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tricyclononene carboxamide derivatives as novel anti-hiv-1 agents.by modifying the chemical structure of anti-orthopoxvirus compound st-246, we designed and synthesized a series of tricyclononene carboxamide derivatives and tested their anti-hiv-1 activity and cytotoxicity. we found that benzoimidazol-containing compound 7g was highly effective in inhibiting hiv-1 r5 infection with an ic(50) value of 0.41 microm and a selectivity index of 292, but it exhibited no significant inhibitory activity on hiv-1 reverse transcriptase, integrase and protease. comfa was ...201020598780
real-time pcr assays for the specific detection of monkeypox virus west african and congo basin strain dna.orthopoxvirus monkeypox (mpxv) forms two distinct clades: the mpxv congo basin clade viruses are endemic in the congo basin, human illness typically presents with symptoms similar to discrete, ordinary smallpox and has a case fatality rate of approximately 10% in unvaccinated populations; the mpxv west african clade viruses have been isolated in west africa and appear to cause a less severe, and less inter-human transmissible disease. recently, monkeypox outbreaks were reported in us and sudan c ...201020643162
single-shot immunization with recombinant adenovirus encoding vaccinia virus glycoprotein a27l is protective against a virulent respiratory poxvirus infection.significant safety issues have emerged concerning the general use of dryvax vaccine. vaccination with replication-defective recombinant adenovirus (rad) vaccines may offer a safer and effective alternative to live vaccinia virus (vv) vaccination. six individual poxvirus glycoproteins: a33r, a34r, a36r, b5r, a27l or l1r that are normally expressed on the surface of infectious vaccinia virus were encoded in rad vaccines and tested in mice in this study. a single-shot intramuscular injection of rad ...201020653083
rapid non-enzymatic extraction method for isolating pcr-quality camelpox virus dna from skin.molecular diagnostic investigations of orthopoxvirus (opv) infections are performed using a variety of clinical samples including skin lesions, tissues from internal organs, blood and secretions. skin samples are particularly convenient for rapid diagnosis and molecular epidemiological investigations of camelpox virus (cmlv). classical extraction procedures and commercial spin-column-based kits are time consuming, relatively expensive, and require multiple extraction and purification steps in ad ...201020654652
a protein-based smallpox vaccine protects non-human primates from a lethal monkeypox virus challenge.concerns about infections caused by orthopoxviruses, such as variola and monkeypox viruses, drive ongoing efforts to develop novel smallpox vaccines that are both effective and safe to use in diverse populations. a subunit smallpox vaccine comprising vaccinia virus membrane proteins a33, b5, l1, a27 and aluminum hydroxide (alum) ± cpg was administered to non-human primates, which were subsequently challenged with a lethal intravenous dose of monkeypox virus. alum adjuvanted vaccines provided onl ...201020659519
diazepam leads to enhanced severity of orthopoxvirus infection and immune suppression.benzodiazepines are drugs widely used as tranquilizers and in various other indications. we treated balb/c mice with diazepam and infected them with cowpox (cpxv) and vaccinia virus (vacv). disease index, weight loss and the antibody response were determined. additionally the influence of different benzodiazepines on the mitogen response of human peripheral blood lymphocytes and spleen cells was tested. diazepam led to earlier disease onset, prolonged duration of symptoms, higher weight loss and ...201020659521
gene expression profiling of monkeypox virus-infected cells reveals novel interfaces for host-virus interactions.monkeypox virus (mpv) is a zoonotic orthopoxvirus and a potential biothreat agent that causes human disease with varying morbidity and mortality. members of the orthopoxvirus genus have been shown to suppress antiviral cell defenses, exploit host cell machinery, and delay infection-induced cell death. however, a comprehensive study of all host genes and virus-targeted host networks during infection is lacking. to better understand viral strategies adopted in manipulating routine host biology on ...201020667104
analysis of a47, an immunoprevalent protein of vaccinia virus, leads to a reevaluation of the total antiviral cd8+ t cell response.vaccinia virus (vacv) is the prototypic orthopoxvirus and was the live vaccine used to eradicate smallpox. in addition, vacv is a possible vector for recombinant vaccines. despite these reasons for study, the roles of many vacv genes are unknown, and some fundamental aspects, such as the total size of immune responses, remain poorly characterized. vacv gene a47l is of interest because it is highly transcribed, has no sequence similarity to any nonpoxvirus gene, and contains a larger-than-expecte ...201020668091
animal models of orthopoxvirus infection.smallpox was one of the most devastating diseases known to humanity. although smallpox was eradicated through a historically successful vaccination campaign, there is concern in the global community that either variola virus (varv), the causative agent of smallpox, or another species of orthopoxvirus could be used as agents of bioterrorism. therefore, development of countermeasures to orthopoxvirus infection is a crucial focus in biodefense research, and these efforts rely on the use of various ...201020682806
interaction of orthopoxviruses with the cellular ubiquitin-ligase system.protein modification by ubiquitin or ubiquitin-like polypeptides is important for the fate and functions of the majority of proteins in the eukaryotic cell and can be involved in regulation of various biological processes, including protein metabolism (degradation), protein transport to several cellular compartments, rearrangement of cytoskeleton, and transcription of cytoprotective genes. the accumulated experimental data suggest that the ankyrin-f-box-like and btb-kelch-like proteins of orthop ...201020703935
localized cowpox infection in a 5-month-old rottweiler.cowpox virus (cpxv) infections are a sporadic cause of localized or disseminated skin disease in domestic animals and humans in europe. rodents are considered the primary reservoir host for cpxv. cats can become infected by close contact with rodents and are the most important source of human infections. recently, public awareness has also been drawn to cpxv infections by an outbreak of rat to human infections in central europe. in dogs, cpxv infections are rare. here we report a case of a 5-mon ...201120735769
cellular impedance measurement as a new tool for poxvirus titration, antibody neutralization testing and evaluation of antiviral substances.impedance-based biosensing known as real-time cell electronic sensing (rt-ces) belongs to an emerging technology for analyzing the status of cells in vitro. in the present study protocols were developed for an rt-ces-based system (xcelligence™, roche applied science, acea biosciences inc.) to supplement conventional techniques in pox virology. first, proliferation of cells susceptible to orthopoxviruses was monitored. for virus titration cells were infected with vaccinia virus and cell status, r ...201020828538
evaluating the orthopoxvirus type i interferon-binding molecule as a vaccine target in the vaccinia virus intranasal murine challenge model.the biological threat imposed by orthopoxviruses warrants the development of safe and effective vaccines. we developed a candidate orthopoxvirus dna-based vaccine, termed 4pox, which targets four viral structural components, a33, b5, a27, and l1. while this vaccine protects mice and nonhuman primates from lethal infections, we are interested in further enhancing its potency. one approach to enhance potency is to include additional orthopoxvirus immunogens. here, we investigated whether vaccinati ...201020844086
[orthopoxviruses: infections in humans. position of the blood working group of the federal ministry of health]. 201020853093
third-generation smallpox vaccines: challenges in the absence of clinical smallpox.smallpox, a disease caused by variola virus, is estimated to have killed hundreds of millions to billions of people before it was certified as eradicated in 1980. however, there has been renewed interest in smallpox vaccine development due in part to zoonotic poxvirus infections and the possibility of a re-emergence of smallpox, as well as the fact that first-generation smallpox vaccines are associated with relatively rare, but severe, adverse reactions in some vaccinees. an understanding of the ...201020860482
comparative sequence analysis of b5r gene of zoonotic buffalo pox virus isolates with other orthopoxviruses.the present paper describes the isolation of buffalo pox virus from scab lesions and its molecular characterization through b5r gene sequencing. during our study, pustular pox lesions were observed on the teats and mammary parenchyma of cattle and buffaloes, and the disease was of significant zoonotic importance since similar lesions were produced on the hands, legs, and face of people in close contact with the affected animals. the collected scab materials were subjected for virus isolation in ...201020936505
interaction of poxvirus intracellular mature virion proteins with the tpr domain of kinesin light chain in live infected cells revealed by two-photon-induced fluorescence resonance energy transfer fluorescence lifetime imaging microscopy.using two-photon-induced fluorescence lifetime imaging microscopy, we corroborate an interaction (previously demonstrated by yeast two-hybrid domain analysis) of full-length vaccinia virus (vacv; an orthopoxvirus) a36 protein with the cellular microtubule motor protein kinesin. quenching of enhanced green fluorescent protein (egfp), fused to the c terminus of vacv a36, by monomeric red fluorescent protein (mdsred), fused to the tetratricopeptide repeat (tpr) domain of kinesin, was observed in li ...201020943972
the inability of vaccinia virus a33r protein to form intermolecular disulfide-bonded homodimers does not affect the production of infectious extracellular virus.the orthopoxvirus protein a33 forms a disulfide-bonded high molecular weight species that could be either a homodimer or a heteromultimer. the protein is a major target for neutralizing antibodies and the majority of antibodies raised against a33 only recognize the disulfide-bonded form. here, we report that a33 is present as a disulfide-bonded homodimer during infection. additionally, we examined the function of intermolecular disulfide bonding in a33 homodimerization during infection. we show ...201020947114
nigericin is a potent inhibitor of the early stage of vaccinia virus replication.poxviruses remain a significant public health concern due to their potential use as bioterrorist agents and the spread of animal borne poxviruses, such as monkeypox virus, to humans. thus, the identification of small molecule inhibitors of poxvirus replication is warranted. vaccinia virus is the prototypic member of the orthopoxvirus genus, which also includes variola and monkeypox virus. in this study, we demonstrate that the carboxylic ionophore nigericin is a potent inhibitor of vaccinia viru ...201020951746
camelpox: epidemiology, diagnosis and control measures.camelpox is an economically important contagious skin disease of camelids caused by camelpox virus (cmlv) and is characterized by mild local skin infection and less common severe systemic infections. the disease is confined to camel-rearing belts particularly in developing countries and causes economic impact due to considerable loss in terms of morbidity, mortality, loss of weight and reduction in milk yield. the virus has gained attention from researchers due to its recent emergence with close ...201020954883
rabbitpox: a model of airborne transmission of smallpox.smallpox is a human disease caused by infection with variola virus, a member of the genus orthopoxvirus. although smallpox has been eradicated, concern that it might be reintroduced through bioterrorism has therefore led to intensive efforts to develop new vaccines and antiviral drugs against this disease. because these vaccines and therapeutics cannot be tested in human trials, it is necessary to test such medical countermeasures in different animal models. although several orthopoxviruses caus ...201020965981
polycyclic n-benzamido imides with potent activity against vaccinia virus.the synthesis and antiviral activity of a series of novel polycyclic analogues of the orthopoxvirus egress inhibitor tecovirimat (st-246) is presented. several of these compounds display sub-micromolar activity against vaccinia virus, and were more potent than cidofovir (cdv). the more active compounds were about 10-fold more active than cdv, with minimum cytotoxic concentrations above 100 μm. chemical manipulations of the two carbon-carbon double bonds present in the compounds were carried out ...201020967819
impact of st-246® on acam2000™ smallpox vaccine reactogenicity, immunogenicity, and protective efficacy in immunodeficient mice.although a highly effective vaccine against smallpox, vaccinia virus (vv) is not without adverse events, some of which can be life-threatening, particularly in immunocompromised individuals. we have recently demonstrated that the immunogenicity and protective efficacy of dryvax(®) in immunocompetent mice is preserved even when co-administered with st-246, an orally bioavailable small-molecule inhibitor of orthopoxvirus egress and dissemination. in addition, st-246 markedly reduced the reactogeni ...201021036130
inhibition of poxvirus spreading by the anti-tumor drug gefitinib (iressa).the threat of smallpox virus as a bioterrorist weapon is raising international concerns again since the anthrax attacks in the usa in 2001. the medical readiness of treating patients suffering from such infections is a prerequisite of an effective civil defense system. currently the only therapeutic option for the treatment of poxvirus infections relies on the virostatic nulceosid analog cidofovir, although severe side effects and drug resistant strains have been described. a growing understandi ...201021094187
lung surfactant dppg phospholipid inhibits vaccinia virus infection.vaccinia virus (vacv) was used as a surrogate of variola virus (genus orthopoxvirus), the causative agent of smallpox, to study orthopoxvirus infection via the respiratory airway. lung surfactant, a physiological barrier to infection encountered by the virus, is predominantly composed of phospholipids whose role during orthopoxvirus infection has not been investigated. an attenuated lister strain, derived from the traditional smallpox vaccine and the western reserve (wr) strain, lethal for mice ...201021095206
formation of antiviral cytoplasmic granules during orthopoxvirus infection.vaccinia virus (vv) mutants lacking the double-stranded rna (dsrna)-binding e3l protein (δe3l mutant vv) show restricted replication in most cell types, as dsrna produced by vv activates protein kinase r (pkr), leading to eif2α phosphorylation and impaired translation initiation. here we show that cells infected with δe3l mutant vv assemble cytoplasmic granular structures which surround the vv replication factories at an early stage of the nonproductive infection. these structures contain the st ...201021147913
therapeutic vaccines and antibodies for treatment of orthopoxvirus infections.despite the eradication of smallpox several decades ago, variola and monkeypox viruses still have the potential to become significant threats to public health. the current licensed live vaccinia virus-based smallpox vaccine is extremely effective as a prophylactic vaccine to prevent orthopoxvirus infections, but because of safety issues, it is no longer given as a routine vaccine to the general population. in the event of serious human orthopoxvirus infections, it is important to have treatments ...201021197387
smallpox vaccines: targets of protective immunity.the eradication of smallpox, one of the great triumphs of medicine, was accomplished through the prophylactic administration of live vaccinia virus, a comparatively benign relative of variola virus, the causative agent of smallpox. nevertheless, recent fears that variola virus may be used as a biological weapon together with the present susceptibility of unimmunized populations have spurred the development of new-generation vaccines that are safer than the original and can be produced by modern ...201121198662
molecular dating in the evolution of vertebrate poxviruses.objectives: the goal of this work was to study the evolutionary history of the vertebrate poxviruses using the bayesian relaxed clock and a large set of highly conserved vitally important viral genes. methods: phylogenetic analysis was performed by the maximum likelihood method using the paup program. the dating method of bayes, realized in the multidivtime, was made. results: the rate of poxviral evolution is estimated as 0.5-7 × 10(-6) nucleotide substitutions per site per year. we inferred th ...201121228539
massively parallel pathogen identification using high-density microarrays.identification of microbial pathogens in clinical specimens is still performed by phenotypic methods that are often slow and cumbersome, despite the availability of more comprehensive genotyping technologies. we present an approach based on whole-genome amplification and resequencing microarrays for unbiased pathogen detection. this 10 h process identifies a broad spectrum of bacterial and viral species and predicts antibiotic resistance and pathogenicity and virulence profiles. we successfully ...200821261824
acute vesiculopapular rash in the setting of atopic dermatitis.atopic dermatitis is a common entity encountered in clinical practice. a subgroup within the atopic dermatitis cohort may develop viral infection on skin lesions appearing as a vesiculopapular pattern. this process is termed eczema herpeticum and may pose a challenge to the clinician as it can appear similar to orthopoxvirus infections, most notably smallpox and monkeypox. because these conditions are considered as potential bioterrorism threats, confirmatory testing via histological examination ...201021265484
n1l is an ectromelia virus virulence factor and essential for in vivo spread upon respiratory infection.the emergence of zoonotic orthopoxvirus infections and the threat of possible intentional release of pathogenic orthopoxviruses have stimulated renewed interest in understanding orthopoxvirus infections and the resulting diseases. ectromelia virus (ectv), the causative agent of mousepox, offers an excellent model system to study an orthopoxvirus infection in its natural host. here, we investigated the role of the vaccinia virus ortholog n1l in ectv infection. respiratory infection of mice with a ...201121270149
solution structure of a dna duplex containing the potent anti-poxvirus agent cidofovir.cidofovir (1(s)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine, cdv) is a potent inhibitor of orthopoxvirus dna replication. prior studies have shown that, when cdv is incorporated into a growing primer strand, it can inhibit both the 3'-to-5' exonuclease and the 5'-to-3' chain extension activities of vaccinia virus dna polymerase. this drug can also be incorporated into dna, creating a significant impediment to trans-lesion dna synthesis in a manner resembling dna damage. cdv and deoxycytidine ...201121280608
[modeling spatial structures of variola and cowpox virus tnf-binding crmb proteins bound to murine or human tnf].orthopoxviruses bear in their genomes several genes coding for homologous secreted proteins able to bind tumor necrosis factor. different species of the genus possess different sets of these tumor necrosis factor-binding proteins. viriola virus encodes the only one of them named crmb. despite sharing high sequence identity, crmb proteins belonging to distinct orthopoxviral species were shown to significantly differ by their physico-chemical and biological properties. we modeled spatial structure ...201021290827
cowpox virus inhibits human dendritic cell immune function by nonlethal, nonproductive infection.orthopoxviruses encode multiple proteins that modulate host immune responses. we determined whether cowpox virus (cpxv), a representative orthopoxvirus, modulated innate and acquired immune functions of human primary myeloid dcs and plasmacytoid dcs and monocyte-derived dcs (mddcs). a cpxv infection of dcs at a multiplicity of infection of 10 was nonproductive, altered cellular morphology, and failed to reduce cell viability. a cpxv infection of dcs did not stimulate cytokine or chemokine secret ...201121334039
efficacy of cmx001 as a prophylactic and presymptomatic antiviral agent in new zealand white rabbits infected with rabbitpox virus, a model for orthopoxvirus infections of humans.cmx001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (cdv), is being developed as a treatment for smallpox. cmx001 has dramatically increased potency versus cdv against all dsdna viruses and, in contrast to cdv, is orally available and has shown no evidence of nephrotoxicity in healthy volunteers or severely ill transplant patients to date. although smallpox has been eliminated from the environment, treatments are urgently being sought due t ...201121369346
genus specific evolution of codon usage and nucleotide compositional traits of poxviruses.poxviruses are complex in their nucleotide compositional features of the coding regions. the codon usages in poxviruses are in accordance with their compositional bias. in the poxviridae family, codon usage patterns and nucleotide compositional traits are widely divergent across species but some conservation was observed within a genus. viruses from six chordopox genera, i.e., avipoxvirus, capripoxvirus, cervidpoxvirus, orthopoxvirus, suipoxvirus, yatapoxvirus, and one entomopox genus- betaentom ...201121369827
efficacy of cmx001 as a post exposure antiviral in new zealand white rabbits infected with rabbitpox virus, a model for orthopoxvirus infections of humans.cmx001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (cdv), is being developed as a treatment for smallpox. in the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. previously, we demonstrated the efficacy of cmx001 in protecting new zealand white rabbits from mortality following intradermal infection with rabbitpox virus as a model for smallpox, monkeypox and for treatment of adverse reactions ...201121373379
poxvirus infection in a cat with presumptive human transmission.the present report describes a case of generalized cowpox virus infection with necrotizing facial dermatitis in a cat and a likely transmission to an animal keeper. the viral aetiology was confirmed by histopathology, immunohistochemistry, pcr, virus isolation, dna sequencing and electron microscopy. histopathological examination of the cat's skin revealed a severe, necrotizing dermatitis with ballooning degeneration and hyperplasia of epithelial cells with pathognomonic cytoplasmic eosinophilic ...201121375609
vaccinia virus as an expression vector.vaccinia virus (vv) is a member of the genus orthopoxvirus, one of seven genera included in the family poxviridae. most of these viruses infect vertebrates (orthopoxvirus, avipoxvirus, capripoxvirus, leporipoxvirus, suipoxvirus, and parapoxvirus), but one genus, entomopoxvirus, infects insects. it is interesting to note that the fibroma and mixoma viruses of the leporipoxvirus genus cause tumors in their hosts (rabbits), these being the only tumorigenic viruses in the family (1,2).199221390715
cd94 is essential for nk cell-mediated resistance to a lethal viral disease.it is well established that natural killer (nk) cells confer resistance to many viral diseases, but in only a few instances the molecular mechanisms whereby nk cells recognize virus-infected cells are known. here we show that cd94, a molecule preferentially expressed by nk cells, is essential for the resistance of c57bl/6 mice to mousepox, a disease caused by the orthopoxvirus ectromelia virus. ectromelia virus-infected cells expressing the major histocompatibility complex (mhc) class ib molecul ...201121439856
orthopox virus infections in eurasian wild rodents.abstract the genus orthopoxvirus includes variola (smallpox) virus and zoonotic cowpox virus (cpxv). all orthopoxviruses (opv) are serologically cross-reactive and cross-protective, and after the cessation of smallpox vaccination, cpxv and other opv infections represent an emerging threat to human health. in this respect cpxv, with its reservoir in asymptomatically infected wild rodents, is of special importance. in europe, clinical cowpox has been diagnosed in both humans and animals. the main ...201121453121
orthopoxvirus dna in eurasian lynx, sweden.cowpox virus, which has been used to protect humans against smallpox but may cause severe disease in immunocompromised persons, has reemerged in humans, domestic cats, and other animal species in europe. orthopoxvirus (opv) dna was detected in tissues (lung, kidney, spleen) in 24 (9%) of 263 free-ranging eurasian lynx (lynx lynx) from sweden. thymidine kinase gene amplicon sequences (339 bp) from 21 lynx were all identical to those from cowpox virus isolated from a person in norway and phylogene ...201121470451
vaccinia virus infections in martial arts gym, maryland, usa, 2008.vaccinia virus is an orthopoxvirus used in the live vaccine against smallpox. vaccinia virus infections can be transmissible and can cause severe complications in those with weakened immune systems. we report on a cluster of 4 cases of vaccinia virus infection in maryland, usa, likely acquired at a martial arts gym.201121470473
buffalopox outbreak in humans and animals in western maharashtra, india.an outbreak of febrile illness with rash was reported in humans and buffaloes with pox lesions in some villages of solapur and kolhapur districts of maharashtra state, india. detailed clinico-epidemiological investigations were done with collection of blood, vesicular fluid and scab from humans and animals. a total of 166 suspected human cases from kasegaon village in solapur district and 185 cases were reported from 21 different villages from kolhapur district. the attack rate in humans in kase ...201121511350
role of sulfatide in vaccinia virus infection.background information: vaccinia virus (vacv) was used as a surrogate of variola virus (genus orthopoxvirus), the causative agent of smallpox, to study orthopoxvirus infection. vacv infects cells via attachment and fusion of the viral membrane with the host cell membrane. glycosphingolipids, expressed in multiple organs, are major components of lipid rafts and have been associated with the infectious route of several pathogens. results: we demonstrate that the vaccinia virus western reserve (vac ...201121554243
development of vaccinia reporter viruses for rapid, high content analysis of viral function at all stages of gene expression.vaccinia virus is the prototypical orthopoxvirus of poxviridae, a family of viruses that includes the human pathogens variola (smallpox) and monkeypox. core viral functions are conserved among orthopoxviruses, and consequently vaccinia is routinely used to study poxvirus biology and screen for novel antiviral compounds. here we describe the development of a series of fluorescent protein-based reporter vaccinia viruses that provide unprecedented resolution for tracking viral function. the reporte ...201121569797
zoonotic cases of camelpox infection in india.this study reports the first conclusive evidence of zoonotic camelpox virus (cmlv) infection in humans associated with outbreaks in dromedarian camels (camelus dromedaries) in northwest region of india during 2009. cmlv infection is usually restricted to camels and causes localised skin lesions but occasionally leads to generalised form of disease. however, the present outbreak involved camel handlers and attendants with clinical manifestations such as papules, vesicles, ulceration and finally s ...201121571451
genes in the terminal regions of orthopoxvirus genomes experience adaptive molecular evolution.abstract: background: orthopoxviruses are dsdna viruses with large genomes, some encoding over 200 genes. genes essential for viral replication are located in the center of the linear genome and genes encoding host response modifiers and other host interacting proteins are located in the terminal regions. the central portion of the genome is highly conserved, both in gene content and sequence, while the terminal regions are more diverse. in this study, we investigated the role of adaptive molecu ...201121605412
establishment of the black-tailed prairie dog (cynomys ludovicianus) as a novel animal model for comparing smallpox vaccines administered pre-exposure in both high and low-dose monkeypox challenges.the 2003 monkeypox virus (mpxv) outbreak and subsequent laboratory studies demonstrated that the black-tailed prairie dog was susceptible to mpxv infection and that the ensuing rash illness was similar to human systemic orthopoxvirus (opxv) infections - including a 7 to 9-day incubation period and likely, in some cases, a respiratory route of infection - which distinguishes this model from others. the need for safe and efficacious vaccines for both endemic and epidemic opvx disease is important ...201121632764
species-specific identification of variola, monkeypox, cowpox, and vaccinia viruses by multiplex real-time pcr assay.a method of one-stage rapid identification of variola (varv), monkeypox (mpxv), cowpox (cpxv), and vaccinia (vacv) viruses, pathogenic for humans, utilizing multiplex real-time taqman pcr (murt-pcr) assay was developed. four pairs of oligonucleotide primers and four hybridization probes with various fluorescent dyes and the corresponding fluorescence quenchers were concurrently used for murt-pcr assay. the hybridization probe specific for the varv sequence contained fam/bhq1 as a dye/quencher pa ...201121635922
detection of north american orthopoxviruses by real time-pcr.the prevalence of north american orthopoxviruses in nature is unknown and may be more difficult to ascertain due to wide spread use of vaccinia virus recombinant vaccines in the wild. a real time pcr assay was developed to allow for highly sensitive and specific detection of north american orthopoxvirus dna in animal tissues and bodily fluids. this method is based on the amplification of a 156 bp sequence within a myristylated protein, highly conserved within the north american orthopoxviruses b ...201121689420
effective antiviral treatment of systemic orthopoxvirus disease: st-246 treatment of prairie dogs infected with monkeypox virus.smallpox preparedness research has led to development of antiviral therapies for treatment of serious orthopoxvirus infections. monkeypox virus is an emerging, zoonotic orthopoxvirus which can cause severe and transmissible disease in humans, generating concerns for public health. monkeypox virus infection results in a systemic, febrile-rash illness closely resembling smallpox. currently, there are no small-molecule antiviral therapeutics approved to treat orthopoxvirus infections of humans. the ...201121697474
transgene optimization, immunogenicity and in vitro efficacy of viral vectored vaccines expressing two alleles of plasmodium falciparum ama1.apical membrane antigen 1 (ama1) is a leading candidate vaccine antigen against blood-stage malaria, although to date numerous clinical trials using mainly protein-in-adjuvant vaccines have shown limited success. here we describe the pre-clinical development and optimization of recombinant human and simian adenoviral (adhu5 and chad63) and orthopoxviral (mva) vectors encoding transgene inserts for plasmodium falciparum ama1 (pfama1).201121698193
induction of noxa-mediated apoptosis by modified vaccinia virus ankara depends on viral recognition by cytosolic helicases, leading to irf-3/ifn-+¦-dependent induction of pro-apoptotic noxa.viral infection is a stimulus for apoptosis, and in order to sustain viral replication many viruses are known to carry genes encoding apoptosis inhibitors. f1l, encoded by the orthopoxvirus modified vaccinia virus ankara (mva) has a bcl-2-like structure. an mva mutant lacking f1l (mva+öf1l) induces apoptosis, indicating that mva infection activates and f1l functions to inhibit the apoptotic pathway. in this study we investigated the events leading to apoptosis upon infection by mva+öf1l. apoptos ...201121698224
ocular vaccinia: a consequence of unrecognized contact transmission.a patient developed severe ocular vaccinia via autoinoculation after acquiring unrecognized contact-transmitted vaccinia from wrestling with vaccinated members of his unit. this case highlights both the need to reinforce infection-control measures among vaccinees and the need for providers to be familiar with the identification and treatment of cutaneous and ocular vaccinia infection.201121702392
the vaccinia virus a56 protein: a multifunctional transmembrane glycoprotein that anchors two secreted viral proteins.the vaccinia virus a56 protein was one of the earliest-described poxvirus proteins with an identifiable activity. while originally characterized as a haemagglutinin protein, a56 has other functions as well. the a56 protein is capable of binding two viral proteins, a serine protease inhibitor (k2) and the vaccinia virus complement control protein (vcp), and anchoring them to the surface of infected cells. this is important; while both proteins have biologically relevant functions at the cell surf ...201121715594
Serological responses in humans to smallpox vaccine LC16m8.In response to potential bioterrorism with smallpox, members of the Japanese Self-Defense Forces were vaccinated with vaccinia virus (VACV) strain LC16m8, an attenuated smallpox vaccine derived from VACV strain Lister. The serological response induced by LC16m8 to four virion surface proteins and the intracellular mature virus (IMV) and extracellular enveloped virus (EEV) were investigated. LC16m8 induced antibody against the IMV protein A27, and the EEV protein A56. LC16m8 also induced IMV-neut ...201121715598
study of camelpox virus pathogenesis in athymic nude mice.camelpox virus (cmlv) is the closest known orthopoxvirus genetically related to variola virus. so far, cmlv was restricted to camelids but, recently, three human cases of camelpox have been described in india, highlighting the need to pursue research on its pathogenesis, which has been hampered by the lack of small animal models. here, we confirm that nmri immunocompetent mice are resistant to intranasal (i.n.) cmlv infection. however, we demonstrate that cmlv induced a severe disease following ...201121738709
deletion of the monkeypox inhibitor of complement enzymes locus impacts the adaptive immune response to monkeypox virus in a non human primate model of infection.monkeypox virus (mpxv) is an orthopoxvirus closely related to variola virus, the causative agent of smallpox. human mpxv infection results in a disease that is similar to smallpox, and can also be fatal. two clades of mpxv have been identified, with viruses of the central african clade displaying more pathogenic properties than those within the west african clade. the monkeypox inhibitor of complement enzymes (mopice), which is not expressed by viruses of the west african clade, has been hypothe ...201121752919
genomic expression libraries for the identification of cross-reactive orthopoxvirus antigens.increasing numbers of human cowpox virus infections that are being observed and that particularly affect young non-vaccinated persons have renewed interest in this zoonotic disease. usually causing a self-limiting local infection, human cowpox can in fact be fatal for immunocompromised individuals. conventional smallpox vaccination presumably protects an individual from infections with other orthopoxviruses, including cowpox virus. however, available live vaccines are causing severe adverse reac ...201121779357
the pathology of experimental poxvirus infection in common marmosets (callithrix jacchus): further characterization of a new primate model for orthopoxvirus infections.zoonotic orthopoxvirus (opv) can induce severe disease in man and the virus has potential for use in bioterrorism. new vaccines and therapeutics against opv infections must be tested in animal models. the aim of this study was to characterize the clinical course and pathology of a new opv isolate, calpox virus, which is infectious in marmosets. infection experiments were performed with 28 common marmosets (callithrix jacchus) exposed to different challenge doses of calpox virus by the intravenou ...201121783202
the strategic use of novel smallpox vaccines in the post-eradication world.we still face a threat of orthopoxviruses in the form of biological weapons and emerging zoonoses. therefore, there is a need to maintain a comprehensive defense strategy to counter the low-probability, high-impact threat of smallpox, as well as the ongoing threat of naturally occurring orthopoxvirus disease. the currently licensed live-virus smallpox vaccine acam2000 is effective, but associated with serious and even life-threatening adverse events. the health threat posed by this vaccine, and ...201121806397
an epitope conserved in orthopoxvirus a13 envelope protein is the target of neutralizing and protective antibodies.primary immunization of humans with smallpox vaccine (live vaccinia virus (vacv)) consistently elicits antibody responses to six vacv virion membrane proteins, including a13. however, whether anti-a13 antibody contributes to immune protection against orthopoxviruses was unknown. here, we isolated a murine monoclonal antibody (mab) against a13 from a mouse that had been infected with vacv. the anti-a13 mab bound to recombinant a13 protein with an affinity of 3.4nm and neutralized vacv mature viri ...201121810533
the genome of yoka poxvirus.yoka poxvirus was isolated almost 4 decades ago from a mosquito pool in the central african republic. its classification as a poxvirus is based solely upon the morphology of virions visualized by electron microscopy. here we describe sequencing of the yoka poxvirus genome using a combination of roche/454 and illumina next generation sequencing technologies. a single consensus contig of ∼175 kb in length was generated that encoded 186 predicted genes. multiple methods were used to show that yoka ...201121813608
myxoma virus induces type i ifn production in murine plasmacytoid dendritic cells via a tlr9/myd88, irf5/irf7, and ifnar-dependent pathway.poxviruses are large dna viruses that replicate in the cytoplasm of infected cells. myxoma virus is a rabbit poxvirus that belongs to the leporipoxvirus genus. it causes lethal disease called myxomatosis in european rabbits but cannot sustain any detectable infection in non-lagomorphs. vaccinia virus is a prototypal orthopoxvirus that was used as a vaccine to eradicate smallpox. myxoma virus is non-pathogenic in mice, whereas systemic infection with vaccinia can be lethal even in immunocompetent ...201121835795
cowpox virus infection of cynomolgus macaques as a model of hemorrhagic smallpox.hemorrhagic smallpox was a rare but severe manifestation of variola virus infection that resulted in nearly 100% mortality. here we describe intravenous (iv) inoculation of cowpox virus brighton red strain in cynomolgus macaques (macaca fascicularis) which resulted in disease similar in presentation to hemorrhagic smallpox in humans. iv inoculation of macaques resulted in a uniformly lethal disease within 12days post-inoculation in two independent experiments. clinical observations and hematolog ...201121840027
Vaccinia viruses: vaccines against smallpox and vectors against infectious diseases and tumors.Less than 200 years after its introduction, widespread use of vaccinia virus (VACV) as a smallpox vaccine has eradicated variola virus. Along with the remarkable success of the vaccination program, frequent and sometimes severe adverse reactions to VACV were encountered. After eradication, VACV has been reserved for select populations who might be at significant risk for orthopoxvirus infections. Events over the past decade have renewed concerns over the potential use of variola virus as a biolo ...201121854314
Microbial inactivation for safe and rapid diagnostics of infectious samples.The high risk associated with biological threat agents dictates that any suspicious sample be handled under strict surety and safety controls and processed under high-level containment in specialized laboratories. This study attempted to find a rapid, reliable, and simple method for the complete inactivation of a wide range of pathogens, including spores, vegetative bacteria, and viruses, while preserving microbial nucleic acid fragments suitable for PCRs and proteinaceous epitopes for detection ...201121856830
chasing jenner's vaccine: revisiting cowpox virus classification.cowpox virus (cpxv) is described as the source of the first vaccine used to prevent the onset and spread of an infectious disease. it is one of the earliest described members of the genus orthopoxvirus, which includes the viruses that cause smallpox and monkeypox in humans. both the historic and current literature describe "cowpox" as a disease with a single etiologic agent. genotypic data presented herein indicate that cpxv is not a single species, but a composite of several (up to 5) species t ...201121858000
comparison of the safety and pharmacokinetics of st-246® after i.v. infusion or oral administration in mice, rabbits and monkeys.st-246® is an antiviral, orally bioavailable small molecule in clinical development for treatment of orthopoxvirus infections. an intravenous (i.v.) formulation may be required for some hospitalized patients who are unable to take oral medication. an i.v. formulation has been evaluated in three species previously used in evaluation of both efficacy and toxicology of the oral formulation.201121858040
Zoonotic Brazilian Vaccinia virus: from field to therapy.Vaccinia virus (VACV), the prototype species of the Orthopoxvirus (OPV) genus, causes an occupational zoonotic disease in Brazil that is primarily associated with the handling of infected dairy cattle. Cattle and human outbreaks have been described in southeastern Brazil since 1999 and have now occurred in almost half of the territory. Phylogenetic studies have shown high levels of polymorphisms among isolated VACVs, which indicate the existence of at least two genetically divergent clades; this ...201121896287
Polyclonal antibody cocktails generated using DNA vaccine technology protect in murine models of orthopoxvirus disease.Previously we demonstrated that DNA vaccination of nonhuman primates (NHP) with a small subset of vaccinia virus (VACV) immunogens (L1, A27, A33, B5) protects against lethal monkeypox virus challenge. The L1 and A27 components of this vaccine target the mature virion (MV) whereas A33 and B5 target the enveloped virion (EV).201121933385
Intrabronchial inoculation of cynomolgus macaques with cowpox virus.The public health threat of orthopoxviruses from bioterrorist attacks has prompted researchers to develop suitable animal models for increasing our understanding of viral pathogenesis and evaluation of medical countermeasures (MCMs) in compliance with the FDA Animal Efficacy Rule. We present an accessible intrabronchial cowpox virus (CPXV) model that can be evaluated under biosafety level-2 laboratory conditions. In this dose-ranging study, utilizing cynomolgus macaques, signs of typical orthopo ...201221940414
genomic analysis of the vaccinia virus strain variants found in dryvax vaccine.smallpox was eradicated using variant forms of vaccinia virus-based vaccines. one of these was dryvax, a calf lymph vaccine derived from the new york city board of health strain. we used genome-sequencing technology to examine the genetic diversity of the population of viruses present in a sample of dryvax. these studies show that the conserved cores of these viruses exhibit a lower level of sequence variation than do the telomeres. however, even though the ends of orthopoxviruses are more genet ...201121976639
A naturally occurring cowpox virus with an ectromelia virus A-type inclusion protein gene displays atypical A-type inclusions.Human orthopoxvirus (OPV) infections in Europe are usually caused by cowpox virus (CPXV). The genetic heterogeneity of CPXVs may in part be due to recombination with other OPV species. We describe the characterization of an atypical CPXV (CPXV-No-H2) isolated from a human patient in Norway. CPXV-No-H2 was characterized on the basis of A-type inclusion (ATI) phenotype as well as the DNA region containing the p4c and atip open reading frames. CPXV-No-H2 produced atypical V(+/) ATI, in which virion ...201221983687
synthesis and early development of hexadecyloxypropylcidofovir: an oral antipoxvirus nucleoside phosphonate.hexadecyloxypropyl-cidofovir (hdp-cdv) is a novel ether lipid conjugate of (s)-1-(3-hydroxy-2-phosphonoylmethoxypropyl)-cytosine (cdv) which exhibits a remarkable increase in antiviral activity against orthopoxviruses compared with cdv. in contrast to cdv, hdp-cdv is orally active and lacks the nephrotoxicity of cdv itself. increased oral bioavailability and increased cellular uptake is facilitated by the lipid portion of the molecule which is responsible for the improved activity profile. the l ...201021994617
development of st-246® for treatment of poxvirus infections.st-246 (tecovirimat) is a small synthetic antiviral compound being developed to treat pathogenic orthopoxvirus infections of humans. the compound was discovered as part of a high throughput screen designed to identify inhibitors of vaccinia virus-induced cytopathic effects. the antiviral activity is specific for orthopoxviruses and the compound does not inhibit the replication of other rna- and dna-containing viruses or inhibit cell proliferation at concentrations of compound that are antiviral. ...201021994624
treatment of vaccinia and cowpox virus infections in mice with cmx001 and st-246.although a large number of compounds have been identified with antiviral activity against orthopoxviruses in tissue culture systems, it is highly preferred that these compounds have activity in vivo before they can be seriously considered for further development. one of the most commonly used animal models for the confirmation of this activity has been the use of mice infected with either vaccinia or cowpox viruses. these model systems have the advantage that they are relatively inexpensive, rea ...201021994637
ectromelia virus infections of mice as a model to support the licensure of anti-orthopoxvirus therapeutics.the absence of herd immunity to orthopoxviruses and the concern that variola or monkeypox viruses could be used for bioterroristic activities has stimulated the development of therapeutics and safer prophylactics. one major limitation in this process is the lack of accessible human orthopoxvirus infections for clinical efficacy trials; however, drug licensure can be based on orthopoxvirus animal challenge models as described in the "animal efficacy rule". one such challenge model uses ectromelia ...201021994714
orthopoxvirus genome evolution: the role of gene loss.poxviruses are highly successful pathogens, known to infect a variety of hosts. the family poxviridae includes variola virus, the causative agent of smallpox, which has been eradicated as a public health threat but could potentially reemerge as a bioterrorist threat. the risk scenario includes other animal poxviruses and genetically engineered manipulations of poxviruses. studies of orthologous gene sets have established the evolutionary relationships of members within the poxviridae family. it ...201021994715
antiviral activity of 4'-thioidu and thymidine analogs against orthopoxviruses.the search for effective therapies for orthopoxvirus infections has identified diverse classes of molecules with antiviral activity. pyrimidine analogs, such as 5-iodo-2'-deoxyuridine (idoxuridine, idu) were among the first compounds identified with antiviral activity against a number of orthopoxviruses and have been reported to be active both in vitro and in animal models of infection. more recently, additional analogs have been reported to have improved antiviral activity against orthopoxvirus ...201021994716
the vaccinia virus-encoded bcl-2 homologues do not act as direct bax inhibitors.many viruses, including members of several poxvirus genera, encode inhibitors that block apoptosis by simultaneously binding the proapoptotic bcl-2 proteins bak and bax. the orthopoxvirus vaccinia virus encodes the bcl-2-like f1 protein, which sequesters bak but not bax. however, n1, a potent virulence factor, is reported to be antiapoptotic and to interact with bax. here we investigated whether vaccinia virus inhibits bak/bax-dependent apoptosis via the cooperative action of f1 and n1. we found ...201222013032
cowpox virus serpin crma is necessary but not sufficient for the red pock phenotype on chicken chorioallantoic membranes.it was previously reported that cowpox virus (cpxv) strain brighton red (br) causes red pocks upon inoculation of chorioallantoic membranes (cams) of embryonated chicken eggs. red pocks are characterized by hemorrhage and reduced numbers of inflammatory cells while white pocks induced by other members of the genus orthopoxvirus lack hemorrhage and have higher numbers of infiltrating heterophils. analyses of cpxv br white pock variants identified the cytokine response modifier a (crma) as the fac ...201122016035
serologic evidence of human orthopoxvirus infections in sierra leone.abstract:201122035219
the munich outbreak of cutaneous cowpox infection: transmission by infected pet rats.cowpox virus infection of humans is an uncommon, potentially fatal, skin disease. it is largely confined to europe, but is not found in eire, or in the usa, australasia, or the middle or far east. patients having contact with infected cows, cats, or small rodents sporadically contract the disease from these animals. we report here clinical aspects of 8 patients from the munich area who had purchased infected pet rats from a local supplier. pet rats are a novel potential source of local outbreaks ...201122041995
efficacy of orally administered low dose n-methanocarbathymidine against lethal herpes simplex virus type-2 infections of mice.n-methanocarbathymidine (n-mct) has previously been shown to be effective against lethal orthopoxvirus and herpes simplex virus type-1 infections in mice. in this investigation, the antiviral activity of n-mct was assessed against herpes simplex virus type-2 (hsv-2) in balb/c mice.201122095521
validation of a high-throughput real-time polymerase chain reaction assay for the detection of capripoxviral dna.capripoxviruses, which are endemic in much of africa and asia, are the aetiological agents of economically devastating poxviral diseases in cattle, sheep and goats. the aim of this study was to validate a high-throughput real-time pcr assay for routine diagnostic use in a capripoxvirus reference laboratory. the performance of two previously published real-time pcr methods were compared using commercially available reagents including the amplification kits recommended in the original publication. ...201122138682
Monkeypox disease transmission in an experimental setting: prairie dog animal model.Monkeypox virus (MPXV) is considered the most significant human public health threat in the genus Orthopoxvirus since the eradication of variola virus (the causative agent of smallpox). MPXV is a zoonotic agent endemic to forested areas of Central and Western Africa. In 2003, MPXV caused an outbreak in the United States due to the importation of infected African rodents, and subsequent sequential infection of North American prairie dogs (Cynomys ludovicianus) and humans. In previous studies, the ...201122164263
the vaccinia virus o1 protein is required for sustained activation of the extracellular signal-regulated kinase (erk) 1/2 and promotes viral virulence.sustained activation of the raf/mek/erk pathway in infected cells has been shown to be crucial for full replication efficiency of orthopoxviruses in cell culture. in infected cells, this pathway is mainly activated by the vaccinia virus growth factor (vgf), an epidermal growth factor (egf)-like protein. we show here that chorioallantois vaccinia virus ankara (cva), but not modified vaccinia virus ankara (mva) induced sustained activation of extracellular signal-regulated protein kinase 1/2 (erk1 ...201122171261
inhibition of cowpox virus and monkeypox virus infection by mitoxantrone.mitoxantrone, an fda-approved therapeutic for the treatment of cancer and multiple sclerosis, was previously reported to exhibit antiviral activity against vaccinia virus. to determine whether this activity extends to other orthopoxviruses, mitoxantrone was tested against cowpox and monkeypox. mitoxantrone demonstrated an ec(50) of 0.25μm against cowpox and 0.8μm against monkeypox. intraperitoneal treatment of cowpox virus-challenged c57bl/6 mice with 0.5mg/kg mitoxantrone resulted in 25% surviv ...201122182595
Human and animal infections by vaccinia-like viruses in the state of Rio de Janeiro: A novel expanding zoonosis.Since 1999, vesicular infections caused by Orthopoxvirus in humans and animals, mainly in dairy cattle, have been identified in 20 municipalities in the Rio de Janeiro state of Brazil. This paper describes studies conducted in counties of the northwestern, middle-Paraíba Valley and southern regions of the Rio de Janeiro state where 77 human, 346 bovine and 78 rodent samples were collected over the past ten years. Laboratory investigations using virus isolation, electron microscopy, molecular bio ...201122185829
Status of human monkeypox clinical disease, epidemiology and research.Monkeypox, a vesiculo-pustular rash illness, was initially discovered to cause human infection in 1970 through the World Health Organization (WHO)-sponsored efforts of the Commission to Certify Smallpox Eradication in Western Africa and the Congo Basin. The virus had been discovered to cause a nonhuman primate rash illness in 1958, and was thus named monkeypox. The causative agents of monkeypox and smallpox diseases both are species of Orthopoxvirus. Orthopoxvirus monkeypox, when it infects huma ...201122185831
emergence and reemergence of smallpox: the need in development of a new generation smallpox vaccine.the review summarizes the archive data on smallpox, history of ancient civilizations, and the most recent data on the genome organization of orthopoxviruses, their evolutionary relationships, and the time points of smallpox emergence. the performed analysis provides the grounds for the hypothesis that smallpox could have emerged several times as a result of evolutionary changes in the zoonotic ancestor virus and disappeared due to insufficient population size of ancient civilizations. smallpox r ...201122185833
whither monkeypox vaccination.monkeypox (mpx) is a virulent orthopoxvirus that is endemic in some regions of central africa. mpx incidence has been rising since the cessation of routine smallpox immunization. while it causes significant disease, there is limited person-to-person spread, the incidence is still relatively low, and cases are generally restricted to remote areas that are difficult to access. therefore, initiating vaccine trials or implementing vaccination programs would be challenging. this paper considers the f ...201122188935
identification of a pyridopyrimidinone inhibitor of orthopoxviruses from a diversity-oriented synthesis library.orthopoxviruses include the prototypical vaccinia virus, the emerging infectious agent monkeypox, and potential biothreat variola (smallpox). there is currently no fda-approved treatment for humans infected with orthopoxviruses. we screened a diversity oriented synthesis library for new scaffolds with antiviral activity against vaccinia. this screen identified a non-nucleoside analog that blocked post-replicative intermediate and late gene expression. viral genome replication was unaffected, and ...201122205744
antiviral activity of the eb peptide against zoonotic poxviruses.abstract: background: the eb peptide is a 20-mer that was previously shown to have broad spectrum in vitro activity against several unrelated viruses, including highly pathogenic avian influenza, herpes simplex virus type i, and vaccinia, the prototypic orthopoxvirus. to expand on this work, we evaluated eb for in vitro activity against the zoonotic orthopoxviruses cowpox and monkeypox and for in vivo activity in mice against vaccinia and cowpox. findings: in yield reduction assays, eb had an e ...201222225618
tricyclo[3.2.2.0(2,4)]non-8-en-6,7-dicarbonic acid derivatives efficiently inhibits the replication of different orthopoxvirus species. 201222227697
molecular analysis of parapoxvirus from a spotted seal phoca largha in japan.a spotted seal phoca largha with nodular and scab lesions on the whole body was brought to an aquarium in nagoya, japan. we extracted dna from the lesions and used the polymerase chain reaction (pcr) method for detecting orthopoxvirus and parapoxvirus dna. parapoxvirus but not orthopoxvirus dna was detected. the partial nucleotide sequence of the envelope gene was determined from the pcr product, and the sequence was seen to be closely related to 2 parapoxvirus strains from spotted seals in alas ...201122235590
vaccinia viruses isolated from skin infection in horses produced cutaneous and systemic disease in experimentally infected rabbits.the susceptibility of rabbits to two isolates of vaccinia virus (vacv) recovered from cutaneous disease in horses in southern brazil was investigated. rabbits were inoculated in the ear skin with both vacv isolates, either in single or mixed infection. all inoculated animals presented local skin lesions characterized by hyperaemia, papules, vesicles, pustules and ulcers. infectious virus was detected in the lungs and intestine of rabbits that died during acute disease. histological examination o ...201222244689
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