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Resistance to HIV turns researchers into genetic sleuths

Once the bubonic plague was thought to have left a legacy of protection against AIDS. Now scientists are looking at an even older disease.

February 16, 2004|Linda Marsa | Special to The Times

The genetic quirk that enables some people to be resistant, or even immune, to the deadly AIDS virus has long been considered a legacy of the bubonic plague, which swept Europe seven centuries ago.

Two UC Berkeley scientists found such a connection highly unlikely, however -- the plague simply hadn't been around long enough to cause a widespread DNA alteration, they believed.

So they set out to unmask the real culprit and in doing so, says Montgomery Slatkin, a population geneticist and study coauthor, demonstrated how humans adapt to evade deadly predators and how infectious diseases such as AIDS can affect evolution.

In the early stages of the AIDS epidemic, doctors noticed that a few people exposed to the AIDS-causing HIV virus survived for years before symptoms surfaced, and a few never got sick. Researchers eventually traced this protection against HIV infection to a genetic mutation on certain immune system cells.

Normally, such cells have two surface receptors, which are like tiny docking sites to which the HIV virus attaches. The mutated gene prevents the production of one or both of these receptors.

About 10% of people of European descent are resistant to HIV. Because they have one aberrant gene, only one receptor is produced, making it difficult for the virus to enter the cells. About 1% are totally immune; they have two of these defective genes, so their cells lack both receptors.

Because AIDS didn't emerge until the late 1970s, which isn't long enough to cause a relatively common genetic abnormality, scientists wondered how this mutation entered and remained in the gene pool -- and why it occurred only among Europeans, not Africans or Asians.

In 1998, National Cancer Institute researchers in Bethesda, Md., determined that the renegade gene appeared among white Europeans about 700 years ago -- the blink of an eye in evolutionary terms. Genetic abnormalities persist if they confer some evolutionary advantage, a process known as natural selection.

"To have reached a 10% incidence in such a short period of time meant that there was intense positive selection for this mutation -- in other words, people who had it were much more likely to survive than those who didn't," says Alison P. Galvani, a UC Berkeley evolutionary epidemiologist and a study coauthor. "But the question was: What exactly was it that they were surviving?"

To many scientists, the bubonic plague was the most obvious suspect because the emergence of the mutation coincided with the plague pandemic that killed 25% to 40% of the European population in the 14th century. A few researchers, however, thought the evidence largely circumstantial.

After that outbreak, bubonic plague occurred sporadically over the next 400 years; the disease stopped being a major cause of death 250 years ago. "Brief episodes of natural selection are not sufficient to increase the frequency of a rare mutation to 10% or more in human populations," Slatkin says.

When the researchers looked for a more likely candidate, they found an even older and more deadly foe: smallpox. It's been around for more than 2,000 years, which would explain why the mutation already existed 700 years ago when the bubonic plague struck; it predominantly kills children, which prevents the nonresistant gene from being passed on, therefore increasing the presence of the mutated gene in the population; and like AIDS, it was caused by a virus. (Bubonic plague is caused by a bacterium.)

Cumulatively, smallpox killed more people than the plague, and until 1978, its presence exerted an intense Darwinian selection pressure. And finally, smallpox first occurred only in Europe, not Africa or Asia, and was transported elsewhere by explorers in the late 15th and 16th centuries.

The two scientists used this information to create a mathematical model that tracked the rise in the prevalence of this mutation over the last 700 years. They found that smallpox can drive incidence of the mutation to 10%, while the plague would increase it by less than 1%.

"Showing that smallpox, and not plague, was probably responsible illustrates something important about genetic evolution," says Slatkin. "Epidemics of short duration, even if they cause substantial mortality, are not enough to cause humans to evolve much genetic resistance."



Different route, similar conclusion

Scientists at Scripps Research Institute in La Jolla, who are developing drugs to block the surface receptors used by HIV, the virus that causes AIDS, were initially intrigued by the possible link between HIV resistance and the bubonic plague.

"If the plague did cause this mutation, then these blocking agents might be potential therapeutic agents there too," says Dr. Donald E. Mosier, an immunologist at Scripps who conducted research on the link.

However, when the bacteria that causes the plague was tested on both mice with and without the HIV resistance mutation, there was no difference in susceptibility between the two groups -- a finding that supported the UC Berkeley study.

The Scripps researchers now plan to test whether mice with this genetic alteration are resistant to mice pox, a cousin of the smallpox virus. Ultimately, their work could lead to a better way to prevent smallpox. Although the smallpox vaccine is effective, it has a lot of side effects, says Mosier.

"Something else, like these HIV blockers that could aid in fighting smallpox, could be very useful," he says.

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