Dec. 6, 1999 As debate continues on whether to destroy the world's last two vials of smallpox virus, scientists have discovered that a virus related to smallpox uses the same route of entry as HIV to invade its host. This is the first virus other than HIV known to exploit structures called chemokine receptors on the surface of immune cells. Its discovery strengthens a new theory on the origins of a rare, life-saving immunity to the AIDS virus.
Like HIV, the myxoma poxvirus -- a pathogen that causes a rapid AIDS-like immune deficiency in rabbits -- hones in on chemokine receptors called CCR5 and CXCR4, reports a research team led by a UC San Francisco scientist. The research is published in the December 3 issue of Science.
Both viruses can dock with CCR5 or CXCR4 for successful invasion, although the scientists don't yet know if the poxvirus exploits another portal known as the CD4 receptor, as HIV does.
Linking CCR5 to an aggressive relative of smallpox strengthens an intriguing theory about the origins of a rare immunity to the HIV virus, so far found only in a small percentage of Caucasians. A mutation in one of the genes for the CCR5 receptor has recently been identified as the strongest source of this protective trait in HIV-resistant people.
Genetic analysis has traced the likely emergence of the mutation to a major epidemic about 700 years ago - possibly the European smallpox plague.
"The protective mutation in the CCR5 chemokine receptor gene almost certainly emerged well before HIV began to infect humans - just about 50 years," said Alshad Lalani, PhD, a post-doctoral researcher at UC San Francisco and lead author of the report on the poxvirus/CCR5 finding. Senior author is Grant McFadden, PhD, professor of microbiology and immunology at the University of Western Ontario and a scientist of the Robarts Research Institute.
"HIV researchers have deduced that the CCR5 mutation probably evolved at least 700 years ago," Lalani said. "Mutations generally persist only when they provide a survival advantage, and certainly smallpox was a major epidemic which claimed countless lives during this timeframe.
"Our new finding that a relative of the smallpox virus uses chemokine receptors such as CCR5 receptors to infect cells strengthens the hypothesis that the smallpox virus itself may have attacked by exploiting CCR5 receptors on the surface of people's immune cells. In so doing, the disease would have imposed the selective pressure for the protective mutation to persist."
And more than 700 years later, the mutation provides HIV immunity to a lucky few.
In the research reported in Science, Lalani, McFadden and their colleagues introduced the myxoma virus to a mouse cell line - normally not a target of myxoma infection -- along with any of three human chemokine receptors - CCR1, CXCR4 and CCR5. They reported that any of the three chemokine receptors induced infection by the virus - evidence that each functioned as a binding or entry receptor for the virus.
Other pathogens, including the malaria parasite and streptococcus bacteria, target chemokine-like receptors, but the only viruses known to employ this strategy are HIV and now the myxoma poxvirus. The cell surface targets of all other poxviruses are as yet unknown.
Since the discovery in 1997 that certain mutations of the CCR5 receptor gene protects some high-risk people from developing AIDS, research on this cell surface receptor has intensified. Apparently CCR5 is dispensible, Lalani points out, since those with the mutation remain perfectly healthy despite having inactive CCR5 receptors.
"Since it appears to be dispensible, this suggests a treatment or prevention strategy - 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 in Science results of a separate series of experiments with CCR5 receptors and the myxoma virus in mouse and primate cell lines. The researchers discovered that by introducing a high concentration of one protein, called RANTES, that normally binds to the human CCR5 receptor, they were able to prevent infection by the myxoma virus. Presumably, this occurred because the protein clogged all the CCR5 receptors and prevented the virus from gaining access to the receptors.
If the human smallpox virus -- a distant relative of the myxoma poxvirus -- once attacked human cells by exploiting the CCR5 receptor, then at the same time it was exacting its terrible toll this virus may have spurred evolution of the life-saving CCR5 receptor mutation. Forged in the fierce fires of an ancient epidemic, the mutation first protected some against smallpox, but now shields a lucky few from a more modern plague.
Evidence that the CCR5 receptor mutation emerged at least 700 years ago has been deduced from studies of distribution and inheritance patterns of the mutation. But the only direct way to prove that smallpox uses the CCR5 receptor as a portal of entry would be studying the smallpox virus now sequestered by the U.S. Centers for Disease Control or its counterpart in Moscow, Lalani explained. Alternatively, researchers could use recombinant genetic technology to see if portions of the virus are configured to interact with CCR5.
Nonetheless, the discovery that the myxoma virus gains access through the CCR5 receptor 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 are Jennefer Masters, BSc, now a graduate student at the University of Toronto; Wei Zeng, a technician in McFadden's laboratory; John Barrett, PhD, a research associate at the university; Rajeet Pannu and Helen Everett, both biochemistry graduate 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 Cancer Institute of Canada.
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