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PubMed2006

Follow-up on diagnostic proficiency of laboratories equipped to perform orthopoxvirus detection and quantification by PCR: the second international external quality assurance study.

Two years after the first external quality assurance study on bioterrorism-relevant viruses, we have conducted a follow-up study on orthopoxvirus detection by PCR. Thirty-three laboratories (27 European, 4 Austral-Asian, and 2 American) participated. Samples contained 0 to 40,000,000 DNA copies of lyophilized monkeypox, cowpox, and vaccinia virus per ml. Laboratories achieved a >80% detection chance above 56,234 copies per ml. Global sensitivity was not significantly improved over that of the first study. Twenty-seven and 9 participants, respectively, were able to genotype and quantify virus. Four of 27 genotyping results were incorrect. Quantification accuracy was significantly better for vaccinia virus than for the other viruses. False-positive results occurred in 22 (11.8%) of all 186 tests on negative samples, but 18 of these were contributed by only five laboratories. Fifty-five percent of laboratories could appropriately detect PCR inhibition. The use of either real-time PCR or commercial diagnostic kits had significant positive influence on laboratory performance.

Clinical Laboratory Techniques↗
PubMed2006

Poxvirus CD8+ T-cell determinants and cross-reactivity in BALB/c mice.

Mouse models of orthopoxvirus disease provide great promise for probing basic questions regarding host responses to this group of pathogens, which includes the causative agents of monkeypox and smallpox. However, some essential tools for their study that are taken for granted with other mouse models are not available for these viruses. Here we map and characterize the initial CD8+ T-cell determinants for poxviruses in H-2d-haplotype mice. CD8+ T cells recognizing these three determinants make up around 40% of the total responses to vaccinia virus during and after resolution of infection. We then use these determinants to test if predicted conservation across orthopoxvirus species matches experimental observation and find an unexpectedly cross-reactive variant peptide encoded by ectromelia (mousepox) virus.

Animals↗
PubMed1986

Identification and nucleotide sequence of the thymidine kinase gene of Shope fibroma virus.

The thymidine kinase (TK) gene of Shope fibroma virus (SFV), a tumorigenic leporipoxvirus, was localized within the viral genome with degenerate oligonucleotide probes. These probes were constructed to two regions of high sequence conservation between the vaccinia virus TK gene and those of several known eucaryotic cellular TK genes, including human, mouse, hamster, and chicken TK genes. The oligonucleotide probes initially localized the SFV TK gene 50 kilobases (kb) from the right terminus of the 160-kb SFV genome within the 9.5-kb BamHI-HindIII fragment E. Fine-mapping analysis indicated that the TK gene was within a 1.2-kb AvaI-HaeIII fragment, and DNA sequencing of this region revealed an open reading frame capable of encoding a polypeptide of 176 amino acids possessing considerable homology to the TK genes of the vaccinia, variola, and monkeypox orthopoxviruses and also to a variety of cellular TK genes. Homology matrix analysis and homology scores suggest that the SFV TK gene has diverged significantly from its counterpart members in the orthopoxvirus genus. Nevertheless, the presence of conserved upstream open reading frames on the 5' side of all of the poxvirus TK genes indicates a similarity of functional organization between the orthopoxviruses and leporipoxviruses. These data suggest a common ancestral origin for at least some of the unique internal regions of the leporipoxviruses and orthopoxviruses as exemplified by SFV and vaccinia virus, respectively.

Base Sequence↗
PubMed2002

Identification of the orthopoxvirus p4c gene, which encodes a structural protein that directs intracellular mature virus particles into A-type inclusions.

The orthopoxvirus gene p4c has been identified in the genome of the vaccinia virus strain Western Reserve. This gene encodes the 58-kDa structural protein P4c present on the surfaces of the intracellular mature virus (IMV) particles. The gene is disrupted in the genome of cowpox virus Brighton Red (BR), demonstrating that although the P4c protein may be advantageous for virus replication in vivo, it is not essential for virus replication in vitro. Complementation and recombination analyses with the p4c gene have shown that the P4c protein is required to direct the IMV into the A-type inclusions (ATIs) produced by cowpox virus BR. The p4c gene is highly conserved among most members of the orthopoxvirus genus, including viruses that produce ATIs, such as cowpox, ectromelia, and raccoonpox viruses, as well as those such as variola, monkeypox, vaccinia, and camelpox viruses, which do not. The conservation of the p4c gene among the orthopoxviruses, irrespective of their capacities to produce ATIs, suggests that the P4c protein provides functions in addition to that of directing IMV into ATIs. These findings, and the presence of the P4c protein in IMV but not extracellular enveloped virus (D. Ulaeto, D. Grosenbach, and D. E. Hruby, J. Virol. 70:3372-3377, 1996), suggest a model in which the P4c protein may play a role in the retrograde movement of IMV particles, thereby contributing to the retention of IMV particles within the cytoplasm and within ATIs when they are present. In this way, the P4c protein may affect both viral morphogenesis and processes of virus dissemination.

Amino Acid Sequence↗
PubMed2005

An orally bioavailable antipoxvirus compound (ST-246) inhibits extracellular virus formation and protects mice from lethal orthopoxvirus Challenge.

ST-246 is a low-molecular-weight compound (molecular weight = 376), that is potent (concentration that inhibited virus replication by 50% = 0.010 microM), selective (concentration of compound that inhibited cell viability by 50% = >40 microM), and active against multiple orthopoxviruses, including vaccinia, monkeypox, camelpox, cowpox, ectromelia (mousepox), and variola viruses. Cowpox virus variants selected in cell culture for resistance to ST-246 were found to have a single amino acid change in the V061 gene. Reengineering this change back into the wild-type cowpox virus genome conferred resistance to ST-246, suggesting that V061 is the target of ST-246 antiviral activity. The cowpox virus V061 gene is homologous to vaccinia virus F13L, which encodes a major envelope protein (p37) required for production of extracellular virus. In cell culture, ST-246 inhibited plaque formation and virus-induced cytopathic effects. In single-cycle growth assays, ST-246 reduced extracellular virus formation by 10 fold relative to untreated controls, while having little effect on the production of intracellular virus. In vivo oral administration of ST-246 protected BALB/c mice from lethal infection, following intranasal inoculation with 10x 50% lethal dose (LD(50)) of vaccinia virus strain IHD-J. ST-246-treated mice that survived infection acquired protective immunity and were resistant to subsequent challenge with a lethal dose (10x LD(50)) of vaccinia virus. Orally administered ST-246 also protected A/NCr mice from lethal infection, following intranasal inoculation with 40,000x LD(50) of ectromelia virus. Infectious virus titers at day 8 postinfection in liver, spleen, and lung from ST-246-treated animals were below the limits of detection (<10 PFU/ml). In contrast, mean virus titers in liver, spleen, and lung tissues from placebo-treated mice were 6.2 x 10(7), 5.2 x 10(7), and 1.8 x 10(5) PFU/ml, respectively. Finally, oral administration of ST-246 inhibited vaccinia virus-induced tail lesions in Naval Medical Research Institute mice inoculated via the tail vein. Taken together, these results validate F13L as an antiviral target and demonstrate that an inhibitor of extracellular virus formation can protect mice from orthopoxvirus-induced disease.

Administration, Oral↗
PubMed2003

Comparative effects of cidofovir and cyclic HPMPC on lethal cowpox and vaccinia virus respiratory infections in mice.

BACKGROUND: Cidofovir is approved for the treatment of cytomegalovirus retinitis in humans. Although highly effective, the drug can cause renal toxicity in patients. There is much interest in cidofovir as a potential treatment for smallpox, monkeypox and other orthopoxvirus infections. A cyclic phosphonate form of cidofovir, 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine (cyclic HPMPC), was reported to be less nephrotoxic than cidofovir in animals. Thus, it was deemed important to directly compare the activities of cidofovir and cyclic HPMPC against poxvirus infections in mouse models. METHODS: The compounds were evaluated by intraperitoneal and intranasal infection routes using multiple doses of each agent, with single doses of compound given 24 h after virus challenge. RESULTS: By intraperitoneal route, cidofovir protected mice from mortality at 40, 80 and 160 mg/kg, whereas cyclic HPMPC was similarly protective only at 160 mg/kg. By intranasal route, cidofovir was active down to 5 mg/kg, compared to cyclic HPMPC efficacy at 20 and 40 mg/kg. Intraperitoneal doses of 40, 80 and 160 mg/kg cidofovir significantly reduced mortality from vaccinia virus infections, compared to doses of 80 and 160 mg/kg cyclic HPMPC. Intranasal treatment with cidofovir at 5-40 mg/kg was comparably effective to cyclic HPMPC doses of 20 and 40 mg/kg in vaccinia virus infections. Active doses significantly reduced lung virus titers and lung consolidation. Overall, the potency of cyclic HPMPC was about 4 times less than that of cidofovir. CONCLUSIONS: Although cyclic HPMPC is reported to exhibit reduced nephrotoxicity in vivo, it is also less potent than cidofovir against orthopoxvirus infections. For this reason, cyclic HPMPC may not offer any advantage over cidofovir in treating these infections in humans.

Administration, Intranasal↗
PubMed2001

Antiviral activity and mode of action studies of ribavirin and mycophenolic acid against orthopoxviruses in vitro.

Two inhibitors of cellular inosine monophosphate dehydrogenase, mycophenolic acid (MPA) and ribavirin, were evaluated for inhibitory activity against orthopoxviruses. Unrelated antipoxvirus agents tested for comparison included 6-azauridine, cidofovir (HPMPC) and cyclic HPMPC. MPA inhibited camelpox, cowpox, monkeypox and vaccinia viruses by 50% in plaque reduction assays at 0.2-3 microM in African green monkey kidney (Vero 76) and mouse 3T3 cells. Ribavirin was considerably more active in 3T3 cells (50% inhibition at 2-12 microM) than in Vero 76 cells (inhibitory at 30-250 microM) against these viruses. In cytotoxicity assays, MPA and ribavirin were more toxic to replicating cells than to stationary cell monolayers, with greater toxicity seen in 3T3 than in Vero 76 cells. The superior antiviral potency and increased toxicity of ribavirin in 3T3 cells was related to greater accumulation of mono-, di- and triphosphate forms of the drug compared with Vero 76 cells. For both MPA and ribavirin, virus inhibition was closely correlated to the extent of suppression of intracellular guanosine triphosphate (GTP) pools. Treatment with extracellular guanosine (which restored intracellular GTP levels) did not lead to complete reversal of the anticowpox virus activity of ribavirin. This suggests that other modes of virus inhibition also appear to contribute to the anti-orthopoxvirus activity of ribavirin. Biological differences in mode of action and immunosuppressive potential between ribavirin and MPA may account for why the former compound is active against orthopoxvirus infections in animals and the latter inhibitor is not.

3T3 Cells↗
PubMed2004

Multi-pathogens sequence containing plasmids as positive controls for universal detection of potential agents of bioterrorism.

BACKGROUND: The limited circulation of many of the agents that are likely to be used in a bioterrorism attack precludes the ready availability of positive controls. This means that only specialized laboratories can screen for the presence of these agents by nucleic amplification assays. Calibrated controls are also necessary for quantitative measurements. Primers and probes to be used in both conventional and real-time PCR assays were designed for the detection of agents likely to be used by a bioterrorist. Three plasmids, each of which contains 4 to 6 specific sequences from agents on the CDC Category A and B list (excluding RNA viruses) were constructed. Two plasmids incorporate the sequences of Category A and B agents, respectively. The third plasmid incorporates sequences from Variola major and organisms that cause rash-like illnesses that may be clinically confused with smallpox. An "exogenic sequence", introducing a NotI restriction site was incorporated in the native sequences of the bioterrorism agents inserted in plasmids. The designed molecular system for detection of bioterrorism agents was tested on each of these agents (except Monkeypox virus, Smallpox virus and 2 Burkholderia species for which no native DNA was available) and a collection of 50 isolates of C. burnetii using constructed plasmids as positive controls. RESULTS: Designed primers and probes allowed molecular detection, in either single or multiplex assays, of agent-specific targets with analytical sensitivities of between 1 and 100 DNA copies. The plasmids could be used as positive controls. False-positive results due to contamination by the positive control were easily detected by sequencing and eliminated by digestion with NotI. CONCLUSION: Plasmid A and B can be used as positive controls in molecular assays for the detection of bioterrorism agents in clinical specimens or environmental samples. Plasmid C can be used as a positive control in differentiation of vesicular rashes. It is also possible to avoid or to ensure immediate detection of false positive results due to contamination by positive controls using these plasmids. These plasmids and the corresponding primers and probes are immediately available for all clinical microbiology laboratories provided they have molecular amplification equipment.

Bacteria↗
PubMed2007

From actually toxic to highly specific--novel drugs against poxviruses.

The potential use of variola virus, the causative agent of smallpox, as a bioweapon and the endemic presence of monkeypox virus in Africa demonstrate the need for better therapies for orthopoxvirus infections. Chemotherapeutic approaches to control viral infections have been less successful than those targeting bacterial infections. While bacteria commonly reproduce themselves outside of cells and have metabolic functions against which antibiotics can be directed, viruses replicate in the host cells using the cells' metabolic pathways. This makes it very difficult to selectively target the virus without damaging the host. Therefore, the development of antiviral drugs against poxviruses has initially focused on unique properties of the viral replication cycle or of viral proteins that can be selectively targeted. However, recent advances in molecular biology have provided insights into host factors that represent novel drug targets. The latest anti-poxvirus drugs are kinase inhibitors, which were originally developed to treat cancer progression but in addition block egress of poxviruses from infected cells. This review will summarize the current understanding of anti-poxvirus drugs and will give an overview of the development of the latest second generation poxvirus drugs.

Animals↗
PubMed2006

Recent animal disease outbreaks and their impact on human populations.

Over the past 20 years, headlines have documented an increasing number of emerging diseases; most have an animal source (zoonoses). Recent examples include West Nile virus, severe acute respiratory syndrome (SARS), avian influenza, and monkeypox. While some emerging diseases occur among both humans and animals, others affect only animals or only humans. Nevertheless, all these new or reemerging infections have societal implications, often tied to local and national economies. It is important to understand the implications of emerging animal diseases and encourage stronger collaboration of veterinary and medical practitioners, especially in rural areas. Illnesses in agricultural workers may be the index cases for newly emerging diseases.

Agricultural Workers' Diseases↗
PubMed2004

Mouse models for studying orthopoxvirus respiratory infections.

Concern regarding the use of variola and monkeypox viruses as bioterrorist agents has led to an increased study of orthopoxviruses to understand the molecular and cellular basis of pathogenesis and develop safe and effective antivirals and vaccines against smallpox. Crucial to these efforts is the availability of animal models, which are inexpensive, genetically homogeneous, and recapitulate the human disease. The popular small-animal orthopoxvirus models employ the inbred mouse as the host, the respiratory tract as the site of virus inoculation, and orthopoxviruses-vaccinia, cowpox, and ectromelia viruses-as surrogates for variola virus. Ectromelia virus is likely the best surrogate for variola virus in a mouse model, as it is infectious at very low doses of virus, and the mousepox disease is associated with high mortality in the susceptible A, BALB/c, and DBA/2 stains of mice, but causes an unapparent infection in the C57BL/6 mouse strain. This chapter describes an ectromelia virus respiratory infection model in the mouse.

Animals↗
PubMed2004

Emerging infectious diseases: vulnerabilities, contributing factors and approaches.

We live in an ever more connected global village linked through international travel, politics, economics, culture and human-human and human-animal interactions. The realization that the concept of globalization includes global exposure to disease-causing agents that were formerly confined to small, remote areas and that infectious disease outbreaks can have political, economic and social roots and effects is becoming more apparent. Novel infectious disease microbes continue to be discovered because they are new or newly recognized, have expanded their geographic range, have been shown to cause a new disease spectrum, have jumped the species barrier from animals to humans, have become resistant to antimicrobial agents, have increased in incidence or have become more virulent. These emerging infectious disease microbes may have the potential for use as agents of bioterrorism. Factors involved in the emergence of infectious diseases are complex and interrelated and involve all classifications of organisms transmitted in a variety of ways. In 2003, outbreaks of interest included severe acute respiratory syndrome, monkeypox and avian influenza. Information from the human genome project applied to microbial organisms and their hosts will provide new opportunities for detection, diagnosis, treatment, prevention, control and prognosis. New technology related not only to genetics but also to satellite and monitoring systems will play a role in weather, climate and the approach to environmental manipulations that influence factors contributing to infectious disease emergence and control. Approaches to combating emerging infectious diseases include many disciplines, such as animal studies, epidemiology, immunology, ecology, environmental studies, microbiology, pharmacology, other sciences, health, medicine, public health, nursing, cultural, political and social studies, all of which must work together. Appropriate financial support of the public health infrastructure including surveillance, prevention, communication, adherence techniques and the like will be needed to support efforts to address emerging infectious disease threats.

Climate↗
PubMed2000

Public health implications of emerging zoonoses.

Many new, emerging and re-emerging diseases of humans are caused by pathogens which originate from animals or products of animal origin. A wide variety of animal species, both domestic and wild, act as reservoirs for these pathogens, which may be viruses, bacteria or parasites. Given the extensive distribution of the animal species affected, the effective surveillance, prevention and control of zoonotic diseases pose a significant challenge. The authors describe the direct and indirect implications for public health of emerging zoonoses. Direct implications are defined as the consequences for human health in terms of morbidity and mortality. Indirect implications are defined as the effect of the influence of emerging zoonotic disease on two groups of people, namely: health professionals and the general public. Professional assessment of the importance of these diseases influences public health practices and structures, the identification of themes for research and allocation of resources at both national and international levels. The perception of the general public regarding the risks involved considerably influences policy-making in the health field. Extensive outbreaks of zoonotic disease are not uncommon, especially as the disease is often not recognised as zoonotic at the outset and may spread undetected for some time. However, in many instances, the direct impact on health of these new, emerging or re-emerging zoonoses has been small compared to that of other infectious diseases affecting humans. To illustrate the tremendous indirect impact of emerging zoonotic diseases on public health policy and structures and on public perception of health risks, the authors provide a number of examples, including that of the Ebola virus, avian influenza, monkeypox and bovine spongiform encephalopathy. Recent epidemics of these diseases have served as a reminder of the existence of infectious diseases and of the capacity of these diseases to occur unexpectedly in new locations and animal species. The need for greater international co-operation, better local, regional and global networks for communicable disease surveillance and pandemic planning is also illustrated by these examples. These diseases have contributed to the definition of new paradigms, especially relating to food safety policies and more generally to the protection of public health. Finally, the examples described emphasise the importance of intersectorial collaboration for disease containment, and of independence of sectorial interests and transparency when managing certain health risks.

Animals↗
PubMed2006

A history of biological disasters of animal origin in North America.

This paper examines past occurrences in North America relevant to the possibility of biological disasters with animal origins. With respect to naturally occurring animal disease outbreaks, North America, while not as adversely affected by epizootics as other regions, has had its fair share of such outbreaks of both 'traditional' and emerging animal diseases. The traditional category includes such diseases as anthrax, classical swine fever, bluetongue, brucellosis, foot and mouth disease, and the family of equine encephalomyelitis viruses. The emerging diseases include relatively more recent culprits such as postweaning multisystemic wasting syndrome, poultry enteritis mortality syndrome, and newly discovered examples of the transmissible spongiform encephalopathies. Additionally, several serious diseases of human beings that involve animal vectors or reservoirs occur naturally in North America or have emerged in recent decades; these include plague, hantavirus, monkeypox, West Nile virus and avian-derived influenza. At the same time, there have been very few intentional attacks on livestock using biological agents and no recorded cases in North America of animals intentionally being used to transmit disease to humans. According to the historical record, therefore, naturally occurring emerging zoonoses probably constitute the greatest threat in terms of biological disasters with animal origins. However, some of the general trends in terrorist activity, such as the intensification of activities by animal rights extremists against facilities undertaking animal research, mean that the possibility of intentional animal-related biological disasters should not be discounted.

Animal Diseases↗
PubMed2005

Orthopoxvirus targets for the development of antiviral therapies.

The potential use of smallpox virus as a bioterror agent and the endemic presence of monkeypox virus in Africa underscores the need for better therapies for orthopoxvirus infections. The only existing clinical experience treating vaccinia and smallpox infections has been with Marboran, which suggested that antiviral therapies could be effective in treating and preventing smallpox infections, but this compound has not been pursued. Drugs that have been approved for other indications, like cidofovir, could be approved for the treatment of orthopoxvirus infections in a timely manner, and this compound has already been approved for emergency treatment of smallpox and complications from vaccination. Its lack of activity when given orally, however, limits its use in a major outbreak involving large numbers of people exposed to the virus. The discovery and development of new therapies can be achieved more rapidly by drawing on the experience and successes with other antiviral agents, particularly with the herpesviruses. This review will discuss the orthopoxvirus replication cycle in detail noting specific viral functions and their associated gene products that have the potential to serve as new targets for drug design and development. This discussion is designed to help investigators relate these targets to parallel functions and existing assays in other virus systems that have been used successfully in drug development. The rapid progress that has been achieved in recent years should yield new drugs for the treatment of these infections and might also reveal new strategies for antiviral therapy with other viruses.

Animals↗
PubMed2005

Hedgehog zoonoses.

Exotic pets, including hedgehogs, have become popular in recent years among pet owners, especially in North America. Such animals can carry and introduce zoonotic agents, a fact well illustrated by the recent outbreak of monkeypox in pet prairie dogs. We reviewed known and potential zoonotic diseases that could be carried and transmitted by pet hedgehogs or by wild-caught hedgehogs that have been rescued.

Animals↗
PubMed2005

Antibodies and CD8+ T cells are complementary and essential for natural resistance to a highly lethal cytopathic virus.

It is believed that CD8+ T lymphocytes or Abs can independently clear many primary viral infections, including those caused by Orthopoxviruses (OPV), a genus that includes the human pathogens variola and monkeypox and the vaccine species vaccinia virus. However, most experiments addressing the role of Abs and CD8+ T cells in protection have used viruses that are not specific for the host. In the present study, we used the mouse-specific OPV ectromelia virus and mice deficient in CD40, B cells, or CD8+ T cells and adoptive transfers of CD8+ T or B lymphocytes to show that the protection afforded by CD8+ T cells is incomplete. Despite sustained CD8+ T cell responses, in the absence of Ab responses ectromelia virus persists. This results in delayed disease and inexorably leads to death. Therefore, CD8+ T lymphocytes and Abs are not redundant but complementary and essential to survive infections with a highly pathogenic viruses in the natural host.

Adoptive Transfer↗
PubMed2005

Diversity in the acute CD8 T cell response to vaccinia virus in humans.

Orthopoxviruses have complex proteomes. Infection provokes a brisk CD8 response, which is required in some systems for recovery from primary infection. Little is known concerning the Ags and epitopes recognized by CD8 T cells. We examined the fine specificity of cloned and bulk human vaccinia-specific CD8 CTL by expressing polypeptide fragments from a library of vaccinia genomic DNA. This epitope discovery method emphasizes virus-specific biological activity, as the responder cells are all reactive with whole vaccinia virus. Sixteen novel epitopes, restricted by several HLA A and B alleles, were defined to the nomamer peptide level in diverse vaccinia open reading frames. An additional seven epitope were mapped to short regions of vaccinia proteins. Targets of the CD8 response included proteins assigned to structural, enzymatic, transcription factor, and immune evasion functions, and included members of all viral kinetic classes. Most epitopes were conserved in other orthopoxviruses. Responses to at least 18 epitopes were detected within a single blood sample, revealing a surprising degree of diversity. These epitopes will be useful in natural history studies of CD8 responses to vaccinia, a nonpersisting virus with long-term memory, and in the design and evaluation of attenuated and replication-incompetent vaccinia strains being tested for variola and monkeypox prevention and for the delivery of heterologous Ags.

Adult↗