Pathogenicity and immunogenicity in mice of vaccinia viruses mutated in the viral envelope proteins A33R and B5R

Gurt, Irina; Abdalrhman, Ihab; Katz, Ehud

doi:10.1016/j.antiviral.2005.11.006

Cited by 15 publications

(12 citation statements)

References 18 publications

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“…However, starting from day 3 and peaking on day 5, AUCs generated for the liver reached a maximal level in the univariate model, indicating that the rate of viral replication in the liver by days 4 to 5 postinfection could determine the outcome of the infection. This finding is indirectly supported by an earlier study showing that WR vaccinia virus was detected at higher titers in the liver than attenuated variant of WR vaccinia virus with mutations in the A33R or B5R genes (12). Surprisingly, predictive models utilizing total fluxes in the nasal cavity and lungs were weaker than the models generated with total fluxes from the liver and spleen.…”

Section: Vol 83 2009 Bioimaging For Prediction Of Lethality 10445supporting

confidence: 72%

Application of Bioluminescence Imaging to the Prediction of Lethality in Vaccinia Virus-Infected Mice

Zaitseva

Kapnick

Scott

et al. 2009

J Virol

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To find an alternative endpoint for the efficacy of antismallpox treatments, bioluminescence was measured in live BALB/c mice following lethal challenge with a recombinant WR vaccinia virus expressing luciferase. Intravenous vaccinia immunoglobulin treatments were used to confer protection on a proportion of animals. Using known lethality outcomes in 200 animals and total fluxes recorded daily in live animals, we performed univariate receiver operating characteristic (ROC) curve analysis to assess whether lethality can be predicted based on bioluminescence. Total fluxes in the spleens on day 3 and in the livers on day 5 generated accurate predictive models; the area under the ROC curve (AUC) was 0.91. Multiple logistic regression analysis utilizing a linear combination of six measurements: total flux in the liver on days 2, 3, and 5; in the spleen on days 1 and 3; and in the nasal cavity on day 4 generated the most accurate predictions (AUC ‫؍‬ 0.96). This model predicted lethality in 90% of animals with only 10% of nonsurviving animals incorrectly predicted to survive. Compared with bioluminescence, ROC analysis with 25% and 30% weight loss as thresholds accurately predicted survival on day 5, but lethality predictions were low until day 9. Collectively, our data support the use of bioimaging for lethality prediction following vaccinia virus challenge and for gaining insight into protective mechanisms conferred by vaccines and therapeutics.

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Section: Vol 83 2009 Bioimaging For Prediction Of Lethality 10445supporting

confidence: 72%

Application of Bioluminescence Imaging to the Prediction of Lethality in Vaccinia Virus-Infected Mice

Zaitseva

Kapnick

Scott

et al. 2009

J Virol

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“…The role of p37 in the orthopoxvirus replication cycle is to mediate, in concert with other viral and cellular proteins, the formation of enveloped virions (EV), which are egress competent and facilitate viral release from the infected cell (15,16) and dissemination within the host (7,17). Mutant viruses defective for EV production are avirulent in vivo (16,(18)(19)(20). Considering the role of p37 in the formation of EV, and the significance of EV in orthopoxvirus virulence, it represents a viable target for drugs capable of treating smallpox or other pathogenic orthopoxvirus diseases.…”

mentioning

confidence: 99%

Efficacy of Tecovirimat (ST-246) in Nonhuman Primates Infected with Variola Virus (Smallpox)

Mucker

Goff

Shamblin

et al. 2013

Antimicrob Agents Chemother

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. Furthermore, in clinical trials thus far, the drug appears to be safe, with a good pharmacokinetic profile. In this study, the efficacy of tecovirimat was evaluated in both a prelesional and postlesional setting in nonhuman primates challenged intravenously with 1 ؋ 10 8 PFU of Variola virus (VARV; the causative agent of smallpox), a model for smallpox disease in humans. Following challenge, 50% of placebo-treated controls succumbed to infection, while all tecovirimat-treated animals survived regardless of whether treatment was started at 2 or 4 days postinfection. In addition, tecovirimat treatment resulted in dramatic reductions in dermal lesion counts, oropharyngeal virus shedding, and viral DNA circulating in the blood. Although clinical disease was evident in tecovirimat-treated animals, it was generally very mild and appeared to resolve earlier than in placebo-treated controls that survived infection. Tecovirimat appears to be an effective smallpox therapeutic in nonhuman primates, suggesting that it is reasonably likely to provide therapeutic benefit in smallpox-infected humans.

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“…When the A33 gene itself is experimentally deleted, the phenotype is also an increased release of virus in vitro (63). Viruses bearing truncated A33 genes also had a markedly diminished virulence in mice (22,33).…”

Section: Discussionmentioning

confidence: 99%

The Structure of the Poxvirus A33 Protein Reveals a Dimer of Unique C-Type Lectin-Like Domains

Singh

Gittis

et al. 2010

J Virol

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The current vaccine against smallpox is an infectious form of vaccinia virus that has significant side effects. Alternative vaccine approaches using recombinant viral proteins are being developed. A target of subunit vaccine strategies is the poxvirus protein A33, a conserved protein in the Chordopoxvirinae subfamily of Poxviridae that is expressed on the outer viral envelope. Here we have determined the structure of the A33 ectodomain of vaccinia virus. The structure revealed C-type lectin-like domains (

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Pathogenicity and immunogenicity in mice of vaccinia viruses mutated in the viral envelope proteins A33R and B5R

Cited by 15 publications

References 18 publications

Application of Bioluminescence Imaging to the Prediction of Lethality in Vaccinia Virus-Infected Mice

Application of Bioluminescence Imaging to the Prediction of Lethality in Vaccinia Virus-Infected Mice

Efficacy of Tecovirimat (ST-246) in Nonhuman Primates Infected with Variola Virus (Smallpox)

The Structure of the Poxvirus A33 Protein Reveals a Dimer of Unique C-Type Lectin-Like Domains

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