Is Smallpox Behind AIDS Immunity?

Roots of resistance may lie in Middle Ages

Randy Dotinga

Randy Dotinga

Published on November 17, 2003

MONDAY, Nov. 17, 2003 (HealthDayNews) -- New research suggests the tiny number of people who are immune to AIDS are the descendants of Europeans who developed resistance to smallpox in the Middle Ages.

"Smallpox has left a signature on our genetic makeup, providing a benefit to us 700 years later," says study coauthor Alison P. Galvani, an epidemiologist at the University of California at Berkeley.

If Galvani is correct, she may have punctured the prevailing wisdom that the prime suspect behind AIDS immunity is bubonic plague, the deadly disease that wiped out a third of Europe in the 14th century.

The new research is "fascinating and provocative," says Cheryl Ann Winkler, a genetic scientist at the National Cancer Institute who helped develop the plague theory in the late 1990s.

Unfortunately, the findings may reveal more about the past than the future. Experts don't expect their research to have any effect on treatment of people with AIDS.

The existence of AIDS immunity itself isn't new. Researchers discovered it in the 1980s during the early years of the AIDS epidemic, when they noticed that some people were repeatedly exposed to the virus but didn't get infected.

In total, about 1 percent of people descended from Northern Europeans are virtually immune to AIDS. They share one trait in common: a pair of mutated genes that prevent their immune cells from developing a "receptor" that lets HIV, the AIDS virus, break in. It's like a lock and key, Galvani explains: The virus can't gain entry because the lock isn't there.

To be born with a pair of the mutated genes, people must inherit them from both parents. About 10 percent to 15 percent of descendants of Northern Europeans have just one mutated gene, which provides limited protection: It takes longer for those infected with the HIV to actually develop AIDS.

The gene mutations are essentially unknown among East Asians, Africans, American Indians and Middle Easterners, although they do appear in Central Asian countries. In Europe, they're most common in Swedes -- 14 percent have at least one of mutated genes -- and less common in southern European countries such as Greece. The percentages imply that the roots of the gene mutations lie somewhere in the history of Northern Europe.

In 1998, a team of researchers calculated the mutations are about 700 years old and began searching for an explanation. "Some strong selective pressure must have jacked up [their] frequency from a single mutation of one chromosome in one individual to approximately 10 percent of the European population," Winkler says.

The prevailing theory is those who had the mutation were spared infection by one or more diseases and lived to pass the mutation to future generations.

Winkler and colleagues pointed a finger at the plague, a disease that killed as many as 40 percent of Europeans during the Black Death around 1350 and made a return visit two centuries years later. The plague appears to use attack immune cells in a similar way as HIV.

The 1998 study left open the possibility that other diseases -- such as smallpox, syphilis or influenza -- could have spurred the spread of the genes. In the new study, published in this week's issue of the Proceedings of the National Academy of Sciences, researchers argue that the clues point to smallpox, not plague.

Smallpox makes more sense for a variety of reasons, the researchers say, including its stubbornness. While plague came and went in huge waves, smallpox was always around and influencing the genetics of humans.

There's other evidence for smallpox, which was eradicated in the 1970s. The illness largely attacked children, while plague sickened people of all ages. A protective gene is more likely to survive through generations if people who have it spend a lot of time reproducing after they avoid death. Older people "have much less impact because they're not going to have children anyway," Galvani says.

But things aren't necessarily all wonderful for those with these kinds of mutations. When nature giveth, nature also taketh away. Or, as scientists like Galvani put it, "there's a cost of resistance."

For example, one type of gene mutation protects people against malaria, but also makes them more susceptible to sickle cell anemia. While the mutation currently in question may make people immune to smallpox and HIV, its effects on immune cells could cause people to be more susceptible to other illnesses. Galvani, however, thinks the effects are probably minor.

The impact of the new findings may also be minor. Neither Winkler nor Galvani expects they'll directly lead to new treatments for AIDS. But the debate over the origins of HIV immunity is sure to continue as long as scientists such as Galvani are intrigued by the possibilities.

"I just find it really fascinating that diseases have left their signatures on our genome," she says.

More information

Learn about bubonic plague from Brigham Young University. Get the facts about smallpox from the Centers for Disease Control and Prevention.

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