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http://www.philly.com/inquirer/breaking/news_breaking/20101104_Herculean_achievement_cracks_HIV_puzzle.html

By Faye Flam

INQUIRER STAFF WRITER

AIDS researchers announced Thursday that they’d finally cracked a long-standing puzzle: Why a few people can get infected with the AIDS virus and remain healthy without treatment?

It was the culmination of a 16-year effort that started with one HIV-positive minister coming into the office of AIDS researcher Bruce Walker and asking to become a human guinea pig.

Episcopal minister Robert Massie was expected to have died from his infection years earlier, and yet felt inexplicably well. He thought if doctors studied him, they might find a way to help others with HIV to stay healthy too.

Eventually, thousands of HIV-postive volunteers joined the effort, including about 20 in Philadelphia, helping scientists to pinpoint a set of genetic differences that allow about 1 in 300 infected people to keep the virus in check.

Thanks to their genetics, these “controllers” have a slightly different immune response – a better ability to signal danger so that “killer” T-cells can keep the AIDS virus from replicating and destroying immune cells.

The researchers hope their findings, released Thursday afternoon in the online version of the journal Science, could help inform the quest for new AIDS therapies. About 33 million people worldwide are infected with the virus – including some 19,000 in Philadelphia, which has one of the nation’s highest infection rates.

Luis Montaner, an immunology professor at Philadelphia’s Wistar Institute, called the work “a very significant and Herculean” achievement. Montaner is engaged in a related project, trying to prompt patients’ immune systems to control the virus even when they’re not gifted with controller genes.

Massie said he discovered he was HIV positive in 1984, the same year he was married. He was 26 years old. Since childhood, he’d been treated for the genetic blood disorder hemophilia, which required him to get frequent blood transfusions. His HIV infection was traced back to a transfusion in 1978, which meant he’d been living with the virus for more than five years.

Doctors at the time told him five years was about as long as anyone had carried the virus before getting deathly ill with AIDS. After he’d had HIV for ten years, that became the new outer limit.

“I always had a sense I was kind of staring right off the cliff,” Massie said.

By 1994, he knew there was something unusual about him, since nobody was supposed to remain symptom-free for sixteen years. A former college roommate who had become a doctor agreed, and after some asking around, Massie connected with Walker at Massachusetts General Hospital.

“He was eager to start doing research on me and asked me a lot of questions,” Massie said. “He was very pleased that I lived just a couple of miles from Mass General so he could draw my blood on a regular basis.”

Walker, who is now a professor of medicine at Harvard Medical School and director of the Partners AIDS Research Center at Massachussetts General, said he’d gotten interested in such cases a few years earlier, after another researcher alerted him to something strange she’d seen among a cohort of gay men who had been tested for hepatitis B. Many had also tested positive for HIV, though a few remained symptom-free years after infection.

Walker said at first he assumed Massie had gotten a false positive test result. But retesting proved he was indeed HIV positive. At a conference, Walker quizzed other doctors and found that many of them had seen a small number of similar cases.

Eventually, he said, he found that about 1 in 300 people were “controllers” – able to carry untreated infection without illness.

Those people showed very little of the virus in their blood – in many cases it was undetectable, though they tested positive for HIV antibodies, proving they’d been exposed.

Meanwhile, Walker kept studying Massie, often going to the minister’s house to take blood and chat over coffee. “We became really good friends,” Massie said. Massie kept asking Walker whether they had any idea what was protecting him from AIDs. For years, the answer was no.

Gradually, Walker’s project grew to encompass researchers all over the world and more than 3,500 HIV-positive volunteers, about 1,500 of whom were probable “controllers.” Some were recruited by Temple University and by the AIDS service group Philadelphia FIGHT.

“The patients were absolutely spectacular in terms of their contributions to this,” said Walker. “They enthusiastically lined up for this study when they heard about it – some of them flew into Boston to have their blood drawn.”

It was a combination of their large volunteer pool and advancing genetics technology that finally allowed them to crack the mystery, said Walker. What they wanted was something these HIV controllers shared that made them different. The human genetic code is 3 billion letters long, Walker said, making it hard to know where to look.

Luckily, by the early 21st century, such studies could take advantage of a group of 3 million genetic signposts, called SNPS, where the human genetic code tends to vary. These can help isolate regions on a chromosome where key differences are likely to be found between one group and another.

Using the SNPs led them to a group of genes on chromosome 6 that code for a component of the immune system called HLA – human leukocyte antigens – which distinguish the body’s own cells from foreign invaders.

A further breakthrough pointed to a specific set of these HLA genes where subtle genetic differences changed the way the immune system worked.

Walker describes the HLA proteins as factory workers. When a virus invades a cell, these HLA proteins can grab a piece of the viral protein and “hang it out the window.” That, he said, signals that something terrible is going on in that cell. “Then, the killer T cells come and blow up the factory.”

In most people, that system doesn’t work well against HIV, since the virus attacks key cells in the immune system faster than they can stop it. But in those fortunate few, the HLA proteins do a better job of displaying the viral proteins, which signals infection and prompts the killer T cells to come in and destroy the infected cell. These so-called controllers showed up among different ethnicities.

Had HIV mutated into a form that was spread by casual contact, these people might make up the majority of the remaining human race. “That’s why variability in the human genome is so important,” Walker said. The human immune system is a balancing act – and at some being too sensitive would lead to false alarms.

Ian Frank, an AIDS researcher at the University of Pennsylvania, said the many volunteers were crucial to this advance. “That really gives them the power to see things you could never see if you were analyzing five or ten of these patients,” he said, “which is the way most of this research goes.”

Massie, who is now 54, used the extra time afforded by his “controller” status to write an award-winning book on apartheid, earn a doctorate in business at Harvard, found a nonprofit that helps companies deal with climate, energy and human rights issues, and run for lieutenant governor of Massachusetts in 1994. He won the primary, he said, making him the first openly HIV-positive candidate for a major office.

Eventually, however, he began getting sick from a latent hepatitis C infection, also picked up from a blood transfusion. His immune system couldn’t fight that so he got a liver transplant last year.

He’s now feeling well enough to start up his career again. And thanks to the liver transplant, he no longer has the uncontrolled bleeding of hemophilia.

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