Out of the ashes of HIV eradication, the phoenix of immune reconstitution is rising. If early studies are any sign, the right combo of HAART, STIs and T-cell tweakers will let even longtime HIVers live in peace with the virus.
For the lucky, health and sickness are easy to keep straight: Our body is us, and disease is not. Infectious bugs try to overrun us, and our immune system tries to kill them. But in fact -- as HIVers know only too well -- the healthy human body is not that simple. It is actually the terrain of a dark, complex war of attrition, a lifelong guerrilla struggle between us and the invaders. Colonized by a host of viruses, we do endless invisible battle with bugs that we never quite get rid of but that rarely make us very sick. This list of pests includes such minor aggravations as chicken pox, herpes and mononucleosis. And if Eric Rosenberg, MD, has anything to do with it, it will include HIV as well.
For years, many scientists assumed that the immune system was hopelessly outmatched by HIV, and that the only way to control it was by inventing better antiviral drugs. But, as we've painfully learned, even the best drugs are a lot less than perfect. Sooner or later, side effects and resistance come knocking. Now, even the most optimistic researchers acknowledge that adhering to an anti-HIV regimen for decades probably won't completely kill off the virus. For this reason, the decade-long efforts of Eric Rosenberg and his colleagues at the Partners AIDS Research Center at Boston's Massachusetts General Hospital have moved center-stage in HIV science. Their research began with a simple question: Why do some people get HIV but never get AIDS? Trying to answer that mystery led them to a series of startling insights: that the immune system puts up a valiant fight against the virus from the first moment of infection, and that it might be possible to boost this effort -- perhaps even to teach the body to control the virus on its own.
This idea has spawned a whole new way of looking at HIV. Perhaps, with the help of an immune-boosting therapeutic vaccine, you and your virus could conspire to coexist. Maybe HIV could become a lifelong nuisance instead of a noose -- a "chronic, manageable disease like diabetes" for real. The Massachusetts General team, led by distinguished immunologist Bruce Walker, MD, is trying to realize that dream. Bolstered by a new theory of how the immune system works, they've been trying to convert a handful of regular HIV positive people into born-again long-term nonprogressors -- those rare HIVers who remain inexplicably healthy for a decade or more without meds.
Rosenberg is studying a small number of volunteers who began taking HAART within the first few weeks of infection, to see if their immune system could learn to protect itself against HIV's devastating immediate effect. Most of his patients have been able to drop the drugs for months at a time while their bodies keep the virus in check. Some have stayed drug-free for years. Still, he's careful not to make the mistake that others have made before: promising, out of innocence or arrogance, the cure that never comes. This is not the black-and-white drama of eradication. Instead, Rosenberg talks about margins of success, the tiny advantages that might make all the difference in your immune system's battle against HIV. He uses terms like viral remission and partial protection, but to people exhausted by the drug roller coaster, his work could go by another name: a different kind of hope.
In the main office of the infectious-diseases department of Massachusetts General Hospital, a fortune-cookie tag is taped to a wall: "Time, nature and patience are the best physicians." It's not a bad introduction to the way Walker's team works. As doctors, they spend a lot of time talking directly to sick people, trying to figure out how to coax forth whatever force of health lies within. As scientists, they are focused on a handful of Big Questions, the ones that get answered only gradually, through direct observation combined with endless fiddling at the lab bench.
This "bedside to bench" approach is partly what convinced Eric Rosenberg to join Walker's group when he came to Massachusetts General in 1995. Although he never thought of himself as a lab guy, he was quickly drawn into the center's research. After all, Rosenberg had gone to medical school in New York City in the mid-'80s, and he'd seen the damage HIV could do. "Thirty percent of the hospital would be occupied with dying AIDS patients," he recalls. "I'd see people my own age coming in, gasping for breath. It was hard."
Rosenberg doesn't come across like anybody's stereotype of a Harvard doc. He's unassuming and casual, with a gift for explaining the intricate operations of the immune system in Gen-X English (the immune system "wigs out" or it "whomps" viruses). But he is 100 percent physician in other ways. Like a lot of doctors, he gets a big charge out of solving the secrets of illness. "I always liked infectious disease [medicine] because people come in, feeling horrible, and they get cured," he says. "It's really rewarding. You are the Sherlock Holmes of medicine. Of course, I quickly learned that's not always the case -- especially with HIV." He and Walker share a kind of intellectual credo: The clinic comes before the test-tube. Though it was their lab research that made them famous, all their insights started in the examining room.
Their work began that way, with the basic observation that certain HIVers seemed to be an awful lot healthier than they should be. Walker wanted to know why. In 1993 he got his first break when a man named Robert Massie walked into his clinic. Massie had had HIV for about 15 years, had never taken any anti-HIV meds and was still perfectly healthy. His question: Did Walker want to study him?
Hell, yes. "We pounced on this chance," he says. "This was the first long-term nonprogressor I could sit and talk to -- a real-live patient! It was impressive to meet him, and see that the guy was doing great." Better yet, Walker got a chance to examine the man's blood, and what he found launched him on a new theory about how HIV does its dirty work.
That theory, revised by Rosenberg and others, runs like this: The immune system seems to lose the game against HIV before it even begins. Right after infection, as the immune system is still gearing up for a counterattack against the billions of virions in the blood and organs, the virus already has the upper hand, wiping out the crucial helper T cells (a.k.a. CD4 cells) that coordinate the immune response. In Rosenberg's words, CD4s are the "generals" of the immune system, while the cytotoxic killer T cells (a.k.a. CD8 cells) are its "soldiers." A crafty tactician, HIV picks off the leaders right away, leaving the soldiers in disarray. These CD8s fight long and hard, but without orders from above, they can't get organized. One by one, each cell gets wiped out by the virus, until eventually there is no immune system left. "It's brilliant," Rosenberg says. "Genius, when you think about it."
When Walker looked at Massie's blood, he discovered something gloriously strange, proof that he was on the right track. People with progressive HIV have few and weak CD4s, so their CD8s have to go it alone. But Massie's blood was teeming with both killers and helpers -- and his viral load was almost undetectable. Walker was thrilled. Clearly, Massie had managed to mount and maintain a powerful immune response.
It sounds rational enough now, but it certainly wasn't a popular line of thinking at the time. From the start, HIV research was headed by virologists, and many thought that studying the immune response to HIV was largely a waste of time. From what they could tell, the virus easily undermined anything that our bodies did to resist it. In almost every other viral infection -- from polio to Ebola -- some fraction of the people who get the disease successfully fight it off. But HIV seemed an inexorable killer. Apparently, our pathetic human machinery was just no match: Only drugs could kill this foe. With research dollars focused on that -- and desperate HIVers demanding "Drugs into bodies!" -- virus hunters set the AIDS research agenda. Immunology remained a poor cousin, and Walker had to jump through hoops to get his brainchild funded.
When Rosenberg joined the Massachusetts General group, he quickly earned his stripes by proving that other long-term nonprogressors had the same robust immune response. Why? The key seemed to be the HIV-specific helper T cells: The more you have, the lower your viral load. This observation was big news, because it suggested that CD4 cells played a major role in keeping the virus at bay. Rosenberg's study, published in 1997 in Science, packed an even bigger implication: Evidently, the human body was not completely helpless against HIV's onslaught.
With that, the team hatched a more ambitious project: to turn ordinary people into Bob Massies. Perhaps if they hit HIV early enough with powerful enough drugs, they could prevent the massacre of helper T cells. With the CD4 cell response still intact, your immune system might be able to rebuild itself and regroup later against the virus -- without the help of meds.
This was, of course, a bizarre moment to talk about stopping treatment. Just a year earlier, a new class of drugs called protease inhibitors had revolutionized HIV treatment; star virologist David Ho at New York City's Aaron Diamond AIDS Research Center had even predicted that the new cocktails might cure HIV in as little as a year or two. Drugs looked like salvation. And yet there Walker stood, at 1998's International AIDS Conference in Geneva, throwing down the immunologists' gauntlet with his proclamation: "Eradication is not required. The immune system can control HIV." Ho's overblown promise may have landed him on the cover of Time -- but in the HIV research world, the Walker manifesto was nearly as grandiose.
James (not his real name), 50, a boston teacher, is convinced that his body "hates" HIV, and that's exactly how he's going to beat it. When he got infected in early 2000, seroconversion illness made him as sick as a dog for three weeks. "Probably other people get as sick as I did," he says. "But I decided I got sicker than anyone else. I envision it this way: When my body recognized it had HIV, it got pissed off." When James heard about Rosenberg's study, he was intrigued. Clearly, his own body was waging a mighty struggle with HIV. Could all that furious virus-fighting energy be tapped to keep him healthy? "The idea of long-term nonprogressors and the theory behind the study made me think maybe I could turn my immune system on," he says, "and have it take care of the virus."
The plan, as Rosenberg and Walker contrived it, was to find a dozen or so people who were so recently infected that they were still suffering seroconversion's fevers and headaches. Each would immediately start on HAART. (The team left it up to each volunteer and his or her physician to decide which combos to choose.) After about a year, if viral load stayed low and immune responses looked good, they would drop the drugs -- a structured treatment interruption (STI). At that point, the virus would undoubtedly roar back. But hopefully the aggressive early treatment would have sheltered the crucial helper CD4s. Theoretically, 12 months' protection would make the cells both more numerous and more highly attuned to the virus. "It's a learning experience for the immune system," Rosenberg says. As the virus roars back, the CD4 and CD8 cells are in a better position to "study" it. "They see the enemy, but in a much more controlled situation -- instead of viral load being 10 million copies, it's a couple thousand."
The team was confident that its volunteers would be OK, and while finding brand-newly infected people was tough, getting them to join the study was easy. Persuading the hospital's scientific oversight board was another matter. "There was all this stuff out there about eradication, and we're coming in saying, 'No, we want to stop therapy,'" Walker says. "It didn't go over too well."
Eventually, they got permission to try it -- with one volunteer. After only a three-week STI, the guy's virus came back with a vengeance. He had to go back on his regimen, and Rosenberg and Walker prepared to go back to the drawing board. But by coincidence, a nasty attack of hepatitis A a few weeks later forced the HIVer to stop his antivirals in order to protect his liver. This time the virus stayed low. The team was jubilant -- and soon got permission to extend the study to the 13 others who'd signed up.
James quit taking his meds for the first time last spring. For 14 weeks, his body managed to control the bug on its own, and he felt great. But eventually his viral load inched up above the 5,000-copy threshold that Rosenberg had set for patients to go back on drugs. And it stayed there. (They picked the conservative cutoff -- the feds' start-HAART recommendation -- both to please the hospital's oversight board and to make sure that their volunteers weren't in danger from resurgent virus.) Now on his second STI, with his viral levels still below 3,000 copies after 16 weeks, James remains hopeful, even confident. "The way I look at it, when I went on meds, my body said, 'I don't have to be pissed off anymore,'" he says. "It said, 'You deal with that, I'll get all fixed up over here, and when I'm ready, I'll give it a try again.'"
In fact, as a proof of his theory, Rosenberg's study has been a brilliant success. Four of the 14 volunteers have done exactly what he'd hoped: stay off drugs for as much as two years, with virus levels below the 5,000 cutoff -- almost like baby long-term nonprogressors. Two lucky souls have been off meds for two years. The other eight eventually had to go back on drugs, after weeks or months off. During a second drug interruption, two more managed to get the upper hand on HIV, and another joined them during his third STI. All the volunteers are still being tracked, and the team hopes that for the remainder, the fourth or fifth STI will do the trick.
So things seem to be turning out pretty nicely for Rosenberg, his team, even his patients. This research is definitely good news for that tiny handful of people who catch their infection right away and who have both an adventurous mind-set and a well-read physician. But what does it mean for the rest of the HIV community?
At first glance, nothing. Rosenberg's study, impressive as it is, is too experimental to be any kind of treatment. Rosenberg himself warns that his on-and-off, or "pulsing," therapy would be very risky for anyone with chronic infection, and he stresses that his volunteers are obsessively monitored for signs of viral rebound and resistance. He also worries that people who are sick and tired of their meds will leap on the results from his small study as a justification to take drug holidays.
Nor has the Massachusetts General group yet proved that their 14 HIVers will live any longer or better, though it seems like the logical conclusion. "The critical finding is that the immune system can control the virus in people who would have otherwise not been able to," Walker says. "Have we done something beneficial? We can't claim that. All we can say is that in almost every case, people have been able to transiently control their virus below a level of 5,000 copies." For Walker, this new fact only highlights how much remains unknown. He ticks off the questions: "What is the durability of this immune response? How long can you wait after infection to get this result? What accounts for it? Will people develop CD4 cell loss at the same rate as those who have never been treated? We don't know."
Instead, the team is looking much further down the road. Rosenberg thinks that studying natural long-term nonprogressors and LTNP wannabes will point the way to a therapeutic vaccine that could regenerate the battered immune systems of all HIVers. "Taking people on and off therapy is a crude way to auto-immunize them," he says. "Rather, it's a proof of principle that one day -- if we can figure out how -- a vaccine might work." For a person with chronic infection, an auto-immunizing shot would activate and "train" their remaining CD4s against HIV. They'd have to stay on the drug cocktail for a while to shield the new cells from viral attack. But if it worked, the immune system could gradually be rebuilt, and the person could eventually go off drugs -- for months, years, maybe for life.
Still, the hurdles are high. First, inducing helper T cell responses in a much-damaged immune system takes some magic. Second, in long-term HIVers, the virus is much more diverse -- the immune system has to defend against many wily viral versions, each with slightly different tactics. It is also possible that the virus has already mutated and escaped from immune responses, so any therapeutically boosted CD4 cells will simply be more of the same -- that is, not working. The challenge then will be to direct the immune system to target new, vulnerable regions of the virus. To this end, Walker and Rosenberg started a study with the experimental vaccine Remune -- shelved when its pharma backer abruptly pulled the plug last summer -- and is eagerly watching the progress of research into DNA vaccines, which seem to have the power to recruit both CD4 and CD8 cell activity (see "Let's Get Naked"). None has made the leap from monkey to man, but Rosenberg is confident. "It will get to that point," he says. "It's just a matter of when."
Rosenberg's offerings in the hope department may seem a bit thin. But this scenario works on a different premise, with a different payoff. No, it isn't the cure. Yet this series of small therapeutic improvements might just add up to a real-world equivalent: the harmonious coexistence of your immune system and your infection, body and bug.
Of course, the vaccine pipeline is littered with failures, and plenty of prominent critics think the current enthusiasm is overblown -- too much, too soon. But these days, you take hope where you find it. The idea that your own immune system, strategically tweaked with drugs and a vaccine, may turn out to be the force that keeps the virus in check is the most powerful one to materialize since the smash-up of eradication. Down the road, this immune-based research might free hundreds of thousands from their difficult, toxic drug regimens. And a therapeutic vaccine might prevent millions of poor HIVers without access to morphine, let alone anti-HIV meds, from dying painful, brutal deaths. For Rosenberg, Walker and their team, that dream is worth chasing.
At New York City's famed Aaron Diamond (AD) AIDS Research Center,scientists have also been tinkering with HAART and STIs injust-infected folks. Their goals, though, are different. For the MassGeneral team, the drugs play second fiddle, a means to an end; at AD,it's the opposite.
The results? AD's volunteers spent years on HAART, and some also gotALVAC, an experimental canarypox vaccine. However, only three saw theirviral loads stay undetectable for 120 days after going off drugs -- andultimately the researchers decided that the early treatment offeredlittle help. Why? Probably because the AD criteria were not as strictas Mass General's -- their volunteers had already been infected for anaverage of 65 days.
But for the AD team, that disappointing result is only furtherevidence that HAART should be improved. To that end, they've beenexperimenting with four- and five-drug combos and bigger doses of olddrugs. "We're more interested in optimizing HAART, trying to suppressviral replication completely, and seeing how far we can go with drugsto reduce total-body viral burden," says staff investigator MartinMarkowitz, MD. "We'll use the immune system to control residual virus, as opposed to hoping that the immune system can handle anything more than that."
This points to an important philosophical split between thesepioneering teams. Both have consistent results but differentrationales. For Rosenberg and Walker, observing the immune system opensthe door to a vaccine. For Markowitz, drugs come first -- unravelingthe secrets of the immune system is just a nice perk. "They are moreinterested in dissecting the immune response," Markowitz says. "We'remore interested in treatment and getting results."