) vaccination induced specific cd8+ t cells harboring two effector functions (cytolytic activity - both in vitro and in vivo- and production of ifngamma) as well as specific cd4+ t cells recognizing all three vaccine antigens. responses were long las ...200717875349
characterization of a second vaccinia virus mrna-decapping enzyme conserved in poxviruses.vaccinia virus (vacv) encodes enzymes that cap the 5' end of viral mrnas, which enhances their stability and translation. nevertheless, recent studies demonstrated that the vacv d10 protein (vacv-wr_115) decaps mrna, an enzymatic activity not previously shown to be encoded by a virus. the decapping activity of d10 is dependent on a nudix hydrolase motif that is also present in the vacv d9 protein (vacv-wr_114), which shares 25% sequence identity with d10. here, we showed that a purified recombin ...200717881455
feeding by the tick, ixodes scapularis, causes cd4(+) t cells responding to cognate antigen to develop the capacity to express il-4.effects of tick feeding on an early antigen-specific t cell response were studied by monitoring a clonotypic population of adoptively transferred t cell receptor (tcr) transgenic cd4 cells responding to a tick-associated antigen. when recipient mice were infested with pathogen-free ixodes scapularis nymphs several days prior to t cell transfer and intradermal injection of soluble cognate antigen at the feeding site, the clonotypic cd4 cells gained the ability to express the th2 effector cytokine ...200717883452
the role of human beta defensins and cathelicidins in atopic dermatitis.atopic dermatitis is a chronic inflammatory skin disease associated with significant barrier disruption, t-helper type 2 mediated skin inflammation, and an impaired innate immune response. these characteristics increase the susceptibility of atopic dermatitis patients to recurrent skin infections, some of which may have potentially fatal implications. the mechanisms resulting in this increased propensity for skin infections have been an area of active investigation.200717873581
inactivation of orthopoxvirus for diagnostic pcr analysis.diagnoses of ongoing viral infections commonly rely on pcr methodology. sample material that may contain hazardous virus should be efficiently inactivated in biological containment or bed-side before diagnostic pcr analysis. surprisingly little documentation is available for inactivation of human viral pathogens by inactivation reagents that allow for subsequent pcr diagnostics. it is now shown that pathogenic dna viruses (orthopoxvirus) are completely inactivated by a commercially available roc ...200717850891
modified vaccinia virus ankara induces toll-like receptor-independent type i interferon responses.modified vaccinia virus ankara (mva) is a highly attenuated vaccinia virus strain undergoing clinical evaluation as a replication-deficient vaccine vector against various infections and tumor diseases. to analyze the basis of its high immunogenicity, we investigated the mechanism of how mva induces type i interferon (ifn) responses. mva stimulation of bone marrow-derived dendritic cells (dc) showed that plasmacytoid dc were main alpha ifn (ifn-alpha) producers that were triggered independently o ...200717855554
antibodies to the a27 protein of vaccinia virus neutralize and protect against infection but represent a minor component of dryvax vaccine--induced immunity.the smallpox vaccine dryvax, which consists of replication-competent vaccinia virus, elicits antibodies that play a major role in protection. several vaccinia proteins generate neutralizing antibodies, but their importance for protection is unknown. we investigated the potency of antibodies to the a27 protein of the mature virion in neutralization and protection experiments and the contributions of a27 antibodies to dryvax-induced immunity. using a recombinant a27 protein (ra27), we confirmed th ...200717763325
viremia in human cowpox virus infection.several poxviruses can infect humans and cause diseases of varying severity. besides the eradicated variola virus that induced high mortality rates, numerous further human pathogenic orthopoxviruses are potentially fatal but generally cause less severe infections. while infection-related viremia was described for variola virus and seems to be rare for monkeypox virus, it is still debated for vaccinia virus. so far, viremia in cowpox virus-infected humans has not been reported.200717765007
extended follow-up following a phase 2b randomized trial of the candidate malaria vaccines fp9 me-trap and mva me-trap among children in kenya."ffm me-trap" is sequential immunisation with two attenuated poxvirus vectors (fp9 and modified vaccinia virus ankara) delivering the pre-erythrocytic malaria antigen me-trap. over nine months follow-up in our original study, there was no evidence that ffm me-trap provided protection against malaria. the incidence of malaria was slightly higher in children who received ffm me-trap, but this was not statistically significant (hazard ratio 1.5, 95% ci 1.0-2.3). although the study was unblinded, an ...200717710125
absence of pharyngeal shedding of vaccinia following smallpox vaccination.to examine oral shedding of vaccinia in volunteers who were recently vaccinated against smallpox, pharyngeal swabs were collected for viral culture between days 3 and 5 and days 6 and 8 after vaccination with diluted sanofi pasteur smallpox vaccine. from 102 adult volunteers (48 vaccinia-naive, 54 vaccinia-experienced), vaccinia was not detected in any specimen (0/201, 95% confidence interval, 0-1.8), which suggests a lack of oral shedding of vaccinia after immunization. this supports recommenda ...200717765564
zoonotic vaccinia virus infection in brazil: clinical description and implications for health professionals.bovine vaccinia virus outbreaks have been occurring in different regions of brazil. we report here the time course of natural human infection by vaccinia virus and describe important clinical and epidemiological aspects of this zoonotic infection. the diagnosis of vaccinia virus infection was based on clinical, serological, and molecular procedures.200717287326
5t4-modified vaccinia ankara: progress in tumor-associated antigen-based immunotherapy.both the expression and biology of the tumor-associated antigen (taa) 5t4 suggest that it is an effective target for cancer immunotherapy. this paper reviews the development of a novel immunotherapeutic vaccine comprising the highly attenuated modified vaccinia ankara virus encoding 5t4 (mva-5t4, aka trovax). preclinical studies have demonstrated that mva-5t4 is safe and highly effective in both the prophylactic and active treatment of syngeneic murine tumor models. more importantly, > 700 doses ...200717727334
il-23 enhances host defense against vaccinia virus infection via a mechanism partly involving il-17.to investigate roles of il-23 in viral infection, we have engineered recombinant vaccinia virus (vv) expressing il-12 (vv-il-12) and expressing il-23 (vv-il-23). we found vv-il-23 was less virulent in balb/c mice than wild-type vv (vv-wt), indicating that il-23 enhances resistance to vv. vv-specific ctl activity in vv-il-23-infected mice was slightly higher than activity in vv-wt-inoculated mice, although antiviral ab production and nk activity were not increased. il-12/23p40-deficient mice surv ...200717785829
detection of human papillomavirus type 16-specific t lymphocytes by a recombinant vaccinia virus-based enzyme-linked immunospot assay.cell-mediated immunity, particularly that induced by t cells, is thought to have a key role in controlling infection. the enzyme-linked immunospot (elispot) assay has been successfully adapted to detect t-cell immune response to a variety of pathogens. however, it still remains a challenge to detect antigen-specific t cells when the numbers of circulating cells are low, such as in a local cervical infection caused by genital human papillomavirus (hpv). the goal of this study was to develop a pro ...200717314231
durable neutralizing antibodies after remote smallpox vaccination among adults with and without hiv infection.the only us licensed vaccine with established efficacy against smallpox, dryvax, is contraindicated for hiv patients. detectable smallpox-neutralizing antibodies are still present among us adults. this study compared vaccinia-neutralizing antibody titers between 20 hiv-infected and 20 uninfected veterans matched for age and military entry. vaccinia-neutralizing antibodies were detected in 95% hiv-infected and 100% uninfected veterans; 40% hiv-infected and 70% uninfected adults had protective tit ...200717301573
inhibiting lentiviral replication by hexim1, a cellular negative regulator of the cdk9/cyclin t complex.tat-dependent transcriptional elongation is crucial for the replication of hiv-1 and depends on positive transcription elongation factor b complex (p-tefb), composed of cyclin dependent kinase 9 (cdk9) and cyclin t. hexamethylene bisacetamide-induced protein 1 (hexim1) inhibits p-tefb in cooperation with 7sk rna, but direct evidence that this inhibition limits the replication of hiv-1 has been lacking. in the present study we examined whether the expression of flag-tagged hexim1 (hexim1-f) affec ...200717314519
a new inhibitor of apoptosis from vaccinia virus and eukaryotes.a new apoptosis inhibitor is described from vaccinia virus, camelpox virus, and eukaryotic cells. the inhibitor is a hydrophobic, multiple transmembrane protein that is resident in the golgi and is named gaap (golgi anti-apoptotic protein). stable expression of both viral gaap (v-gaap) and human gaap (h-gaap), which is expressed in all human tissues tested, inhibited apoptosis induced by intrinsic and extrinsic apoptotic stimuli. conversely, knockout of h-gaap by sirna induced cell death by apop ...200717319741
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