Disease relevance of Orthopoxvirus

• Vaccinia virus (VV) and other orthopoxviruses express a soluble type I interferon (IFN) receptor that for VV strain Western Reserve is encoded by gene B18R [1].
• Recent notable discoveries are the broad species specificity of orthopoxvirus interferon receptors, herpesvirus and poxvirus proteins related to chemokine receptors and proteins that bind more than one cytokine, interferon or chemokine [2].
• We have used ectromelia virus (ECTV), an orthopoxvirus very closely related to variola virus, to investigate the importance of IFN function in recovery from a secondary infection [3].
• Hybridization and sequence data indicated that a phosphatase related to the VH1 phosphatase is highly conserved in the genomes of smallpox variola virus and other orthopoxviruses [4].
• The orthopoxviruses cowpox virus and rabbitpox virus each encode three members of the serpin family of proteinase inhibitors, designated SPI-1, SPI-2, and SPI-3 [5].

High impact information on Orthopoxvirus

• The IL-1 beta binding activity is present in other orthopoxviruses [6].
• An active SECRET domain was found in another viral TNFR (CrmD) and three secreted proteins encoded by orthopoxviruses [7].
• Possessing up to three TNFRs, including CrmD, which is secreted as disulfide-linked complexes in varied amounts by CPV and ECT, likely enhances the dynamics of the immune modulating mechanisms of orthopoxviruses [8].
• Differential inhibition of the Fas- and granule-mediated cytolysis pathways by the orthopoxvirus cytokine response modifier A/SPI-2 and SPI-1 protein [5].
• Recent evidence suggests that orthopoxviruses have an obligate requirement for arachidonic acid metabolites during replication in vivo and in vitro [9].

Chemical compound and disease context of Orthopoxvirus

• Previous studies showed that the CDV and cyclic cidofovir (cCDV) analogs 1-O-hexa-decyloxypropyl-CDV (HDP-CDV) and 1-O-hexadecyloxypropyl-cCDV (HDP-cCDV), show >100-fold increases in antiviral activity versus the unmodified nucleosides against cells infected with orthopoxviruses, cowpox, and vaccinia virus [10].
• Thus, the presence of two genes that belong to the plasma serine protease inhibitor superfamily may be characteristic of orthopoxviruses [11].
• An orally bioavailable antipoxvirus compound (ST-246) inhibits extracellular virus formation and protects mice from lethal orthopoxvirus Challenge [12].
• Treatment with the N glycosylation inhibitor tunicamycin converted the two SPI-3 proteins to a single 40-kDa protein, close to the size of 42 kDa predicted from the DNA sequence, suggesting that the SPI-3 protein, unlike the other two orthopoxvirus serpins, is a glycoprotein [13].
• The alkoxyalkyl esters of (S)-HPMPA are promising new compounds worthy of further investigation for treatment of infections caused by herpes viruses and orthopoxviruses [14].

Biological context of Orthopoxvirus

• In this report we demonstrate that a number of orthopoxviruses express a type I interferon (IFN)-binding protein, which is encoded by the B18R open reading frame in the WR strain of vaccinia virus [15].
• All orthopoxviruses tested express the A34R protein, but most viruses, including variola virus, have the WR rather than the IHD-J A34R genotype [16].
• By application of these results to human orthopoxvirus infections, it is anticipated that resistant viruses may be untreatable with cidofovir but their virulence may be attenuated [17].
• To examine possible naturally occurring drug resistance among a large number of variola isolates obtained from different geographical regions and at different times, we examined the sensitivity of 35 different strains of variola as well as other orthopoxviruses to a subset of three of the most active compounds: cidofovir, cHPMPC, and ribavirin [18].
• The subunits of DNA-dependent RNA polymerase, as well as the transcription factors, mRNA-capping enzymes, and proteins necessary for the virion morphogenesis proved to be highly conservative within orthopoxviruses [19].

Anatomical context of Orthopoxvirus

• Interferon- gamma -Mediated Antiviral Immunity against Orthopoxvirus Infection Is Provided by gamma delta T Cells [20].
• These results are compatible with a model of orthopoxvirus replication that has an obligate requirement for arachidonic acid or one of its metabolic forms, possibly in the assembly of virus-specific membranes [21].

Gene context of Orthopoxvirus

• The AmEPV TK was shown to be biologically functional as cloning of the gene into a TK-derivative of the orthopoxvirus vaccinia creates a TK+ virus [22].
• The oligonucleotides used in the PCR amplification were based on residues conserved amongst the orthopoxviruses on the 5' and 3' sides of the TK gene [23].
• However, the IFN-gamma R encoded by orthopoxviruses (vaccinia, cowpox, camelpox, ectromelia) shows a novel, broad species specificity suggesting that these viruses have evolved in several species [24].
• The orthopoxvirus serpin SPI-3 is N-glycosylated and suppresses fusion between infected cells [25].
• Lack of perforin renders the relatively resistant mouse strain C57BL/6 highly susceptible to the natural mouse pathogen ectromelia virus, a cytopathic orthopoxvirus [26].

Analytical, diagnostic and therapeutic context of Orthopoxvirus

• Diagnostic testing by both polymerase chain reaction and culture revealed infectious monkeypox virus in skin lesions of all 3 patients; 2 patients had orthopoxvirus detected by immunohistochemistry in skin lesions [27].
• Attempts to amplify the ATI gene (ati) by PCR, currently used to identify orthopoxviruses, were unsuccessful [28].
• Cidofovir (CDV) is a highly effective inhibitor of orthopoxvirus replication and may be used intravenously to treat smallpox or complications arising from the smallpox vaccine under an investigational new drug application (IND) [29].
• Characterization of antibodies to orthopoxviruses in human sera by radioimmunoassay [30].
• Clinical diagnosis can be confirmed by electron microscopy to identify the presence of orthopoxvirus, as well as by virologic culture, polymerase chain reaction, and/or restriction endonuclease analysis of viral isolates [31].

References