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.

U.N. to Say It Overstated H.I.V. Cases by Millions

By DONALD G. McNEIL Jr.
Correction Appended
The United Nations’ AIDS-fighting agency plans to issue a report today acknowledging that it overestimated the size of the epidemic and that new infections with the deadly virus have been dropping each year since they peaked in the late 1990s.
The agency, Unaids, will lower the number of people it believes are infected worldwide, to 33.2 million from the 39.5 million it estimated late last year.
The statistical changes reflect more accurate surveys, particularly in India and some populous African countries. Some epidemiologists have criticized for years the way estimates were made, and new surveys of thousands of households in several countries have borne them out.
In only a few countries, such as Kenya and Zimbabwe, do the figures reflect widespread behavioral changes, such as decisions by many people to have sex with fewer partners.
Excerpts from the report were given to the news media in advance for release this evening, but an embargo on it was broken by other news organizations. Despite the revised estimates, the epidemic remains one of the great scourges of mankind. This week’s analysis predicts that 2.1 million people died of AIDS in the last year, and 2.5 million were newly infected — or about 6,800 every day.
The agency now believes that the number of new infections each year with H.I.V., the virus that causes AIDS, probably peaked in the late 1990s, or by 2001, at about 3 million.
Although new infections have dropped, the number of people with the disease is growing because more people infected with H.I.V. are living longer, thanks to antiretroviral drugs. With the world’s population growing, the agency believes that the percentage of adults who are now infected remains roughly constant, at about 0.8 percent.
“This is not a surprise,” said Daniel Halperin, an expert on H.I.V. infection rates at the Harvard School of Public Health and co-author of an article published three years ago arguing that estimates of infection rates were too high. “The writing was on the wall years ago,” he said.
“But,” he added, “this doesn’t mean the epidemic is going away, everything is fine and now forget about it — not at all. There are still about 10 countries in southern Africa that are real nightmares.”
In the past, global health officials have treated the epidemic as a cyclone spiraling ever upward with no end to new infections in sight.
But better surveys, particularly a household survey in India, have driven the figures down.
Until recently, most national estimates were made by giving anonymous blood tests to some young women who came into public health clinics because they were pregnant or feared they had a sexually transmitted disease; those results were expanded with statistical models.
But epidemiologists have realized that such a method — usually applied in big urban clinics because it was more efficient — oversampled prostitutes, drug abusers and people with multiple partners, and ignored rural women. Then the statistical extrapolations exaggerated those errors.
Recently, the United States Agency for International Development began financing surveys that chose thousands of households at random in both urban and rural areas and sent in health care workers to take detailed medical and lifestyle histories and blood samples; though expensive, they produced results that are considered more accurate.
In July, India’s estimated caseload was revised downward, to 2.5 million, from 5.7 million — a change that accounts for about half the drop in the new Unaids figures. Officials said then that India’s epidemic was not “generalized” — that is, it had not spread far from the original high-risk groups like brothel workers and clients, truckers, heroin users and gay men. Also, rates among prostitutes appeared to have fallen as condoms gained acceptance. Instead of being considered the world’s worst-hit country, India fell to third place behind South Africa and Nigeria.
Also, some African countries have seen real drops in new cases. It happened relatively early in Uganda, after an aggressive “no grazing” (meaning no casual sex) campaign started 20 years ago. Similar declines appear to have happened in Zimbabwe and Kenya, especially since people saw many friends and relatives die. Rather than embracing condoms, people decided to have sexual relations with fewer people, Dr. Halperin said.
“You don’t need a Ph.D. to figure out that if you reduce your number of partners, you reduce your risk,” he added.
A small decline in new infections can quickly cut a country’s total caseload because large numbers of people infected early in the epidemic are still dying.
AIDS advocates fear that any suggestion that the epidemic is lessening in intensity will cause fatigued donors to contribute less.
In September, for example, the Global Fund to Fight AIDS, Malaria and Tuberculosis received pledges of only $9.7 billion, well short of the $15 billion to $18 billion it had hoped to raise.
“There’s still a huge epidemic out there that still needs huge resources to win the battle,” said Paul Zeitz, executive director of the Global AIDS Alliance, a non-profit advocacy group.
Correction: November 21, 2007
A front-page article in some editions yesterday about lower estimates of the number of H.I.V. infections worldwide misstated a researcher’s explanation for a drop in infection rates in some African countries. The researcher, Daniel Halperin of the Harvard School of Public Health, said surveys indicated that people in Kenya and Zimbabwe chose to have fewer sexual partners rather than to use condoms more often. He did not mention circumcision to prevent AIDS as a consideration in those countries.