|HIV-Positive Group May Hold the Key to Defeating AIDS
Infected but not ill, 'elite controllers' make up less than 1% of those with the virus.
They may hold the key to its cure.
Los Angeles Times | July 6, 2006
SAN FRANCISCO — Matt Traywick's personal life has been a treatise on how to contract AIDS.
A gay man, he'd been "very sexually active" in San Francisco in the late 1970s, he said, and tended toward unprotected encounters. Then he entered a long-term monogamous relationship, and after he lost both it and his job as a computer specialist, he sank into a life of hard revelry and so much intravenous methamphetamine use that he wound up homeless on the streets of the city's Tenderloin district.
"I always knew I would be HIV-positive," Traywick recalled. "I hit all the major risk factors. It seemed there was no way I would have been negative. When I tested positive, my doctor cried and I didn't. Walking home, I wondered if there was something psychologically broken in me because, for some reason, I wasn't worried."
Against all logic and expectation, his nonchalance has turned out to be justified.
Traywick was diagnosed 21 years ago and has been healthy ever since, despite never having taken anti-HIV medications. Antibody tests demonstrate conclusively that he harbors the virus. But his immune system has controlled it so effectively that repeated blood assays have never shown a detectable level of the invader, even though Traywick still occasionally uses speed and engages in unprotected sex.
A graying, rumpled man of 46 with darting eyes and nervous hands, Traywick said he has "spent a lot of time trying to figure out why I was a survivor. There's got to be a reason some people are chosen not to die."
In the argot of AIDS research, Traywick is an "elite controller." Elites are extremely rare, accounting for an estimated one-third of 1% of known HIV-positive people and numbering perhaps 2,000. They and so-called viremic controllers, healthy infected people whose immune systems keep the virus at very low, although detectable, levels in the blood without drugs, are of keen interest to AIDS researchers.
"I would say we still don't have the faintest idea why these people are doing as well as they are," said Harvard medical professor Bruce Walker, director of the Partners AIDS Research Center at Massachusetts General Hospital. "Achieving the state that these guys have reached in their bodies — if we could do that through some intervention, we would solve the AIDS epidemic."
Being a long-term controller is not an unalloyed blessing, as Kai Brothers' journey illustrates.
Brothers, 43, a computer technician for Wells Fargo bank in San Francisco, got his first indication something was amiss in 1987. A frequent blood donor, he received a certified letter from his blood bank stating that someone had donated HIV-tainted blood and asking him to be tested.
Brothers couldn't bring himself to respond. As a gay man, he knew he was in a high-risk group. Eventually he had himself tested but couldn't face learning the results. It was 1989 before he had himself retested, confirming his suspicions.
"I deep-down knew," he said in a recent interview. "There was a heavy feeling but not a surprise or shock. There was fear: 'Am I getting sick? How long will it take before this time bomb went off?' "
Not knowing his future, he quit his job and cashed in his 401(k) account to travel in Europe. On his return, he learned his infection-fighting T-cells — HIV's target — had dipped slightly below the normal range, and his doctor wrote him a prescription for AZT, the first effective HIV drug but one with often dreadful side effects.
"I decided I was not going to get it filled," Brothers recalled. "Something instinctively told me not to. I decided to wait it out."
Wait he did, and although his T-cells occasionally dipped, he also declined to use the effective multi-drug HIV cocktail when it became available in 1996. A man of moderate habits, Brothers took to practicing safe sex — although researchers think it unlikely that controllers can infect others, he has taken no chances — and listening more closely to his body when it requested food or rest or exercise.
While the AIDS epidemic roared through San Francisco's gay community, killing his partner and several close friends, Brothers escaped unharmed.
"But it was a bittersweet feeling," he said. "It's hard to call yourself a survivor when you've been through so much devastation, so profoundly affected by loss and grief. Isolated was definitely something I felt at the end of the '90s. I used to go to support groups and hear what everybody else was dealing with, having AIDS and opportunistic infections. It was uncomfortable because a lot of them were upset or angry or frustrated. I couldn't identify with them, and I couldn't identify with those who were HIV-negative."
Such feelings of isolation are common among controllers, said Dr. Florencia Pereyra of the Partners AIDS Research Center. She established a small support group for controllers in Boston and found that "because they're not on medication and don't have high mortality rates, they feel apart from the rest of the HIV community."
Another common sentiment among them was a desire to be studied. "The question seems to come back to them all the time," said Pereyra: "Why me? What's so special about me?"
To divine the answer, researchers are, among other efforts, probing the body's so-called innate immune system, trying to discern if controllers harbor a defective form of the virus and undertaking an unprecedented study of hundreds of controllers in an attempt to learn if there is anything genetically unique about them.
Human beings have two immune systems, the innate and the adaptive. The innate system is a general response to any incoming pathogen, and it can kick in almost immediately. Its component cells, including some known as "natural killer cells," dismantle viruses, kill off early cancer cells and engulf and eliminate foreign bacteria.
The adaptive system, which is dependent largely on infection-fighting T-cells and antiviral antibodies, is more finely tuned and needs to identify an invader precisely before going into action, a process that takes days or weeks. Thus far, the great bulk of HIV research has centered on the adaptive system.
Researchers at UC San Francisco have assembled a group of 50 elite controllers (including Traywick), and research on them has produced an intriguing discovery.
About half of the elites control the virus, as expected, through a powerful response by T-cells.
The other half shows no such T-cell response.
"The 25 people in our cohort who have no T-cell reaction can provide insight into whole new ways of thinking," says Dr. Steven Deeks, a prominent HIV researcher at UC San Francisco. "There are 25 guys who have no reason for controlling the virus."
Because their adaptive immune systems appear to play little or no part in controlling the virus, they are prime subjects for investigation into the innate immune system.
Since 1984, Dr. Jay Levy, director of the Laboratory for Tumor and AIDS Virus Research at UC San Francisco and one of the first to isolate HIV, has focused on the innate immune system and its unique infection-fighting tools.
In all of the controllers he has tested, Levy found evidence of an effective antiviral protein secreted by certain innate immune system cells. Over the last two decades, he and his team have searched through the thousands of proteins these cells make in the hope of identifying the antiviral protein. They've managed to narrow the number to about 80, but they need to winnow it further.
They've also been trying to identify the gene that causes controllers' cells to express the antiviral protein. Of the body's 37,000 genes, Levy's team identified, through several experiments, eight that look promising; they expect to identify five or six more.
Eventually, they'll introduce the most promising genes into human cells and look for the antiviral protein activity.
Levy is also looking at another tool of the innate immune system, a small number of cells that produce virus-crippling interferon. He has found that controllers have higher numbers of these cells than even healthy HIV-negative people.
Essentially, controllers show that the human immune system is capable of containing HIV naturally, Levy said. "This has been a long time coming, but in my opinion we can look forward to long-term survival without toxic drugs."
Some researchers have theorized that controllers are able to contain the virus because the strain of the virus they're infected with is somehow defective. Although the current belief is that a defective form of the virus does not in itself explain controllers' success — it might even be that the virus is capable of repairing itself — researchers haven't been able to tease the virus out of some elite controllers so that it can be examined for defectiveness.
"Whenever researchers find the virus, it usually looks normal," Deeks said. "But some of the people in whom it can't be found, it may be they were exposed to a defective virus."
To examine every controller for defective virus would be prohibitively expensive, he said. If such a study were mounted, he said, the idea would be "to see if the virus is there and if it is defective, because in theory that virus will give good insights into making an effective vaccine."
One of the problems with studying elites is that there are so few that researchers haven't been able to assemble local research cohorts large enough to study effectively. Now, however, Walker of Massachusetts General and his collaborators hope to collect blood samples from 500 to 1,000 elite controllers and a similar number of viremic controllers, subject them to detailed genetic analysis and compare the findings with those from two groups: HIV-negative people and HIV-positive people in whom the virus has progressed.
Working through AIDS caregivers and AIDS advocacy groups, the Massachusetts General team has amassed 76 elite controllers and 100 viremic controllers from across the country and is funding collaboration with UC San Francisco's cohort of 50 elites and 50 viremic controllers, including Brothers.
"Basically, we want to recruit every single one of these people in the United States," Walker said. "We have to have a large enough sample to begin to see patterns in this population."
He is optimistic that the genetic survey "will show exactly what the mechanisms are that will reveal drug targets that we can focus upon."
While researchers pursue various avenues for explaining his uniqueness, Matt Traywick is trying to put his life back together.
After his two years of homelessness, which included a brutal beating that hospitalized him for more than two months, he is living in Catholic Charities-supported housing, where he shares a bathroom with another tenant and visitors must leave identification at the front desk.
He said he still uses methamphetamine "only every couple of months" and remains sexually active. "I don't always keep myself safe, but I'd never put someone else at risk," he said. "I always disclose. I've never been so high that I didn't remember or think to disclose."
A potential irony of the highest order: Levy's research suggests that the protection provided elite controllers by the mystery antiviral protein fades in about a year after exposure to HIV, so that regular re-exposure might play a role in keeping a controller safe.
In any case, Traywick recently posted a resume on the Internet and has drawn a few interested responses from potential employers.
"For the first time in many years, it looks promising," he said.
He knows he's got to return to a productive life in order to save for retirement.
"I didn't think I'd make it to 30, much less 46," he said. "I never dreamed I'd retire. Now it looks like I might. That's the ultimate joke that God plays on us guys."