Global Alert and Response (GAR)

Abstracts summarizing recent research overseen by the WHO Advisory Committee on Variola Virus Research - 2004


Variola Morphogenesis effected by a by an erb-B Tyrosine Kinase Inhibitor: Possible therapeutic functions

Tiara Harms1, Hailin Yang2, Mikyung Kim2, Sung-Kwon Kim3, Ellis Reinherz2, Raymond Welsh3, and Inger Damon1

1Centers for Disease Control and Prevention, Atlanta, United States of America

2Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA, United States of America

3Department of Pathology, University of Massachusetts Medical Center, Worchester, MA, United States of America.

Please direct all queries to the authors at the addresses given.

The variola major strain Bangladesh ORF D4R, encoding the homolog of the vaccinia virus growth factor (VGF), was evaluated as a potential therapeutic target. VGF, which demonstrates areas of significant homology with the epidermal growth factor (EGF) superfamily, previously suggested to be a ligand for vaccinia cell entry, mediates host cell proliferation and is a viral virulence factor in vivo.

A 40 amino acid region of the variola protein (SPGF), homologous to the active moiety of EGF, was cloned, expressed, and found to be functional as a growth factor. Neither SPGF, nor two monoclonal antibodies (mAbs) raised against SPGF could block the ability of variola to form plaques on primary or transformed cell lines.

An irreversible inhibitor of erb-B receptor tyrosine kinase pathways, CI-1033, in a dose-dependent manner, dramatically reduces the size of individual variola plaques and significantly (p<0.05) decreases the number of comets at CI-1033 concentrations of ≥500nM. Single-step growth curves, using two different cell lines, exhibit a delay and absolute decrease in extracellular enveloped virus (EEV) formation, as well as some decrease in cell associated virus (CAV) formation.

No difference was found in viral DNA accumulation by use of quantitative orthopoxvirus PCR. Murine intranasal vaccinia challenge studies demonstrate a protective benefit of CI-1033 against SPGF, and this benefit is more pronounced when an intracellular mature virus (IMV) neutralizing mAb is used. These results suggest that CI-1033 blocks specific step(s) in viral morphogenesis and may be of therapeutic benefit.

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