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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↗

PubMed1982

Surveillance of orthopoxvirus infections, and associated research, in the period after smallpox eradication.

In 1980, the World Health Assembly declared the global eradication of smallpox and recommended the universal discontinuation of smallpox vaccination; nevertheless, it recommended that surveillance and research on orthopoxvirus infections should continue. By early 1982, all except 8 countries in the world had stopped routine vaccination programmes and all except 1 no longer required an international certificate of smallpox vaccination for travellers. Since 1978, as a result of continuing active surveillance, 176 smallpox rumours have been investigated in 60 countries. Two of these concerned the two laboratory-associated cases that occurred in the United Kingdom in 1978; all the others were false alarms. Special surveillance programmes for human monkeypox have been developed in West and Central Africa. The number of laboratories retaining variola virus stocks has been reduced to four. Investigations to determine the identity and origin of the six known isolates of "whitepox" virus have continued. Research on mapping of variola DNA and on monoclonal antibodies against certain orthopoxvirus antigens is continuing. All these measures are aimed at ensuring that the achievement of smallpox eradication is permanent.

DNA, Viral↗

PubMed2007

Immunopathogenesis of poxvirus infections: forecasting the impending storm.

Variola virus, the causative agent of smallpox, is a member of the poxvirus family and one of the most virulent human pathogens known. Although smallpox was eradicated almost 30 years ago, it is not understood why the mortality rates associated with the disease were high, why some patients recovered, and what constitutes an effective host response against infection. As variola virus infects only humans, our current understanding of poxvirus infections comes largely from historical clinical data from smallpox patients and from animal studies using closely related viruses such as ectromelia, myxoma and monkeypox. The outcome of an infection is determined by a complex interaction between the type of immune response mounted by the host and by evasion mechanisms that the virus has evolved to subvert it. Disease pathogenesis is also a function of both host and viral factors. Poxviruses are not only cytopathic, causing host tissue damage, but also encode an array of immunomodulatory molecules that affect the severity of disease. The ability of the host to control virus replication is therefore critical in limiting tissue damage. However, in addition to targeting virus, the immune response can inadvertently damage the host to such a degree that it causes illness and even death. There is growing evidence that many of the symptoms associated with serious poxvirus infections are a result of a 'cytokine storm' or sepsis and that this may be the underlying cause of pathology.

Animals↗

PubMed1977

Identification of Orthopox virus by isoelectrofocusing in a granulated gel.

Twenty strains of Orthopox viruses (vaccina (3), cowpox (2), monkeypox (2), variola major and minor (7) and whitepox (6)) have been tested by electrofocusing in a granulated gel. From our preliminary results, it appears that there is a clearcut distinction between smallpox and whitepox. If our results are confirmed, it will be the first real genetic marker identified because other in vitro or in vivo test have heretofore failed to differentiate between smallpox and whitepox. Further work is now in progress, to evaluate of the test and it is hoped to find and explanation for the observations now reported.

Isoelectric Focusing↗

PubMed1983

Human monkeypox transmitted by a chimpanzee in a tropical rain-forest area of Zaire.

A case of monkeypox infection in a six-month-old baby girl who had been bitten by a wild chimpanzee in Kivu, Zaire, was investigated. The child had not been exposed to any monkeypox-like disease and no cases of such disease had occurred in the surrounding area during previous months. The time of onset of rash was consistent with the virus having been transmitted from the chimpanzee. However, it is still not known whether chimpanzees and other primates or lower mammals are the primary reservoir of monkeypox infection.

Accidents, Home↗

PubMed2004

Cutaneous infections of mice with vaccinia or cowpox viruses and efficacy of cidofovir.

Orthopoxviruses, including smallpox, monkeypox and molluscipox, pose risks to human health through bioterrorist acts or natural transmission. There is no approved therapy for orthopoxvirus infections; however, cidofovir (CDV) has been approved as an investigational new drug for emergency treatment of adverse effects following smallpox vaccination. For evaluation of new therapies directed against orthopoxvirus infections, we have utilized immunocompetent, hairless mice (SKH-1) inoculated by a cutaneous route with cowpox virus (CV) or vaccinia virus (VV). Mice subsequently developed skin lesions and virus was recovered from the site of inoculation and quantified. Skin biopsies were evaluated microscopically, revealing brick-like eosinophilic, intracytoplasmic inclusion bodies characteristic of orthopoxvirus infection. SKH-1 mice fully recovered from either CV or VV infection. Immunodeficient Athymic or Rhino mice inoculated with CV or VV had more lesions and severe disease than SKH-1 mice. CV-infected SKH-1 mice were treated either with systemic or topical CDV. Although some protection was achieved with systemic treatment, 5% topical CDV was most effective at reducing virus titers in skin, lung, kidney, and spleen. These models may provide a means for evaluating efficacy of new therapies directed against orthopoxvirus diseases and further confirm the topical activity of CDV against cutaneous infections.

Administration, Cutaneous↗

PubMed2003

Efficacy of multiple- or single-dose cidofovir against vaccinia and cowpox virus infections in mice.

Orthopoxviruses, including variola and monkeypox, pose risks to human health through natural transmission or potential bioterrorist activities. Since vaccination has not recently been utilized for control of these infections, there is renewed effort in the development of antiviral agents not only for postexposure smallpox therapy but also for treatment of adverse reactions following vaccination. The objectives of this study were to expand on the results of others that cidofovir (CDV) is effective in mice inoculated with cowpox virus (CV) or vaccinia virus (VV) and to document the efficacy of single and interval dosing beginning prior to or after infection, particularly including evaluations using suboptimal doses of CDV. We utilized BALB/c or SCID mice inoculated with CV or VV as models for systemic poxvirus infections. BALB/c mice were inoculated intranasally with CV or VV and treated with CDV prior to or after virus inoculation. CDV, at concentrations as low as 0.7 to 6.7 mg/kg of body weight/day for 5 days, conferred significant protection when treatment was initiated as late as 72 to 96 h postinfection. A single-dose pretreatment or posttreatment with CDV at 3 to 100 mg/kg was effective when given as early as 5 days prior to infection or as late as 3 days after infection with either VV or CV. Interval treatments given every third day beginning 72 h postinfection using 6.7 or 2 mg of CDV/kg also proved effective against CV infections. When SCID mice were inoculated intraperitoneally with CV or VV and treated for 7 to 30 days with CDV, all the mice eventually died during or after cessation of treatment; however, significant delays in time to death and reduction of virus replication in organs occurred in most treated groups, and no resistance to CDV was detected.

Animals↗

PubMed2003

Real-time PCR assay to detect smallpox virus.

We developed a highly sensitive and specific assay for the rapid detection of smallpox virus DNA on both the Smart Cycler and LightCycler platforms. The assay is based on TaqMan chemistry with the orthopoxvirus hemagglutinin gene used as the target sequence. With genomic DNA purified from variola virus Bangladesh 1975, the limit of detection was estimated to be approximately 25 copies on both machines. The assay was evaluated in a blinded study with 322 coded samples that included genomic DNA from 48 different isolates of variola virus; 25 different strains and isolates of camelpox, cowpox, ectromelia, gerbilpox, herpes, monkeypox, myxoma, rabbitpox, raccoonpox, skunkpox, vaccinia, and varicella-zoster viruses; and two rickettsial species at concentrations mostly ranging from 100 fg/ microl to 1 ng/ microl. Contained within those 322 samples were variola virus DNA, obtained from purified viral preparations, at concentrations of 1 fg/ microl to 1 ng/ microl. On the Smart Cycler platform, 2 samples with false-positive results were detected among the 116 samples not containing variola virus tested; i.e., the overall specificity of the assay was 98.3%. On the LightCycler platform, five samples with false-positive results were detected (overall specificity, 95.7%). Of the 206 samples that contained variola virus DNA ranging in concentrations from 100 fg/ microl to 1 ng/ microl, 8 samples were considered negative on the Smart Cycler platform and 1 sample was considered negative on the LightCycler platform. Thus, the clinical sensitivities were 96.1% for the Smart Cycler instrument and 99.5% for the LightCycler instrument. The vast majority of these samples were derived from virus-infected cell cultures and variola virus-infected tissues; thus, the DNA material contained both viral DNA and cellular DNA. Of the 43 samples that contained purified variola virus DNA ranging in concentration from 1 fg/ microl to 1 ng/ microl, the assay correctly detected the virus in all 43 samples on both the Smart Cycler and the LightCycler platforms. The assay may be useful for the early detection of smallpox virus infections should such infections occur as a result of a deliberate or an accidental recurrence.

Animals↗

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↗

PubMed2002

Cidofovir in the therapy and short-term prophylaxis of poxvirus infections.

Although it is often stated that only vaccination would be able to contain or protect the population against a catastrophic smallpox outbreak, the acyclic nucleoside phosphonate analog cidofovir offers a valuable alternative for the therapy and short-term pre- and post-exposure prophylaxis, not only of smallpox but also of other poxvirus infections and DNA viruses. Cidofovir has proven effective against vaccinia, cowpox and monkeypox in various animal model infections. In cell culture, cidofovir has demonstrated activity against variola virus, the etiological agent of smallpox, and in patients it has shown marked efficacy against molluscum contagiosum and orf, two poxvirus infections. Cidofovir is available as an aqueous solution for intravenous administration and could be reformulated for topical (cream or gel), intranasal (aerosol) or peroral (as a lipid prodrug) use, should the need arise.

Antiviral Agents↗

PubMed2001

Species-specific differences in the structure of orthopoxvirus complement-binding protein.

Vaccinia virus complement-binding protein (VCP) is secreted from the cells infected with the virus and controls the complement activation reactions. This protein contains four short consensus repeats (SCR), typical of the protein family of complement activation regulators. Organization of the VCP genes/proteins of orthopoxviruses-monkeypox (MPV), variola, cowpox and vaccinia viruses-and their cellular homologues (DAF and C4BP) were studied comparatively. For this purpose, VCP genes of three MPV strains were sequenced. VCP gene sequences of other human-pathogenic orthopoxvirus species and strains determined earlier were involved in the analysis. It has been demonstrated that a premature termination of the MPV VCP open reading frame results in a truncated protein sequence carrying a deletion of the C-terminal SCR4. This is an essential distinction of MPV from other orthopoxvirus species.

Amino Acid Sequence↗

PubMed2006

Microarray assay for detection and discrimination of Orthopoxvirus species.

A microarray method was developed for simultaneous detection and identification of six species of Orthopoxvirus (OPV) including Variola, Monkeypox, Cowpox, Camelpox, Vaccinia, and Ectromelia viruses. The method allowed us to discriminate OPV species from varicella-zoster virus (VZV), Herpes Simplex 1 virus (HSV-1), and Herpes Simplex 2 virus (HSV-2) that cause infections with clinical manifestations similar to OPV infections. The nucleotide sequences of the C23L/B29R and the B19R genes identified for 86 and 72 different OPV strains, respectively, were used to design species-specific microarray oligonucleotide probes (oligoprobes). The microarray also contained several oligoprobes selected from the ORF31, US4, and US5 genes of VZV, HSV-1, and HSV-2, respectively. The samples (from HSVs or OPVs) of ssDNAs for analyses were prepared by using asymmetric PCR followed by chemical labeling of ssDNA with Cy3 dye. DNA from 52 samples of various OPV species, two isolates of VZV, two of HSV-1, and three of HSV-2 were tested using the developed microarray assay; all tested viruses were accurately identified. To ensure the robustness of the microarray assay, three additional unrelated variola virus strains with unknown sequences of the C23L/B29R and the B19R genes were tested. In each instance the microarray unambiguously identified them as Variola virus species. The results obtained in this study demonstrated that this new microarray method is a valuable tool for the rapid and accurate detection and differentiation of these important viral pathogens.

Carbocyanines↗

PubMed2003

Studying the global distribution of infectious diseases using GIS and RS.

West Nile virus, severe acute respiratory syndrome and monkeypox are infectious diseases that have recently been introduced into areas far from their region of origin. The greatest risk of new diseases comes from zoonoses--pathogens that circulate among wild animals and are occasionally transferred to humans by intermediate invertebrate hosts or vectors that are sensitive to climatic conditions. Analytical tools that are based on geographical information systems and that can incorporate remotely sensed information about the environment offer the potential to define the limiting conditions for any disease in its native region for which there are at least some distribution data. The direction, intensity or likelihood of its spread to new regions could then be predicted, potentially allowing disease early-warning systems to be developed.

Animals↗

PubMedDate not supplied

Combining the benefits of decision science and financial analysis in public health management: a county-specific budgeting and planning model.

State public health agencies are charged with providing and overseeing the management of basic public health services on a population-wide basis. These activities have a re-emphasized focus as a result of the events of September 11, 2001, the subsequent anthrax events, and the continuing importance placed on bioterrorism preparedness, West Nile virus, and emerging infectious diseases (eg, monkeypox, SARS). This has added to the tension that exists in budgeting and planning, given the diverse constituencies that are served in each state. State health agencies must be prepared to allocate finite resources in a more formal manner to be able to provide basic public health services on a routine basis, as well as during outbreaks. This article describes the use of an analytical approach to assist financial analysis that is used for budgeting and planning in a state health agency. The combined benefits of decision science and financial analysis are needed to adequately and appropriately plan and budget to meet the diverse needs of the populations within a state. Health and financial indicators are incorporated into a decision model, based on multicriteria decision theory, that has been employed to acquire information about counties and public health programs areas within a county, that reflect the impact of planning and budgeting efforts. This information can be used to allocate resources, to distribute funds for health care services, and to guide public health finance policy formulation and implementation.

Budgets↗

PubMed2003

Tropical dermatology: viral tropical diseases.

Viruses are important pathogens in tropical areas; most of them, especially the tropical hemorrhagic fevers, produce mucocutaneous manifestations. More than any other kind of pathogen, viruses have the possibility for being widespread, since they have a greater probability of mutation than do bacteria, can cross species barriers easily, and infect both human beings and animals in habitats with a great biodiversity. Tropical habitats also have been subject to major ecologic changes in the last few decades, exposing humans to direct contact with these viruses and allowing hemorrhagic fevers due to new emergent viruses such as flaviviruses, filoviruses, arenaviruses, and hantaviruses to become major threats to public health. The collapse of eradication programs in many countries, as well as population increases and ecologic modifications, have led to the spread of dengue and yellow fever to large portions of the world owing to the dissemination of vectors, especially mosquitoes, with broad ecologic ranges. Viruses previously restricted to some geographic areas, such as Rift Valley fever, Crimean-Congo hemorrhagic fever, West Nile fever, and monkeypox are now affecting new countries and populations. Other viruses such as herpes B infection often affect travelers and animal handlers in most parts of the world. Dermatologic lesions occur in all these diseases and can facilitate a rapid diagnosis, leading to control of the virus and helping prevent possible outbreaks.

Animals↗

PubMedDate not supplied

Outbreak of human monkeypox, Democratic Republic of Congo, 1996 to 1997.

Human monkeypox is a zoonotic smallpox-like disease caused by an orthopoxvirus of interhuman transmissibility too low to sustain spread in susceptible populations. In February 1997, 88 cases of febrile pustular rash were identified for the previous 12 months in 12 villages of the Katako-Kombe Health Zone, Democratic Republic of Congo (attack rate = 22 per 1,000; case-fatality rate = 3.7%). Seven were active cases confirmed by virus isolation. Orthopoxvirus- neutralizing antibodies were detected in 54% of 72 patients who provided serum and 25% of 59 wild-caught animals, mainly squirrels. Hemagglutination-inhibition assays and Western blotting detected antibodies in 68% and 73% of patients, respectively. Vaccinia vaccination, which protects against monkeypox, ceased by 1983 after global smallpox eradication, leading to an increase in the proportion of susceptible people.

Adolescent↗

PubMed2003

Are we ready for pandemic influenza?

During the past year, the public has become keenly aware of the threat of emerging infectious diseases with the global spread of severe acute respiratory syndrome (SARS), the continuing threat of bioterrorism, the proliferation of West Nile virus, and the discovery of human cases of monkeypox in the United States. At the same time, an old foe has again raised its head, reminding us that our worst nightmare may not be a new one. In 2003, highly pathogenic strains of avian influenza virus, including the H5N1 and H7N7 subtypes, again crossed from birds to humans and caused fatal disease. Direct avian-to-human influenza transmission was unknown before 1997. Have we responded to these threats by better preparing for emerging disease agents, or are we continuing to act only as crises arise? Here we consider progress to date in preparedness for an influenza pandemic and review what remains to be done. We conclude by prioritizing the remaining needs and exploring the reasons for our current lack of preparedness for an influenza pandemic.

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↗