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WHAT ARE THE ODDS? That you will never need drugs to keep your HIV in check? // That you will live longer than your doctor’s first prediction? His second? His third? // That you hold a vital clue to preventing, even curing, AIDS? The Rare Few

by charles slack // Photographs by Gregory Heisler

t first Karen Pancheau figured her son whose samples showed they had been infected with HIV Tyler’s nasty rash came from friction on in the late 1970s; many had already died, but some weren’t A the mats at judo class. But when the rash even sick. Then, in 1994, Walker met a hemophiliac in Bos- began dissolving layers of flesh, his father ton named Bob Massie, who had become infected with HIV took the teenager for tests, which revealed through a blood transfusion in 1978—three years before he had HIV. Karen, too, tested positive AIDS was even identified as a disease. “People keep telling for HIV, the virus that causes AIDS, which she’d apparently me I’m going to die, and I keep living,” Massie told Walker. acquired from a blood transfusion in June 1982 and to which Walker immediately began to study his immune system. she exposed Tyler during childbirth and breast-feeding. Yet as A few years later, speaking before several hundred doctors Tyler slowly progressed to AIDS, Karen remained healthy. at an AIDS conference in New York City, Walker asked how Various drug cocktails kept AIDS from killing Tyler, but they many had run across similar patients. When at least half the left him constantly fatigued, and on Nov. 11, 2005, the 23-year- audience raised their hands, Walker realized that people like old committed suicide. Remarkably, 26 years after receiving Massie represented a real opportunity for research. He also HIV-tainted blood, Karen Pancheau has yet to develop AIDS. understood why these rare individuals—no more than one in She isn’t alone. Bruce Walker, now director of the Part- every 300 cases, or perhaps 5,000 of the more than 1 million ners AIDS Research Center at the Massachusetts General infected Americans—had remained so well hidden: “They Hospital and director of the Center for AIDS Research at weren’t sick. They weren’t coming to the hospital.” Harvard University, first became aware in 1992 that there Those protected few came to be called “elite controllers” were others like Karen Pancheau who seemed somehow because their ability to combat the virus puts them in excep- protected from AIDS. He learned about the phenomenon tional company among infected individuals. Their existence from Susan Buchbinder, an epidemiologist in San Francisco injects a note of hope into a field of research that has be- who was analyzing blood samples from homosexual men come accustomed to failure and disappointment since HIV taken years earlier (for the trial of a hepatitis vaccine) to was identified in 1981. Early on, drawing on the experiences understand how AIDS progresses. She started studying men of medical science with mumps, measles, smallpox and other

protomag.com // Winter 09 < Solitary figures among legions of AIDS sufferers, “elite controllers,” such as Joseph O’Brien of Atlanta, test positive for HIV but never seem to get sick. Despite not having taken the antiviral drug AZT for more than a decade (and then only briefly), O’Brien remains healthy.

Winter 09 // protomag.com Karen Pancheau Portland, Ore. HIV positive since 1982 <

the failure of its latest attempt at a vaccine, London’s Indepen- dent newspaper surveyed more than 35 leading AIDS research- ers in the United States and Great Britain. About two-thirds 24 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 re- cently 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 com- bination 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.

ike many other viruses, the human immunodeficiency virus does its damage by entering healthy cells, repro- L ducing and releasing copies of itself that then infiltrate other cells. The immune system fights back with several infectious diseases, researchers confidently predicted a vaccine mechanisms, including B cells, which produce antibodies that within five years. That hope faded as one high-profile effort coat invading viruses, thus preventing them from entering after another faltered and the death toll from AIDS mounted. other cells; and T cells, which find and dispatch infected cells. Since 1981 AIDS has claimed more than 25 million lives, and (There are two main types of T cells: CD4+ cells, which over- today some 33 million people worldwide are infected with HIV. see the immune response, and CD8+ cells, or “killer” T cells, Though pharmaceutical advances have greatly increased how which do most of the actual killing.) In the typical progression long many patients survive, those innovations have merely of HIV, a patient’s viral load—the number of viral copies per commuted what once seemed an automatic death sentence to milliliter of blood—creeps higher while the number of CD4+ a lifetime of battling a chronic disease. Unlike, say, a measles cells declines. When a patient’s T cell count falls to about 200 vaccine, which can be delivered to masses of people a single per milliliter of blood and an “opportunistic” infection (often shot at a time, AIDS medications are expensive and must be pneumocystic pneumonia or Kaposi’s sarcoma) takes hold, taken daily, creating a logistical nightmare for reaching the the patient is considered to have progressed to AIDS. poorer parts of the world in which AIDS proliferates. People with AIDS may have viral loads of several hundred Many scientists have openly questioned whether truly con- thousand copies per milliliter. In contrast, the viral loads of quering AIDS, with a vaccine or a cure, is even possible. In elite controllers range from a scant 50 copies per milliliter 2008, after pharmaceutical manufacturer Merck announced down to levels so small that even the most sensitive tests

protomag.com // Winter 09 can’t detect them. Doctors know these people have the virus only because separate tests have revealed the presence of anti- bodies to HIV in their systems. In other words, elite control- lers 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 im- mense 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 pas- sages and hepatitis infecting the liver. But HIV targets T cells 25 themselves, depleting the very system needed to fight disease. What’s more, unlike most other viruses, HIV can mutate rap- idly 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 immu- nologist 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.

arly on, researchers discovered that elite controllers aren’t infected with a less virulent strain of the disease. E 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 Joseph O’Brien the Mark and Lisa Schwartz Foundation Atlanta, Ga. HIV positive since 1992 Unlike most other and recently boosted by a $22 million grant from the Bill & Melinda Gates viruses, HIV can Foundation, the International HIV Controllers Study is work- ing to identify elite controllers, collect samples of their blood mutate rapidly into and DNA, and distribute the samples to labs for analysis. Burton, at Scripps, is studying the immune systems of HIV- countless variations positive people, some of whom are elite controllers but most of whom simply have low viral loads, whose antibodies are ca- within a single patient, pable of acting against many different strains of the virus. At making it extremely the MGH, Marylyn Addo investigates regulatory T cells, which prevent the immune system from destroying healthy cells in difficult to develop an its quest to quell invaders. Though her work is at an early stage, she is hopeful the comparison will eventually yield effective vaccine. clues about how elite controllers’ regulatory T cells maintain

Winter 09 // protomag.com “Rodney” Flagstaff, Ariz. HIV positive since 1983 > Another Route to a Cure? // One step ahead of elite controllers: people who are immune to HIV infection.

Elite controllers are not the only people able to resist AIDS; within another tiny group, a genetic mutation called delta 32 renders T cells (HIV’s usual targets) impenetrable—and in fact, protects them from becoming infected in the first place. It was stem cells from one of these exceptional individuals that German physicians used to purportedly cure a man of HIV infection, an achievement that was presented to scientists at a think tank at the destroying the real virus. But AIDS has re- Massachusetts Institute of Technology in early 2008 and that received widespread publicity 26 sisted every effort to develop a vaccine. following a Wall Street Journal article in November. The results were startling: Almost two years after receiving two stem cell transplants in an attempt to cure his leukemia, the Love and his team want to know wheth- patient, a 40-year-old American who also had AIDS, stopped all HIV medications. With no er the T cells in elite controllers have spe- detectable trace of the virus, he appears “functionally cured” of AIDS, according to scientists cial properties that enable them to fight at the think tank who reviewed the case. off HIV. The answer will require a much Though the word cure led to a spate of coverage, prominent AIDS researchers and even more detailed understanding of just how the physicians who performed the transplant cautioned against optimism. The rarity of the mutation, the cost of the procedure (around $250,000) and the dangers involved (infection T cells function, so the team has devel- and immune system complications yield a mortality rate as high as 30%) make transplants oped a system to examine T cells destroy- impractical for addressing the worldwide AIDS epidemic, they say. ing infected cells. They start by molding However intriguing, the German case represents, at best, a lone victory. In an article on cell-size wells into a piece of polymer the Website of the Foundation for AIDS Research, Jeffrey Laurence, a physician and senior similar to a laboratory slide. Then they scientific consultant for the organization, says it’s unknown to what extent delta 32 was trap a single T cell along with a single actually necessary; it’s conceivable that the very process of undergoing stem cell transplants played a major role in eliminating the patient’s AIDS. cell infected with HIV—with as many as In this case, as with elite controllers, answers may not be known until researchers better 300,000 specimens fitting onto a single understand the basic workings of the immune system and how the virus subverts them. three-inch slide. That allows researchers to watch T cells attacking infected cells the delicate balance between doing too much and too little. and to compare the action of elite controllers’ cells with those Some blood samples have made their way to the Massachu- of patients whose HIV has progressed into AIDS. By examin- setts Institute of Technology, where scientists versed in nano- ing the differences, they hope to understand the qualities in technology—the study of very small structures—are examin- the controllers’ cells that enable them to ward off the disease. ing how the immune system fights off disease at the most basic One clue may already have emerged. In the December 19 level. Along with his research group, J. Christopher Love, a issue of the journal Immunity, researchers at the National In- chemical engineer whose specialty is building structures out stitute of Allergy and Infectious Diseases concluded that the of metal rods as small as one one-thousandth the width of a killer T cells of elite controllers accumulate more of two im- human hair, is trying to dissect the immune system to discover portant proteins—perforin and granzyme B—than do those of what might be different about elite controllers. other people with HIV. Perforin released by the T cells punches The immune system uses an array of defenses—broadly clas- holes in the infected cell through which granzyme B enters and sified into innate and adaptive immunity—to fight off viruses, destroys the cell. In studies of cells taken from elite controllers bacteria and other invaders. Innate immunity refers to defens- and from patients with AIDS, controllers’ T cells killed 68% es humans are born with; the skin and mucous membranes, for of infected cells in an hour, compared with just 8.1% for those example, help keep out most attackers. But it’s adaptive im- with AIDS. It’s a promising find, but to discover many of the munity that is compromised in AIDS. That subsystem depends hows and whys of the phenomenon will require further study. on B cell antibodies and killer T cells that not only seek out and destroy intruders but also remember them the next time they ne theory about elite controllers holds that they pos- attempt to invade, thus providing adaptive immunity. sess special genetic traits, beyond any differences in Vaccines normally work by introducing a dead or harmless O their immune systems, that better equip them to bat- piece of virus that stimulates the adaptive immune system tle AIDS. Geneticist Paul de Bakker of Brigham and Women’s to attack. In that way, the body builds defenses capable of Hospital in Boston is combing through the human genome to

protomag.com // Winter 09 Elite controllers might possess special genetic traits, beyond any differences in their immune systems, that better equip them to battle AIDS. 27

as a million SNPs at once, but de Bak- ker 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 find those characteristics. But it’s a daunting endeavor. The or even a cure. Controllers themselves are as mystified as any- genome comprises 3 billion coded pieces of information that one about what makes their bodies special. For many, including determine who a person is. Some 99.9% of these pieces are the Karen Pancheau, survival is bittersweet—their own good health same in all people, but there are points of difference—known is counterbalanced by the pain of having lost friends or family as single nucleotide polymorphisms (SNPs, pronounced to the disease. “I have my glass-half-empty days, but I try not snips)—that set apart one individual from the next. to dwell on those,” Pancheau says. She thinks that an answer to In his search for SNPs along the 3 billion–link chain, de the disease, derived in a way from her own blood, would be a Bakker isn’t looking for an AIDS-causing gene but rather for fitting tribute to the son she lost. “That’s why I do this.” something more subtle and elusive, a predisposition that em- powers controllers to keep HIV from taking hold. Though at the outset of his quest he had no idea where to look for such Dossier crucial differences, de Bakker insists that may actually be an advantage. “We don’t have to make any assumptions about 1. “Elite HIV Controllers: Myth or Reality?” by Nitin K. Saksena et al., AIDS Reviews, October–December 2007. Despite the skeptical title, HIV AIDS how or works, or about the immunology behind researchers cite elite controllers as a rare bright hope in the fight it,” he says. “We just let the data tell us what is important.” against AIDS. To conduct his experiments, de Bakker uses powerful 2. “ Human Immunodeficiency Virus Controllers: Mechanisms of Durable Virus Control in the Absence of Antiretroviral Therapy,” by DNA scanners at the Broad Institute in Cambridge, Mass., a Steven G. Deeks and Bruce D. Walker, Immunity, September 2007. A joint Harvard and MIT research center devoted to genomics comprehensive analysis by two leading researchers of the various studies. Researchers deposit DNA samples on a “SNP chip” means by which elite controllers may be keeping AIDS at bay. 3. “No Vaccine Against HIV Yet—Are We Not Perfectly Equipped?” by and insert it into a machine that produces color-coded maps Mahender Singh, Virology Journal, Aug. 29, 2006. A good discussion of of a subject’s DNA. Researchers can now examine as many why HIV and AIDS have thwarted so many attempts to defeat them.

Winter 09 // protomag.com