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HIV

Published On January 15, 2009

CLINICAL RESEARCH

The Rare Few

Of every 300 people infected with HIV, one doesn’t get AIDS. Understanding this uncanny protection might help science imitate nature.

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 exposed Tyler during childbirth and breast-feeding. Yet as Tyler 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, 26 years after receiving HIV-tainted blood, Karen Pancheau has yet to develop AIDS.

She isn’t alone. Bruce Walker, now director of the Partners AIDS Research Center at the Massachusetts General Hospital and director of the Center for AIDS Research at Harvard University, first became aware in 1992 that there were others like Karen Pancheau who seemed somehow protected from AIDS. He learned about the phenomenon from Susan Buchbinder, an epidemiologist in San Francisco who was analyzing blood samples from homosexual men taken years earlier (for the trial of a hepatitis vaccine) to understand how AIDS progresses. She started studying men whose samples showed they had been infected with HIV in the late 1970s; many had already 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 even identified as a disease. “People keep telling me I’m going to die, and I keep living,” Massie told Walker. Walker immediately began to study his immune system.

A few years later, speaking before several hundred doctors at an AIDS conference in New York City, 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. He 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. Early on, drawing on the experiences of medical science with mumps, measles, smallpox and other infectious diseases, researchers confidently predicted a vaccine within five years. That hope faded as one high-profile effort ?after another faltered and the death toll from AIDS mounted.

Since 1981 AIDS has claimed more than 25 million lives, and today some 33 million people worldwide are infected with HIV. Though 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. Unlike, say, a measles vaccine, which can be delivered to masses of people a single shot at a time, 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. In 2008, after pharmaceutical manufacturer Merck announced the failure of its latest attempt at a vaccine, London’s Independent newspaper surveyed more than 35 leading AIDS researchers in the United States and Great Britain. About two-thirds of those who responded said an HIV vaccine wouldn’t appear within the next decade. Several predicted a vaccine would never be developed.

Against that gloomy outlook stands the relative handful of elite controllers, who, somehow, have managed to do what medicine’s best efforts have been unable to accomplish. No one yet knows how their bodies keep AIDS at bay. Are their immune systems exceptionally strong and effective? (One recently published study suggests that elite controllers have a heightened ability to kill HIV-infected cells.) Do they possess some elusive 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 are hopeful that 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, thus preventing them from entering other cells; and T cells, which find and dispatch infected cells. (There are two main types of T cells: CD4+ cells, which oversee the immune response, and CD8+ cells, or “killer” T cells, which do most of the actual killing.) 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 CD4+ cells declines. When a patient’s T cell count falls to about 200 per milliliter of blood 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 copies per milliliter 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 condition an immense challenge for the body—and 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, depleting the very system needed to fight disease. What’s more, unlike most other viruses, HIV can mutate rapidly into countless variations within a single patient, 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 opportunistic mutations to fill. “HIV is really an elegant replicating machine built to evade almost every defense humans have against pathogens,” explains Steven Deeks, an HIV specialist at San Francisco General Hospital.

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, and that’s a situation Deeks, Burton, Walker and a growing number of other researchers are determined to change.

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.

Burton, at Scripps, is studying the immune systems of HIV-positive people, some of whom are elite controllers but most of whom simply have low viral loads, whose antibodies are capable of acting against many different strains of the virus. At the MGH, Marylyn Addo investigates regulatory T cells, which prevent the immune system from destroying healthy cells in its quest to quell invaders. Though her work is at an early stage, she is hopeful the comparison will eventually yield clues about how elite controllers’ regulatory T cells maintain the delicate balance between doing too much and too little.

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 at the most basic level. Along with his research group, J. Christopher Love, a chemical engineer whose specialty is building structures out of metal rods as small as one one-thousandth the width of a human hair, is trying to dissect the immune system to discover what might be different about elite controllers.

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, thus providing adaptive immunity.

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.

Love and his team want to know whether the T cells in elite controllers have special properties that enable them to fight off HIV. The answer will require a much more detailed understanding of just how T cells function, so the team has developed a system to examine T cells destroying infected cells. They start by molding cell-size wells into a piece of polymer similar to a laboratory slide. Then they trap a single T cell along with a single cell infected with HIV—with as many as 300,000 specimens fitting onto a single three-inch slide. 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. By examining the differences, they hope to understand the qualities in the controllers’ cells that enable them to ward off the disease.

One clue may already have emerged. In the December 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 accumulate more of two important proteins—perforin and granzyme B—than do those of other people with HIV. Perforin released by the T cells punches holes in the infected cell through which granzyme B enters and destroys the cell. In studies of cells taken from elite controllers and from patients with AIDS, controllers’ T cells killed 68% of infected cells in an hour, compared with just 8.1% for those with AIDS. It’s a promising find, but to discover many of the hows and whys of the phenomenon will require further study.

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. But it’s a daunting endeavor. The genome comprises 3 billion coded pieces of information that determine who a person is. Some 99.9% of these pieces are the same in all people, but there are points of difference—known as single nucleotide polymorphisms (SNPs, pronounced snips)—that set apart one individual from the next.

In his search for SNPs along the 3 billion-link chain, de Bakker isn’t looking for an AIDS-causing gene but rather for something more subtle and elusive, a predisposition that empowers controllers to keep HIV from taking hold. Though at the outset of his quest he had no idea where to look for such crucial differences, de Bakker insists that may actually be an advantage. “We don’t have to make any assumptions about how HIV or AIDS works, or about the immunology behind it,” he says. “We just let the data tell us what is important.”

To conduct his experiments, de Bakker uses powerful DNA scanners at the Broad Institute in Cambridge, Mass., a joint Harvard and MIT research center devoted to genomics studies. Researchers deposit DNA samples on a “SNP chip” and insert it into a machine that produces color-coded maps of a subject’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 to find points of variation. Somewhere in there, he thinks, will be clues to how elite controllers fend off AIDS; early indications signal a cluster of genes that involve the immune system.

De Bakker’s goal, like those of dozens of other scientists focusing on controllers, is to learn secrets that could lead to a vaccine or even a cure. 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 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, derived in a way from her own blood, would be a fitting tribute to the son she lost. “That’s why I do this.”

 

DOSSIER

1. “Elite HIV Controllers: Myth or Reality?” by Nitin K. Saksena et al.,AIDS Reviews, October–December 2007. Despite the skeptical title, researchers cite elite controllers as a rare bright hope in the fight against AIDS.

2. “Human Immunodeficiency Virus Controllers: Mechanisms of Durable Virus Control in the Absence of Antiretroviral Therapy,” by Steven G. Deeks and Bruce D. Walker, Immunity, September 2007. A comprehensive analysis by two leading researchers of the various means by which elite controllers may be keeping AIDS at bay.

3. “No Vaccine Against HIV Yet—Are We Not Perfectly Equipped?” by Mahender Singh, Virology Journal, Aug. 29, 2006. A good discussion of why HIV and AIDS have thwarted so many attempts to defeat them.

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