"This study helps illuminate the cellular machinery used by poxviruses to exit infected cells, and also provides new support for the concept of treating viral infections by targeting specific host cell molecules rather than the viruses themselves," says NIAID Director Anthony S. Fauci, M.D.
The senior author of the paper, published online this week in the journal Nature Medicine, is Daniel Kalman, Ph.D., of Emory University School of Medicine in Atlanta.
Like all viruses, poxviruses co-opt various cellular molecules and processes to enter a cell, replicate and then spread to uninfected cells. Using lab-grown cells, Dr. Kalman and his colleagues identified specific cell proteins vaccinia uses to detach from an infected cell and move toward an uninfected cell. The proteins, members of the Abl-family (pronounced "able") of tyrosine kinases, are well known to cancer investigators because mutation of one family member, Abl, causes a rare form of cancer known as chronic myelogenous leukemia (CML). Gleevec inhibits Abl-family tyrosine kinases and has proved very useful in treating CML.
To learn whether Gleevec could prevent or lessen vaccinia's ability to spread in a living organism, the researchers treated mice with either saline solution or with Gleevec at a dose equivalent to that given to humans being treated for CML. Ne xt, they exposed the mice to ordinarily lethal amounts of vaccinia. All of the Gleevec-treated mice survived, while 70 percent of the untreated mice died.
This finding, if confirmed in additional animal model studies, suggests that Gleevec might play a role in addressing a public health emergency in the event of a smallpox outbreak, Dr. Kalman says. Specifically, Gleevec might be useful as a preventative against adverse effects of smallpox vaccine, enabling clinicians to use the vaccine even in people who otherwise could not take it. Given for a short period, Gleevec theoretically could hamper the cell-to-cell spread of virus and allow the body's immune system to mount a successful defense, he explains. Experiments to test whether Gleevec might work against smallpox virus as well as against vaccinia virus are now being planned, Dr. Kalman says. "The approach of fighting disease by targeting drugs to cellular molecules rather than to disease agents themselves may be applicable to a wide variety of pathogenic microorganisms," he says.
Routine vaccinations for smallpox ended in this country in the early 1970s, and the World Health Organization declared smallpox eradicated in 1980. Nevertheless, concern remains that smallpox virus could be unleashed through an act of bioterror. For this reason, scientists are working to better understand the mechanisms of smallpox disease and to develop new and improved smallpox treatments and vaccines.
NIAID is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies.
Referenc e: PM Reeves et al. Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases. Nature Medicine DOI: 10.1038/nm1265 (2005).