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July 12, 2009

BehindTheMedspeak: The mystery of 'elite controllers' — HIV-positive and taking no antivirals, they never get AIDS

Long story short: Of the more than 1 million Americans infected with HIV, one in 300 will never get AIDS even without taking antiviral medications.

What's different about them has so far defied the very best efforts by researchers trying to determine what exactly it is they have that an overwhelming majority of people don't.

Here's Charles Slack's July 7, 2009 Washington Post Health section front article about this puzzle.


HIV Positive... So Why Don't They Get AIDS?

Researches hope 'elite' group holds clues for others

At first Karen Pancheau figured her son Tyler's nasty rash came from friction on the mats at judo class. But when the rash began dissolving layers of flesh, his father took the teenager for tests, which revealed he had HIV. Karen, too, tested positive for HIV, the virus that causes AIDS, which she'd apparently acquired from a blood transfusion in June 1982 and to which she'd exposed Tyler during childbirth and breast-feeding. Yet as Tyler's HIV slowly progressed to AIDS, Karen remained healthy.

Various drug cocktails kept AIDS from killing Tyler, but they left him constantly fatigued, and on Nov. 11, 2005, the 23-year-old committed suicide. Remarkably, 27 years after receiving HIV-tainted blood, Karen Pancheau of Portland, Ore., has yet to develop AIDS.

She isn't alone. Bruce Walker, who now directs the Partners AIDS Research Center at Massachusetts General Hospital and the Center for AIDS Research at Harvard University, first became aware in 1992 that some people seemed somehow protected from AIDS. He learned about the phenomenon from Susan Buchbinder, an epidemiologist in San Francisco who was analyzing blood from homosexual men whose samples showed they had been infected with HIV in the late 1970s; many had died, but some weren't even sick. Then, in 1994, Walker met a hemophiliac in Boston named Bob Massie, who had become infected with HIV through a blood transfusion in 1978 -- three years before AIDS was identified. "People keep telling me I'm going to die, and I keep living," Massie told Walker.

A few years later, speaking before several hundred doctors at an AIDS conference in New York, Walker asked how many had run across similar patients. When at least half the audience raised their hands, Walker realized that people like Massie represented a real opportunity for research. Walker also understood why these rare individuals -- no more than one in every 300 cases, or perhaps 5,000 of the more than 1 million infected Americans -- had remained so well hidden: "They weren't sick. They weren't coming to the hospital."

Those protected few came to be called "elite controllers" because their ability to combat the virus puts them in exceptional company among infected individuals. Their existence injects a note of hope into a field of research that has become accustomed to failure and disappointment.

Since HIV was identified in 1981, AIDS has claimed more than 25 million lives, and today some 33 million people worldwide are infected with HIV. Although pharmaceutical advances have greatly increased how long many patients survive, those innovations have merely commuted what once seemed an automatic death sentence to a lifetime of battling a chronic disease. AIDS medications are expensive and must be taken daily, creating a logistical nightmare for reaching the poorer parts of the world, in which AIDS proliferates. Many scientists have openly questioned whether truly conquering AIDS, with a vaccine or a cure, is even possible. Against that gloomy outlook stands the relative handful of elite controllers. No one knows how their bodies keep AIDS at bay. Are their immune systems exceptionally strong and effective? Do they possess some genetic trait that protects them? Or does a combination of still-unknown factors set them apart? As more and more elite controllers emerge -- some 500 in the United States have so far volunteered for testing -- scientists hope they will be able to uncover what shields these rare few from AIDS. And perhaps in the process they'll find a way to safeguard everyone else as well.

Like many other viruses, the human immunodeficiency virus does its damage by entering healthy cells, reproducing and releasing copies of itself that then infiltrate other cells. The immune system fights back with several mechanisms, including B cells, which produce antibodies that coat invading viruses, preventing them from entering other cells; and T cells, which find and destroy infected cells. In the typical progression of HIV, a patient's viral load -- the number of viral copies per milliliter of blood -- creeps higher while the number of T cells declines. When a patient's T cell count falls to about 200 per milliliter and an "opportunistic" infection (often pneumocystic pneumonia or Kaposi's sarcoma) takes hold, the patient is considered to have progressed to AIDS.

People with AIDS may have viral loads of several hundred thousand copies per milliliter. In contrast, the viral loads of elite controllers range from a scant 50 down to levels so small that even the most sensitive tests can't detect them. Doctors know these people have the virus only because separate tests have revealed the presence of antibodies to HIV in their systems. In other words, elite controllers aren't HIV-free; they may still be able to pass the virus to others, in whom it may be deadly.

Two characteristics of HIV make the infection an immense challenge for the body -- and for vaccines -- to combat. Most viruses attack particular parts of the body, with, for example, the common cold virus going after the nasal passages and hepatitis infecting the liver. But HIV targets T cells themselves, weakening the very system needed to fight disease. What's more, unlike most other viruses, HIV can mutate rapidly, making it extremely difficult to develop an effective vaccine.

"This isn't just one virus," says Dennis Burton, an immunologist at the Scripps Research Institute in La Jolla, Calif. "You're talking about tens of thousands of different viruses." Even worse, neutralizing one HIV variant simply creates a niche for other mutations to fill.

Early on, researchers discovered that elite controllers aren't infected with a less virulent strain of the disease. But little else about their condition is certain.

Since 2006, Walker and his colleagues have been organizing an international contingent of more than 250 researchers and more than 200 physicians who have elite controllers as patients. Initially funded by a gift from the Mark and Lisa Schwartz Foundation and recently boosted by a $22 million grant from the Bill & Melinda Gates Foundation, the International HIV Controllers Study is working to identify elite controllers, collect samples of their blood and DNA, and distribute the samples to labs for analysis.

Some blood samples have made their way to the Massachusetts Institute of Technology, where scientists versed in nanotechnology -- the study of very small structures -- are examining how the immune system fights off disease..

The immune system uses an array of defenses -- broadly classified into innate and adaptive immunity -- to fight off viruses, bacteria and other invaders. Innate immunity refers to defenses humans are born with; the skin and mucous membranes, for example, help keep out most attackers. But it's adaptive immunity that is compromised in AIDS. That subsystem depends on B cell antibodies and killer T cells that not only seek out and destroy intruders but also remember them the next time they attempt to invade.

Vaccines normally work by introducing a dead or harmless piece of virus that stimulates the adaptive immune system to attack. In that way, the body builds defenses capable of destroying the real virus. But AIDS has resisted every effort to develop a vaccine.

The MIT team wants to know whether the T cells in elite controllers have special properties. The answer will require a much more detailed understanding of how T cells function. So the team has developed a system to trap a single T cell along with a single cell infected with HIV. That allows researchers to watch T cells attacking infected cells and to compare the action of elite controllers' cells with those of patients whose HIV has progressed into AIDS.

One clue may already have emerged. In the Dec. 19 issue of the journal Immunity, researchers at the National Institute of Allergy and Infectious Diseases concluded that the killer T cells of elite controllers killed 68 percent of infected cells in an hour, compared with just 8.1 percent for those with AIDS.

One theory about elite controllers holds that they possess special genetic traits, beyond any differences in their immune systems, that better equip them to battle AIDS. Geneticist Paul de Bakker of Brigham and Women's Hospital in Boston is combing through the human genome to find those characteristics. It's a daunting endeavor. The genome comprises 3 billion coded pieces of information that determine who a person is. Some 99.9 percent of these pieces are the same in all people, but there are points of difference known as single nucleotide polymorphisms (SNPs, pronounced "snips").

In his search for SNPs along the 3-billion-link chain, de Bakker isn't looking for an AIDS-causing gene but for something more subtle, a predisposition that empowers controllers to keep HIV from taking hold.

To conduct his experiments, de Bakker uses powerful DNA scanners. Researchers deposit DNA samples on a "SNP chip" and insert it into a machine that produces color-coded maps of a person's DNA. Researchers can now examine as many as a million SNPs at once, but de Bakker thinks that within five years scanners will be able to compare the entire code of thousands of people. Somewhere in there, he thinks, will be clues to how elite controllers fend off AIDS.

Controllers themselves are as mystified as anyone about what makes their bodies special. For many, including Karen Pancheau, survival is bittersweet: Their own good health is counterbalanced by the pain of having lost friends or family members to the disease.

"I have my glass-half-empty days, but I try not to dwell on those," Pancheau says. She thinks that an answer to the disease, an answer derived in a way from her own blood, would be a fitting tribute to the son she lost: "That's why I do this."


longer version of this story ran in Proto, a quarterly biomedical magazine published by Massachusetts General Hospital.

July 12, 2009 at 04:01 PM | Permalink


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