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PubMedDate not supplied

Potential virulence determinants in terminal regions of variola smallpox virus genome.

Smallpox eradication culminated the most successful antimicrobial campaign in medical history. To characterize further the linear double-stranded DNA genome of the aetiological agent of smallpox, we have determined the entire nucleotide sequence of the highly virulent variola major virus, strain Bangladesh-1975 (VAR-BSH; 186,102 base pairs, 33.7% G + C; Genbank accession number, L22579). Here we highlight features of the molecule and focus on a few of the 187 putative proteins that probably contribute to pathogenicity and virus host-range properties. One hundred and fifty proteins were markedly similar to those of vaccinia virus (smallpox vaccine), for which a complete sequence has been reported for strain Copenhagen (VAC-CPN; 191,636 base pairs, 33.3% G + C). The remaining 37 proteins reflected variola-specific sequences or open reading frame divergences for variant proteins, which are often truncated or elongated compared with their vaccinia counterparts.

Animals↗
PubMed1995

Myxoma virus and Shope fibroma virus encode dual-specificity tyrosine/serine phosphatases which are essential for virus viability.

Sequence analysis of the genomes of the Leporipoxviruses myxoma virus and Shope fibroma virus (SFV) led to the discovery of open reading frames homologous to the vaccinia H1L gene encoding a soluble protein phosphatase with dual tyrosine/serine specificity. These viral phosphatase genes were subsequently localized to the myxoma BamHI-I fragment and the SFV BamHI-M fragment, and the resulting encoded proteins were designated I1L and M1L, respectively. The localization and orientation of the myxoma I1L and SFV M1L open reading frames within the well conserved central core of the viral genomes closely mirror that of the Orthopoxviruses vaccinia virus and variola virus. The myxoma I1L and SFV M1L phosphatases each contain the conserved tyrosine phosphatase signature sequence motif, (I/V)HCXAGXXR(S/T)G, including the active site cysteine, found previously to be essential for phosphotyrosine dephosphorylation. The vaccinia H1L phosphatase was originally shown to have the ability to dephosphorylate phosphotyrosyl and phosphoseryl residues in vitro. To assess whether this is a common feature of poxvirus phosphatases, myxoma I1L was expressed as a GST-fusion protein, purified, and shown to dephosphorylate substrates containing tyrosine and serine phosphorylated residues, in a similar fashion to vaccinia H1L. A myxoma I1L variant, in which the active site cysteine 110 was mutated to serine, was expressed in a parallel fashion to the wild-type I1L protein and found to be completely deficient in its ability to dephosphorylate both phosphotyrosine and phosphoserine amino acids. In an attempt to ascertain the biological requirement for the myxoma I1L phosphatase, we constructed a recombinant myxoma virus containing a disrupted I1L open reading frame. This I1L mutant virus was able to successfully propagate in tissue culture only in the presence of a wild-type complementing gene, and pure virus clones containing only the disrupted allele were not viable. Thus, we conclude that the myxoma I1L dual specificity phosphatase is an essential factor for virus viability.

Amino Acid Sequence↗
PubMed2006

Chimpanzee/human mAbs to vaccinia virus B5 protein neutralize vaccinia and smallpox viruses and protect mice against vaccinia virus.

Chimpanzee Fabs against the B5 envelope glycoprotein of vaccinia virus were isolated and converted into complete mAbs with human gamma 1 heavy chain constant regions. The two mAbs (8AH8AL and 8AH7AL) displayed high binding affinities to B5 (Kd of 0.2 and 0.7 nM). The mAb 8AH8AL inhibited the spread of vaccinia virus as well as variola virus (the causative agent of smallpox) in vitro, protected mice from subsequent intranasal challenge with virulent vaccinia virus, protected mice when administered 2 days after challenge, and provided significantly greater protection than that afforded by a previously isolated rat anti-B5 mAb (19C2) or by vaccinia immune globulin. The mAb bound to a conformational epitope between amino acids 20 and 130 of B5. These chimpanzee/human anti-B5 mAbs may be useful in the prevention and treatment of vaccinia virus-induced complications of vaccination against smallpox and may also be effective in the immunoprophylaxis and immunotherapy of smallpox.

Amino Acid Sequence↗
PubMed1996

Vaccinia virus glycoprotein A34R is required for infectivity of extracellular enveloped virus.

The vaccinia virus strain Western Reserve (WR) A34R gene encodes a C-type lectin-like glycoprotein, gp22-24, that is present in the outer membrane of extracellular enveloped virus (EEV) with type II membrane topology (S.A. Duncan and G.L. Smith, J. Virol. 66:1610-1621, 1992). Here we that a WR A34R deletion mutant (WR delta A34R) released 19- to 24-fold more EEV from infected cells than did WR virus, but the specific infectivity of the released virions was reduced 5- to 6-fold. Rupture of the WR delta A34R EEV outer envelope by freeze-thawing increased virus infectivity by five- to sixfold, because of the release of infectious intracellular mature virus. All other known EEV-specific proteins are incorporated into WR delta A34R EEV, and thus the loss of gp22-24 is solely responsible for the reduction of EEV specific infectivity. The WR delta A34R virus is highly attenuated in vivo compared with WR or a revertant virus in which the A34R gene was reinserted into WR delta A34R. This attenuation is consistent with the known important role of EEV in virus dissemination and virulence. Vaccinia virus strain International Health Department-J (IHD-J) produces large amounts of EEV and forms comets because of an amino acid substitution within the A34R protein (R. Blasco, R. Sisler, and B. Moss, J. Virol. 67:3319-3325, 1993), but despite this, IHD-J EEV has a specific infectivity equivalent to that of WR EEV. Substitution of the IHD-J A34R gene into the WR strain induced comet formation and greater release of EEV, while coexpression of both genes did not; hence, the WR phenotype is dominant. All orthopoxviruses tested express the A34R protein, but most viruses, including variola virus, have the WR rather than the IHD-J A34R genotype. The A34R protein affects plaque formation, EEV release, EEV infectivity, and virus virulence.

Animals↗
PubMed2002

The genome of swinepox virus.

Swinepox virus (SWPV), the sole member of the Suipoxvirus genus of the Poxviridae, is the etiologic agent of a worldwide disease specific for swine. Here we report the genomic sequence of SWPV. The 146-kbp SWPV genome consists of a central coding region bounded by identical 3.7-kbp inverted terminal repeats and contains 150 putative genes. Comparison of SWPV with chordopoxviruses reveals 146 conserved genes encoding proteins involved in basic replicative functions, viral virulence, host range, and immune evasion. Notably, these include genes with similarity to genes for gamma interferon (IFN-gamma) receptor, IFN resistance protein, interleukin-18 binding protein, IFN-alpha/beta binding protein, extracellular enveloped virus host range protein, dUTPase, hydroxysteroid dehydrogenase, superoxide dismutase, serpin, herpesvirus major histocompatibility complex inhibitor, ectromelia virus macrophage host range protein, myxoma virus M011L, variola virus B22R, four ankyrin repeat proteins, three kelch-like proteins, five vaccinia virus (VV) A52R-like family proteins, and two G protein-coupled receptors. The most conserved genomic region is centrally located and corresponds to the VV region located between genes F9L and A38L. Within the terminal 13 kbp, colinearity is disrupted and multiple poxvirus gene homologues are absent or share a lower percentage of amino acid identity. Most of these differences involve genes and gene families with likely functions involving viral virulence and host range. Three open reading frames (SPV018, SPV019. and SPV020) are unique for SWPV. Phylogenetic analysis, genome organization, and amino acid identity indicate that SWPV is most closely related to the capripoxvirus lumpy skin disease virus, followed by the yatapoxvirus yaba-like disease virus and the leporipoxviruses. The gene complement of SWPV better defines Suipoxvirus within the Chordopoxvirinae subfamily and provides a basis for future genetic comparisons.

Animals↗
PubMed2005

Detection of vaccinia virus DNA on the LightCycler by fluorescence melting curve analysis.

After eradication of variola virus the worldwide vaccination program was stopped to avoid the severe complications observed in a small fraction of vaccinees. Hence, there is at least one non-vaccinated generation in the human population that is immunologically naive with respect to variola virus infections. The possibility of a deliberate release of variola virus by bioterrorist attacks has led to the resumption of vaccination of hospital employees and military personnel with vaccinia virus in certain parts of the world. However, the appearance of a single confirmed smallpox case worldwide would result in vaccination of possible contact persons with vaccinia virus. Therefore, reliable confirmation of vaccinia virus in patients presenting with smallpox-like syndromes is required. A vaccinia virus-specific single nucleotide polymorphism was identified in the gene B8R coding for a vaccinia virus IFNgamma receptor. Based on this polymorphism, the LightCycler real-time PCR assay detects vaccinia virus DNA in a linear range from 10(6) to 10 genome equivalents and discriminates vaccinia virus from other orthopoxviruses by fluorescence melting curve analysis (DeltaT = 9 degrees C). While the assay amplifies generically DNA of all orthopoxviruses tested, amplification curves are only displayed for vaccinia virus strains including strains formerly used for vaccination. In addition, an internal amplification control is described that allows reliable interpretation of results.

Base Sequence↗
PubMed1996

Comparative studies of gamma-interferon receptor-like proteins of variola major and variola minor viruses.

To study specific properties of the human gamma-interferon (gamma-IFN) receptor-like proteins of the highly virulent and low virulent strains of variola (smallpox) virus (VAR) recombinant plasmids determining synthesis of these proteins in E. coli cells have been constructed. The recombinant viral gamma-IFN receptor-like proteins have been found to have high interferon-neutralising activity with regard to human gamma-IFN but not murine gamma-IFN and human alpha-IFN. The variola major and variola minor proteins under study do not differ in the efficiency of human gamma-IFN antiviral activity inhibition.

Amino Acid Sequence↗
PubMed2004

Bichat guidelines for the clinical management of smallpox and bioterrorism-related smallpox.

Smallpox is a viral infection caused by the variola virus. It was declared eradicated worldwide by the Word Health Organization in 1980 following a smallpox eradication campaign. Smallpox is seen as one of the viruses most likely to be used as a biological weapon. The variola virus exists legitimately in only two laboratories in the world. Any new case of smallpox would have to be the result of human accidental or deliberate release. The aerosol infectivity, high mortality, and stability of the variola virus make it a potential and dangerous threat in biological warfare. Early detection and diagnosis are important to limit the spread of the disease. Patients with smallpox must be isolated and managed, if possible, in a negative-pressure room until death or until all scabs have been shed. There is no established antiviral treatment for smallpox. The most effective prevention is vaccination before exposure.

Bioterrorism↗
PubMedDate not supplied

[Construction of DNA-fragments' libraries with complete genomes of different variola strains].

Libraries of hybrid plasmids carrying DNA fragments of complete genomes of 8 variola virus strain from the Russian Collection belonging to 2 epidemical types and isolated in various geographic regions of the world were obtained. Genomic sequences of variola virus can be thus preserved for a long time in a biologically safe form and provide the research work on studying the genetic organization of this unique virus and on developing modern methods for rapid detection of variola virus and other orthopoxviruses.

DNA, Viral↗