Survivors’ Benefit?

Some AIDS resistance may stem from ancient smallpox epidemics

One virus, causing agonizing pain, kills a person in less than 2 weeks. The other, stealthily weakening its host’s immune defenses, can take years to bring about death. Before a worldwide vaccination effort eradicated it, the first virus may have taken the lives of more people throughout history than any other infectious agent has. The second, for which there is yet no vaccine or cure, currently infects more than 47 million people.

These killers are variola and HIV, the viruses that cause smallpox and AIDS, respectively. Despite dramatically different ways of attacking the bodies they infect, the two viruses may have more in common than scientists have suspected.

Researchers recently found that HIV and a member of the poxvirus family, which includes variola, infect cells by using some of the same cell-surface proteins. This unexpected finding, if extended to variola itself, may help biologists develop a better smallpox vaccine and design antiviral drugs in case smallpox reemerges or is used as a biological weapon.

Moreover, the discovery raises a fascinating conjecture. Some people with natural resistance to the AIDS virus may owe their good fortune to a genetic mutation handed down to them by survivors of ancient smallpox outbreaks.

Dangerous work

Since it’s so dangerous to work with variola, scientists know remarkably little about the smallpox virus. Basic facts, such as which cells it infects and what proteins it latches onto to get inside those cells, remain mysteries.

“People have been looking for the poxvirus receptors for years and years,” says Grant McFadden of the University of Western Ontario in London.

The World Health Organization (WHO) permits only two laboratories, one in the United States and one in Russia, to maintain repositories of variola, and scientists there rarely conduct research with the live virus. McFadden and his colleagues have instead pursued studies of myxoma virus, a variola relative that infects rabbits.

The researchers had found that myxoma makes proteins that bind and inhibit chemokines, chemicals that attract immune cells to sites of injury or infection. Recently, they treated rabbit cells with a well-studied chemokine called RANTES to see if it would hinder the ability of myxoma virus to infect the cells. It did.

RANTES normally binds to one of several cell-surface proteins, known as chemokine receptors. This fact led the investigators to wonder if the chemokine was blocking one or more receptors that myxoma needs to infect cells.

McFadden’s team then worked with rodent cells that are naturally resistant to the virus and lack chemokine receptors. The scientists added various human chemokine-receptor genes to the cells and found that several made the cells susceptible to the virus.

Describing their results in the Dec. 3, 1999 Science, the biologists conclude that myxoma virus, and probably variola and other poxviruses, somehow use the chemokine receptors to gain entry to cells. They believe that the poxviruses target migrating immune cells, which may explain how the viruses spread quickly through an infected body.

McFadden’s group may have an opportunity to test whether this story holds true for smallpox.

WHO recently delayed, until 2002, plans to destroy its stocks of variola, in part because of concerns that terrorists or a rogue country might use smallpox as a weapon. When WHO announced this delay, it also solicited proposals for research on the virus that could lead to a more effective vaccine or, for people who can’t take the vaccine, antiviral drugs.

McFadden has asked the Centers for Disease Control and Prevention (CDC) in Atlanta, home of the U.S. variola stocks, to test whether variola uses chemokine receptors to infect cells. “It strikes me as an extremely important experiment to do,” says Joseph J. Esposito, head of CDC’s poxvirus section, who plans to ask WHO to approve the research.

McFadden also hopes to collaborate with CDC to examine whether the virus for monkeypox makes use of the receptors. This disease, which shares many symptoms with smallpox, is killing small but increasing numbers of people in Africa.

Good fortune

The results from such work may shed light on the good fortune of some people who are resistant to HIV. While McFadden believes that HIV and poxviruses infect immune cells in different ways, the AIDS virus also depends upon chemokine receptors, primarily one called CCR5 (SN: 6/22/96, p. 390:

An unexpectedly large number of people have mutations in the gene for CCR5, eliminating this portal for the virus and making them less susceptible to it. Indeed, as many as 20 percent of white people harbor one particular mutation, a deletion of DNA, in one of their two CCR5 genes (SN: 11/2/96, p. 284). Such people—and even the few who lack CCR5 altogether—seem to live healthy lives.

Some scientists believe that for the deletion in the CCR5 gene to persist at such a high frequency, it must have in the past conferred a survival advantage on people harboring the mutant genes. Researchers speculate that mutations in the gene protected past European generations from an infectious agent other than HIV. In fact, according to an analysis by Michael Dean of the National Cancer Institute in Frederick, Md., the frequency of the CCR5 gene deletion in different populations suggests that an outbreak of this putative agent occurred around 700 years ago.

That time frame points to Yersinia pestis, the plague-causing bacterium believed responsible for the Black Death that swept through Europe in the Middle Ages. Yet Y. pestis infects cells without using chemokine receptors, according to tests done by Joan Mecsas of Tufts University in Boston. The microbe’s ability to infect human cells or live mice remains the same regardless of the presence or absence of chemokine receptors, she says. That also holds true for the bacteria that cause salmonella, another disease that has beset mankind for ages.

With the newfound link between myxoma virus and chemokine receptors, smallpox now emerges as the best explanation for the continued widespread presence of CCR5 gene mutations, says McFadden. Over centuries, people with such mutations probably proved more resistant to smallpox and thus had a better chance of passing on their genes. The descendants of those survivors, concludes McFadden, now enjoy the added benefit of resistance to HIV.

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