Gene Variation May Increase Vulnerability to H.I.V.

By NICHOLAS WADE
17 july 2008--A genetic variation that once protected people in sub-Saharan Africa from a now extinct form of malaria may have left them somewhat more vulnerable to infection by H.I.V., the virus that causes AIDS. The gene could account for 11 percent of the caseload in Africa, explaining why the disease is more common there than expected, researchers based in Texas and London say.
The researchers said there were no immediate public health consequences of their finding. But if confirmed, it will offer an important new insight into the biology of the virus.
The genetic variation has been studied in U.S. Air Force personnel whose H.I.V. infections have been followed for 25 years. African-Americans who carry it were 50 percent more likely to acquire H.I.V. than African-Americans who do not carry the variation, although their disease progressed more slowly, say researchers led by Sunil K. Ahuja, director of the Veterans Administration HIV/AIDS Center, San Antonio, , and Matthew J. Dolan of the Uniformed Services University in Bethesda, Md.
Their results are reported in the journal Cell Host & Microbe.
David Goldstein, a geneticist who studies H.I.V. at Duke University, said that the new result “would be pretty exciting if it holds up” and that many other researchers would now test it. “If the results are confirmed, it would mean that selection for resistance to malaria has created a vulnerability to infection with HIV-1,” he said, referring to the principal form of the AIDS virus.
The genetic variation, called a SNP (“snip”), involves a change in a single unit of DNA. This particular snip has a far-reaching consequence, that of preventing red blood cells from inserting a certain protein on their surface. The protein is called a receptor because it receives signals from a hormone known as CCL5, which is part of the immune system’s regulatory system.
The receptor is also used by a malarial parasite called Plasmodium vivax to gain entry to the red blood cells it feeds on. Some 10,000 years ago, people in Africa who possessed the SNP gained a powerful survival advantage from not being vulnerable to the ancestor of Plasmodium vivax. The SNP eventually swept through the population and the vivax parasite died out in Africa, to be replaced by its current successor, Plasmodium falciparum.
More than 90 percent of people in Africa now lack the receptor on their red blood cells, as do some 60 percent of African-Americans.
The possibility that the receptor might have a bearing on H.I.V. infection first occurred to Robin Weiss, a biologist at University College, London, after he noticed that the virus seemed to be hitchhiking on red blood cells. Dr. Weiss, a coauthor of the new report, showed in laboratory tests that H.I.V. latches onto the receptor in place of its intended guest, the CCL5 hormone.
The Texas-London research team is not sure of the mechanism by which lack of the receptor promotes H.I.V. infection, but Dr. Ahuja said the red blood cells acted like a sponge for CCL5. Since CCL5 is known to obstruct the virus’s multiplication, having lots of the hormone in the bloodstream may prevent infection. Conversely, people whose blood cannot soak up the hormone could be more vulnerable.
Dr. Weiss said the red blood cell receptor was similar to another receptor, CCR5, which occurs on the surface of the white blood cells that are H.I.V.’s major target. A few percent of Europeans have a mutation that prevents the CCR5 receptor from being displayed on the surface of white blood cells, and they are protected against H.I.V.
It is somewhat puzzling that absence of the two receptors has the opposite effect — vulnerability to H.I.V. when the red cell receptor is missing, protection when the white cell receptor is withdrawn. The researchers offer an explanation that they concede is far from straightforward. “If you found the paper plain sailing, most of my students didn’t,” Dr. Weiss said. As is often the case with provocative new findings, the researchers may have some way to go before convincing others that their observation is correct. Dr. Goldstein said that in parts of the United States, African-Americans have a higher infection rate than European Americans, and that patients with a higher proportion of African genes may be more vulnerable to H.I.V. for reasons unconnected to the SNP. Nonetheless, the SNP would show up in a greater proportion of infected individuals simply because of their African heritage. If so, the gene’s apparent association with H.I.V. infection could be just coincidental, not causal.
The researchers took steps to rule out this possibility, but Dr. Goldstein said those steps might not be adequate.
Dr. Carl Dieffenbach, director of the AIDS division of the National Institute of Allergy and Infectious Diseases, said the new finding, if confirmed, was intriguing because it pointed to the many ways in which the body’s receptors have been shaped by pathogens. Although HIV is too recent an infection to have left an evolutionary mark on the genome, human ancestors would have been exposed to malarial parasites and to SIV, the AIDS virus that infects monkeys, and the genome still bears the marks of these challenges to survival. Better knowledge of these adapations will help understand the biology of HIV infection, he said.