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At least 271 records · Page 15Linked to original sources
PubMed2002

The genome of camelpox virus.

Camelpox virus (CMLV), a member of the Orthopoxvirus genus in the Poxviridae, is the etiologic agent of a disease of camels. Here we report the CMLV genomic sequence with analysis. The 205,719-bp CMLV genome contains 211 putative genes and consists of a central region bound by identical inverted terminal repeats of approximately 7 kb. A high degree of similarity in gene order, gene content, and amino acid composition in the region located between CMLV017 and CMLV184 (average 96% amino acid identity to vaccinia virus (VACV)) indicates a close structural and functional relationship between CMLV and other known orthopoxviruses (OPVs). Notably, CMLV contains a unique region of approximately 3 kb, which encodes three ORFs (CMLV185, CMLV186, CMLV187) absent in other OPVs. These ORFs are most similar to B22R homologues found in other chordopoxvirus genera. Among OPVs, CMLV is the most closely related to variola virus (VARV), sharing all genes involved in basic replicative functions and the majority of genes involved in other host-related functions. Differences between CMLV and VARV include deletion and disruption of a large number of genes. Twenty-seven CMLV ORFs are absent in VARV, including seven full-length homologues of NMDA-like receptor, phospholipase D, Schlafen, MT-4 virulence, kelch, VACV C8L, and cowpox (CPXV) B21R proteins. Thirty-eight CMLV ORFs, some of which are fragments of larger genes, differ in size from corresponding VARV ORFs by more than 10% (amino acids). Genome structure and phylogenetic analysis of DNA sequences for all ORFs indicate that CMLV is clearly distinct from VARV and VACV and, as it has been suggested for VARV, it may have originated from a CPXV virus-like ancestor.

Animals↗
PubMed2001

Vaccinia virus inhibitors as a paradigm for the chemotherapy of poxvirus infections.

Poxviruses continue to pose a major threat to human health. Monkeypox is endemic in central Africa, and the discontinuation of the vaccination (with vaccinia virus) has rendered most humans vulnerable to variola virus, the etiologic agent of smallpox, should this virus be used in biological warfare or terrorism. However, a large variety of compounds have been described that are potent inhibitors of vaccinia virus replication and could be expected to be active against other poxviruses as well. These compounds could be grouped in different classes: (i) IMP dehydrogenase inhibitors (e.g., EICAR); (ii) SAH hydrolase inhibitors (e.g., 5'-noraristeromycin, 3-deazaneplanocin A, and various neplanocin A derivatives); (iii) OMP decarboxylase inhibitors (e.g., pyrazofurin) and CTP synthetase inhibitors (e.g., cyclopentenyl cytosine); (iv) thymidylate synthase inhibitors (e.g., 5-substituted 2'-deoxyuridines); (v) nucleoside analogues that are targeted at viral DNA synthesis (e.g., Ara-A); (vi) acyclic nucleoside phosphonates [e.g., (S)-HPMPA and (S)-HPMPC (cidofovir)]; and (vii) polyanionic substances (e.g., polyacrylic acid). All these compounds could be considered potential candidate drugs for the therapy and prophylaxis of poxvirus infections at large. Some of these compounds, in particular polyacrylic acid and cidofovir, were found to generate, on single-dose administration, a long-lasting protective efficacy against vaccinia virus infection in vivo. Cidofovir, which has been approved for the treatment of cytomegalovirus retinitis in immunocompromised patients, was also found to protect mice, again when given as a single dose, against a lethal aerosolized or intranasal cowpox virus challenge. In a biological warfare scenario, it would be advantageous to be able to use a single treatment for an individual exposed to an aerosolized poxvirus. Cidofovir thus holds great promise for treating human smallpox, monkeypox, and other poxvirus infections. Anecdotal experience points to the efficacy of cidofovir in the treatment of the poxvirus infections molluscum contagiosum and orf (ecthyma contagiosum) in immunosuppressed patients.

Antiviral Agents↗
PubMed2003

[Neurological effects of chemical and biological weapons].

Neurological manifestations of chemical and biological weapons are reviewed. Nerve agents in current use, storage, or production include tabun, sarin, soman and VX. The initial effects of exposure to a nerve agent depend on the dose and on the route of exposure. Sarin, the agent studied most thoroughly in man in Matumoto and Tokyo attacked by Aum shinrikyo will cause miosis, rhinorrehea and shortness of breath are initial complaints immediately after inhalation exposure of the vapor. The severe cases showed loss of consciousness and convulsions. Respiratory arrest may occur. The most toxic of the nerve agents is VX. It is thought to be 100 times as toxic as sarin for humans by the percutaneous rout. The similar findings to sarin exposure are also observed in cases exposured to VX. Atropin and PAM will be effective in the early stage. BZ (benzilate) is a delayed onset incapacitation agent. It causes severe hallucination. The cyanide compounds are among the most rapidly acting of war gases, resulting in death. Anthrax has been the most attractive biological weapon for a long time. Anthrax is an acute bacterial infection of the skin and lungs in man and animals. Meningoencephalitis has been reported in the terminal stage in anthrax infection. In autopsy, it is really confirmed in the characteristic findings of the meningeal abnormality. The potential weaponization of variola virus continues to pose a military threat because the aerosol infectivity of the virus and the development of susceptible populations. A high rate of lethality, a staunch resistance to treatments and a rapid onset of severe generalised muscle weakness make botulinum toxin a suitable agent for biological warfare particularly by oral administration.

Animals↗
PubMed1979

Evaluation of smallpox vaccination policy.

During 1978 and 1979 the Global Commission for the Certification of Smallpox Eradication will proceed with verification of smallpox eradication in 31 countries. If current surveillance activities do not discover any further cases before the end of 1979, the world will be declared smallpox free. However, the recent occurrence of two laboratory associated smallpox cases in Birmingham, England, revealed that the stocks of variola virus held in at least 12 laboratories in the world pose a real danger to the achievement of smallpox eradication and efforts are being made to reduce the number of laboratories retaining the virus to not more than 4-all WHO collaborating centres-by 1980. Scientific data indicate the unlikelihood of smallpox recurring once it has been eradicated from the human population, although further confirmatory studies are continuing. If the Global Commission verifies the eradication of smallpox, continuation of smallpox vaccination will be unjustifiable in view of its severe complications, however infrequent, and the expected global savings that would result from the termination of vaccination programmes.

Animals↗
PubMed1961

Studies of smallpox antibody levels of sera from samples of the vaccinated adult population of Madras.

In view of the endemicity of smallpox in Madras and the poor take rate on revaccination with the lymph in current use, it was felt that the immunity of the general adult population might be relatively low. In an attempt to obtain some measure of this, sera were obtained from over 300 adults in Madras for the estimation of serum antibody. The results of neutralization tests against variola virus made on these sera showed that about 10% of those who had good scars from infant vaccination showed little or no antibody. A comparison of the antibody titres of adult sera showing good antibody levels when used undiluted was made with that of sera from smallpox convalescents. The antibody level in the latter sera was 20-100 times that of the sera of adult persons who showed good vaccination scars.

Adult↗
PubMed2006

An update on smallpox vaccine candidates and their role in bioterrorism related vaccination strategies.

The threat of using variola virus in a bioterrorist attack urged different countries to renew the production of traditional vaccines and develop new generations of smallpox vaccines. Manufacturers try to combine smallpox vaccine past experience with technological advances in vaccine development to achieve protection similar to that of the traditional vaccines with a higher level of safety and fewer contraindications. In light of the reported immunogenicity and reactogenicity of the stockpiled smallpox vaccines employed in the last immunization campaigns of "first responders", we review recently accumulated data on the assessment of new smallpox vaccine candidates and discuss their role in possible vaccination policies.

Bioterrorism↗
PubMed2005

Osler and the infected letter.

The spread of infectious agents through the mail has concerned public health officials for 5 centuries. The dissemination of anthrax spores in the US mail in 2001 was a recent example. In 1901, two medical journals reported outbreaks of smallpox presumably introduced by letters contaminated with variola viruses. The stability and infectivity of the smallpox virus are reviewed from both a historical (anecdotal) perspective and modern virologic studies. Bubonic plague was the contagious disease that led to quarantines as early as the 14th century in port cities in southern Europe. Later, smallpox, cholera, typhus, and yellow fever were recognized as also warranting quarantine measures. Initially, attempts were made to decontaminate all goods imported from pestilential areas, particularly mail. Disinfection of mail was largely abandoned in the early 20th century with newer knowledge about the spread and stability of these 5 infectious agents.

Correspondence as Topic↗
PubMed2004

Design and development of oral drugs for the prophylaxis and treatment of smallpox infection.

Smallpox was eradicated by the World Health Organization (WHO) vaccination campaign in the 1970s and the variola virus was restricted to repositories in the United States and Russia. Recently, however, concerns have arisen about the possible existence of variola outside these sites and the potential for using the virus as a weapon of bioterror. The world population now has little residual immunity to smallpox and supplies of the smallpox vaccine are being reconstituted. Large numbers of individuals with various skin diseases or immunosuppression owing to AIDS or organ transplantation medications, or who are pregnant or have heart disease might not be ideal candidates for vaccination with the current live vaccines. It would be useful to have an orally active drug that could be self-administered in case of an outbreak of smallpox.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Transmission potential of smallpox: estimates based on detailed data from an outbreak.

Recent discussions on the use of variola virus by bioterrorists have rekindled interest in the parameters that govern the transmissibility of smallpox. Here, the authors estimate by maximum likelihood the parameters of the spread of smallpox from historical data on an epidemic in 1967 in the town of Abakaliki, Nigeria, afflicting a religious group that refused vaccination. According to the authors' estimates, 79.9% (95% confidence interval (CI): 63.6, 87.9) of the infectious contacts occurred within the compounds of the cases and 93.3% (95% CI: 80.6, 98.8) among compound members and other close contacts. Each case had 0.164 (95% CI: 0, 1.31) sufficiently close contacts on average during the fever period that preceded the rash and 6.87 (95% CI: 4.52, 10.1) sufficiently close contacts during the whole course of infectivity. These results support the widely held belief that smallpox spreads slowly, mainly among close contacts, and that infectivity before the onset of rash was negligible.

Adolescent↗
PubMed2005

Draft versus finished sequence data for DNA and protein diagnostic signature development.

Sequencing pathogen genomes is costly, demanding careful allocation of limited sequencing resources. We built a computational Sequencing Analysis Pipeline (SAP) to guide decisions regarding the amount of genomic sequencing necessary to develop high-quality diagnostic DNA and protein signatures. SAP uses simulations to estimate the number of target genomes and close phylogenetic relatives (near neighbors or NNs) to sequence. We use SAP to assess whether draft data are sufficient or finished sequencing is required using Marburg and variola virus sequences. Simulations indicate that intermediate to high-quality draft with error rates of 10(-3)-10(-5) (approximately 8x coverage) of target organisms is suitable for DNA signature prediction. Low-quality draft with error rates of approximately 1% (3x to 6x coverage) of target isolates is inadequate for DNA signature prediction, although low-quality draft of NNs is sufficient, as long as the target genomes are of high quality. For protein signature prediction, sequencing errors in target genomes substantially reduce the detection of amino acid sequence conservation, even if the draft is of high quality. In summary, high-quality draft of target and low-quality draft of NNs appears to be a cost-effective investment for DNA signature prediction, but may lead to underestimation of predicted protein signatures.

Computational Biology↗
PubMed2003

Case isolation and contact tracing can prevent the spread of smallpox.

Fears that terrorist groups may have gained access to variola virus have led to widespread discussions on how to prevent the reintroduction of smallpox by vaccination and on the availability of sufficiently large amounts of vaccine. In this paper, the author examines how the spread of smallpox is affected by isolating overt cases and taking their contacts under close surveillance for up to 3 weeks. The author assumes that case detection gradually improves from initially 7 days to 3 days. This intervention should be accompanied by vaccination, but its outcome does not depend on the vaccine's efficacy. It may, therefore, be especially important in controlling outbreaks caused by pathogens whose immunologic properties have been modified by genetic engineering. Using stochastic computer simulations, the author demonstrates that contact tracing and case isolation can extinguish smallpox outbreaks in highly susceptible populations within less than half a year without causing totals of more than 550 secondary cases per 100 index cases. The author also derives simple approximate expressions that allow prognostication on how efficiently an outbreak can be controlled by the described measures alone and prediction of the expected number of cases in an outbreak and the number of people that must be taken under surveillance.

Biological Warfare↗
PubMed2005

Vaccinia virus induces strong immunoregulatory cytokine production in healthy human epidermal keratinocytes: a novel strategy for immune evasion.

Iatrogenic cutaneous infection with vaccinia virus (VV) and naturally occurring systemic infection with variola virus both lead to the characteristic skin "pox" lesions. Despite significant medical experience with both viruses, surprisingly little is understood about the interactions between these poxviruses and healthy resident skin cells. In recent years, it has become clear that skin plays an essential role in modulating both innate and adaptive immune responses, in part by producing and responding to a variety of cytokines and chemokines upon stimulation. Antagonists of many of these compounds are encoded in poxvirus genomes. Infection of skin cells with poxvirus may lead to a unique pattern of cytokine and chemokine production that might alter the cutaneous immune surveillance function. In this study, we infected primary cultures of human skin cells with VV and monitored antigen expression, virus replication, and cytokine production from the infected cells. While T cells, Langerhans cells, and dermal dendritic cells were infected abortively, keratinocytes, dermal fibroblasts, and dermal microvascular endothelial cells (HMVEC-d) all supported the complete virus life cycle. In contrast to the robust viral replication in fibroblasts and HMVEC-d, only limited viral replication was observed in keratinocytes. Importantly, VV infection of keratinocytes led to up-regulation of immunoregulatory and Th2 cytokines, including transforming growth factor beta, interleukin-10 (IL-10), and IL-13. We propose that the rapid induction of keratinocyte Th2 and immunoregulatory cytokines represents a poxvirus strategy to evade immune surveillance, and the limited viral multiplication in keratinocytes may be a protective mechanism to help the immune system "win the race."

Cytokines↗
PubMed1995

Functional organization of variola major and vaccinia virus genomes.

Comparison of the genomic organization of variola and vaccinia viruses has been carried out. Molecular factors of virulence of these viruses is the focus of this review. Possible roles of the genes of soluble cytokine receptors, complement control proteins, factors of virus replication, and dissemination in vivo for variola virus pathogenesis are discussed. The existence of "buffer" genes in the vaccinia virus genome is proposed.

Animals↗
PubMed2006

Structure of vaccinia virus thymidine kinase in complex with dTTP: insights for drug design.

BACKGROUND: Development of countermeasures to bioterrorist threats such as those posed by the smallpox virus (variola), include vaccination and drug development. Selective activation of nucleoside analogues by virus-encoded thymidine (dThd) kinases (TK) represents one of the most successful strategies for antiviral chemotherapy as demonstrated for anti-herpes drugs. Vaccinia virus TK is a close orthologue of variola TK but also shares a relatively high sequence identity to human type 2 TK (hTK), thus achieving drug selectivity relative to the host enzyme is challenging. RESULTS: In order to identify any differences compared to hTK that may be exploitable in drug design, we have determined the crystal structure of VVTK, in complex with thymidine 5'-triphosphate (dTTP). Although most of the active site residues are conserved between hTK and VVTK, we observe a difference in conformation of residues Asp-43 and Arg-45. The equivalent residues in hTK hydrogen bond to dTTP, whereas in subunit D of VVTK, Asp-43 and Arg-45 adopt a different conformation preventing interaction with this nucleotide. Asp-43 and Arg-45 are present in a flexible loop, which is disordered in subunits A, B and C. The observed difference in conformation and flexibility may also explain the ability of VVTK to phosphorylate (South)-methanocarbathymine whereas, in contrast, no substrate activity with hTK is reported for this compound. CONCLUSION: The difference in conformation for Asp-43 and Arg-45 could thus be used in drug design to generate VVTK/Variola TK-selective nucleoside analogue substrates and/or inhibitors that have lower affinity for hTK.

Binding Sites↗
PubMed2000

Monkeypoxvirus infections.

During and after the smallpox eradication campaign, human cases of monkeypox appeared in West and Central Africa, as isolated cases or as small epidemics. Since inter-human transmission has never or only very exceptionally been documented, monkeypox does not represent a serious threat to humans. The virus reservoir is among tree squirrels living in the tropical rain forests of Africa and humans are infected by hunting, killing and skinning these animals. However, the modernization of society lessens human contact with the virus reservoir. Since the eradication of smallpox, stocks of variola virus have been maintained; whether these stocks should now be destroyed is a political question, which is seriously compromised by mistrust between countries.

Animals↗
PubMed1997

The cowpox virus-encoded homolog of the vaccinia virus complement control protein is an inflammation modulatory protein.

Vaccinia virus complement control protein (VCP) is encoded by vaccinia virus, with its homolog encoded by other pathogenic poxviruses including variola virus. Since rodents are the primary reservoir hosts of cowpox virus (CPV) and since CPV encodes a highly conserved functional homolog of VCP, termed here the inflammation modulatory protein (IMP), the effects of injection of CPV into the footpads of mice was determined in order to study the precise in vivo effects of IMP. Macroscopic examination of the site of injection with a recombinant virus lacking IMP (CPV-IMP) showed greater tissue damage, with more hemorrhage and induration, than sites injected with the wild-type cowpox virus. In addition, the measurement of the specific swelling response carried out for several weeks revealed significantly greater swelling in mice injected with CPV-IMP. Thus, IMP modulates the complement-activated inflammatory response in vivo. Furthermore, the diminished destruction of host tissue observed in the presence of IMP indicates symbiosis in which the virus ensures the preservation of surrounding host tissue, possibly to support the growth of its progeny.

Amino Acid Sequence↗