As debate continues on whether to destroy the world's last two vials ofsmallpox virus, scientists have discovered that a virus related to smallpoxuses the same route of entry as HIV to invade its host. This is the first virusother than HIV known to exploit structures called chemokine receptors on thesurface of immune cells. Its discovery strengthens a new theory on the originsof a rare, life-saving immunity to the AIDS virus.
Like HIV, the myxoma poxvirus -- a pathogen that causes a rapid AIDS-likeimmune deficiency in rabbits -- hones in on chemokine receptors called CCR5 andCXCR4, reports a research team led by a UC San Francisco scientist. Theresearch is published in the December 3 issue of Science.
Both viruses can dock with CCR5 or CXCR4 for successful invasion, although thescientists don't yet know if the poxvirus exploits another portal known as theCD4 receptor, as HIV does.
Linking CCR5 to an aggressive relative of smallpox strengthens an intriguingtheory about the origins of a rare immunity to the HIV virus, so far found onlyin a small percentage of Caucasians. A mutation in one of the genes for theCCR5 receptor has recently been identified as the strongest source of thisprotective trait in HIV-resistant people.
Genetic analysis has traced the likely emergence of the mutation to a majorepidemic about 700 years ago - possibly the European smallpox plague.
"The protective mutation in the CCR5 chemokine receptor gene almost certainlyemerged well before HIV began to infect humans - just about 50 years," saidAlshad Lalani, PhD, a post-doctoral researcher at UC San Francisco and leadauthor of the report on the poxvirus/CCR5 finding. Senior author is GrantMcFadden, PhD, professor of microbiology and immunology at the University ofWestern Ontario and a scientist of the Robarts Research Institute.
"HIV researchers have deduced that the CCR5 mutation probably evolved at least700 years ago," Lalani said. "Mutations generally persist only when theyprovide a survival advantage, and certainly smallpox was a major epidemic whichclaimed countless lives during this timeframe.
"Our new finding that a relative of the smallpox virus uses chemokine receptorssuch as CCR5 receptors to infect cells strengthens the hypothesis that thesmallpox virus itself may have attacked by exploiting CCR5 receptors on thesurface of people's immune cells. In so doing, the disease would have imposedthe selective pressure for the protective mutation to persist."
And more than 700 years later, the mutation provides HIV immunity to a luckyfew.
In the research reported in Science, Lalani, McFadden and their colleaguesintroduced the myxoma virus to a mouse cell line - normally not a target ofmyxoma infection -- along with any of three human chemokine receptors - CCR1,CXCR4 and CCR5. They reported that any of the three chemokine receptors inducedinfection by the virus - evidence that each functioned as a binding or entryreceptor for the virus.
Other pathogens, including the malaria parasite and streptococcus bacteria,target chemokine-like receptors, but the only viruses known to employ thisstrategy are HIV and now the myxoma poxvirus. The cell surface targets of allother poxviruses are as yet unknown.
Since the discovery in 1997 that certain mutations of the CCR5 receptor geneprotects some high-risk people from developing AIDS, research on this cellsurface receptor has intensified. Apparently CCR5 is dispensible, Lalani pointsout, since those with the mutation remain perfectly healthy despite havinginactive CCR5 receptors.
"Since it appears to be dispensible, this suggests a treatment or preventionstrategy - blocking the CCR5 receptors to keep HIV out," Lalani suggests."There should be no ill effects."
In a parallel of this strategy, Lalani and his colleagues also reported inScience results of a separate series of experiments with CCR5 receptors and themyxoma virus in mouse and primate cell lines. The researchers discovered thatby introducing a high concentration of one protein, called RANTES, thatnormally binds to the human CCR5 receptor, they were able to prevent infectionby the myxoma virus. Presumably, this occurred because the protein clogged allthe CCR5 receptors and prevented the virus from gaining access to thereceptors.
If the human smallpox virus -- a distant relative of the myxoma poxvirus --once attacked human cells by exploiting the CCR5 receptor, then at the sametime it was exacting its terrible toll this virus may have spurred evolution ofthe life-saving CCR5 receptor mutation. Forged in the fierce fires of anancient epidemic, the mutation first protected some against smallpox, but nowshields a lucky few from a more modern plague.
Evidence that the CCR5 receptor mutation emerged at least 700 years ago hasbeen deduced from studies of distribution and inheritance patterns of themutation. But the only direct way to prove that smallpox uses the CCR5 receptoras a portal of entry would be studying the smallpox virus now sequestered bythe U.S. Centers for Disease Control or its counterpart in Moscow, Lalaniexplained. Alternatively, researchers could use recombinant genetic technologyto see if portions of the virus are configured to interact with CCR5.
Nonetheless, the discovery that the myxoma virus gains access through the CCR5receptor may help in vaccine development, either for HIV or for other diseases,since poxviruses are commonly used as vectors for vaccines, Lalani noted.
Co-authors with Lalani and McFadden and collaborators in the research areJennefer Masters, BSc, now a graduate student at the University of Toronto; WeiZeng, a technician in McFadden's laboratory; John Barrett, PhD, a researchassociate at the university; Rajeet Pannu and Helen Everett, both biochemistrygraduate students at the University of Alberta; and Christopher W. Arendt, PhD,a post-doctoral researcher at New York University Medical Center.
The research is funded by the Medical Research Council and the National CancerInstitute of Canada.
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