Mayo Clinic researchers working with colleagues in Germany havediscovered a way to fight cancer by using parts of a virus found intree shrews, small Southeast Asian mammals. The researchers used thevirus to create a disguise for an engineered measles virus that enablesit to sneak past the immune system. It kills cancer cells withoutharming healthy cells.
The work is still experimental. But it is a key step forward in thescience of redirecting or retargeting a virus through geneticengineering. Retargeted measles virus can recognize surface moleculesfound only on cancerous cells, allowing selective killing. In this way,retargeted cancer-killing viruses help the body, rather than harming itas natural viruses do when they infect cells.
In the current issue of the Journal of Virology, the researchersdescribe how they invented a way to engineer an alternative outercovering (coat) for the virus, using pieces from an animal virus thatcannot infect humans.
"Our group's perspective is to exchange pieces on the envelope, theviral coat, with the pieces from the coat of a related virus that hasno known relatives that can infect humans," says Roberto Cattaneo,Ph.D., lead researcher and an internationally recognized pioneer inviral targeting technology. "If we can modify the virus and take partsfrom the Tupaia paramyxovirus (the shrew virus) and put them on themeasles virus, then we have a virus in stealth. It will not berecognized by the immune system because it's disguised in another coat-- and that way we can get the virus past the immune system."
Significance of the Research
A different Mayo Clinic research team was the first to engineer ameasles virus retargeted at the cell entry level and reported on thisearlier this year. The current investigation takes the technology astep closer to being useful to human patients by paving the way to getthe retargeted measles virus past the immune system so it can actuallyreach the tumor and destroy it.
Background and Next Steps
Viruses are parasites. They:
* attach to, or penetrate a partner on the target cell
* fuse membranes to enter the target cell
* commandeer the cellular machinery to produce more virus
* modulate or control the host immune response
While the stealth approach works, there's a problem -- the disguiseworks only once because a healthy immune system is so good at its job,it makes antibodies against the modified viral coat and won't betricked twice. But researchers at Mayo are designing alternativedisguises.
"That means we'll have to make another coat to disguise it again,and we have already identified candidate animal viruses that can helpus do that, which means we have the prospect of using the sameretargeted measles virus with different coats," says Dr. Cattaneo.
Noting that safety is of utmost priority, Dr. Cattaneo stresses thatmultiple safeguards prevent the unintended creation of a super viruscapable of causing a new human disease.
"With this paper we really make the point that there is an untappedresource in the form of animal viruses that can be used as a source ofmodules that can be combined with human viruses to evade the immunesystem," Dr. Cattaneo says. "Our lab can do this safely because we havequite an elaborate safety system -- four levels of specificity -- thatblock, interfere and provide an emergency brake to a virus' ability tospread in normal human cells and cause illness."
Collaboration and Support
In addition to Dr. Cattaneo, the Mayo Clinic research team includesChristoph Springfeld, M.D., Dr. P.H.; and Veronika von Messling,D.V.M.; in Rochester. Collaborators in Heidelberg, Germany areChristian Tidona, Ph.D.; and Gholamreza Darai, M.D., Ph.D. The work wassupported by research grants from Mayo Foundation, the SiebensFoundation and the National Institutes of Health, and a researchscholarship from the German Research Foundation.
[Springfeld C. et al. Envelope targeting: hemagglutinin attachmentspecificity rather than fusion protein cleavage-activation restrictsTupaia paramyxovirus tropism. J. Virol.]
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