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Wed July 18, 2012
HIV Cure Is Closer As Patient's Full Recovery Inspires New Research
Originally published on Wed July 18, 2012 7:30 pm
Ask AIDS researchers why they think a cure to the disease is possible and the first response is "the Berlin patient."
That patient is a wiry, 46-year-old American from Seattle named Timothy Ray Brown. He got a bone marrow transplant five years ago when he was living in Berlin.
Brown, who now lives in San Francisco, is something of a rock star in the AIDS community. He has made himself endlessly available to researchers, who regularly bleed and biopsy him to learn as much as possible about his amazing cure.
"I have sort of a guilt feeling about being the only person in the world who's been cured so far," Brown said in an interview with NPR. "I'd like to dispel that guilt feeling by making sure that other people are cured."
The transplant was to cure leukemia unrelated to his HIV infection. The German doctors gave Brown a new immune system from a bone marrow donor who is immune to HIV by virtue of a genetic mutation shared by 1 percent of Caucasians.
Brown stopped taking his HIV drugs at the time of the transplant. Five years later, he's still free of HIV drugs — and apparently free of HIV. And he's still the only person to be cured of HIV, doctors say, although everyone acknowledges that bone marrow transplantation is not something that could be used routinely for this purpose.
Dr. Steven Deeks at San Francisco General Hospital is following Timothy Brown closely. He's an organizer of a two-day symposium on curing HIV this week in advance of the International AIDS Conference in Washington, D.C.
Until recently, Deeks says, it was virtually taboo to use "HIV" and "cure" in the same sentence.
"It was the C-word," he says. "It was something that we weren't allowed to talk about. We weren't allowed to pursue. I'm not entirely sure why it got to that point."
One big reason is research back in the late 1990s that showed how HIV hides out in certain immune cells. They're called memory cells because they contain a memory of all the infections we encounter in life. They stand ready to attack if a germ reappears.
"HIV has really taken advantage of this very fundamental aspect of the immune system and found a way to essentially hide in these long-lived T-cells," says Robert Siliciano, a professor of medicine at Johns Hopkins University.
Years ago, Siliciano showed that HIV-infected memory cells hang around for 60 or 70 years — basically, a lifetime. But the virus invariably roars to life again as soon as somebody stops taking antiviral drugs.
"People actually began to think this was not going to be a problem that we could solve in the foreseeable future," Siliciano said in an interview.
That's changed. Lately Siliciano and others have discovered that some drugs — such as one that treats alcoholism, another that fights cancer — can wake up the sleeping cells and cause them to spit out hidden AIDS viruses.
The goal is to purge HIV from its secret reservoirs throughout the body. Scientists hoped the memory cells that harbored them would be killed in the process, wiping out the HIV reservoirs. Unfortunately, they were wrong.
"That's been one of the recent discoveries that's been a little bit discouraging," Siliciano says. "Some of the drugs we thought would turn on latent HIV in fact do that, but the cells don't die. Nor are they readily killed by the immune system."
Researchers think it might be possible to make a vaccine that would prime the immune system to mop up infected HIV cells after a drug smokes the virus out. Researchers are also on the trail of drugs that are more efficient at purging HIV.
Other scientists are pursuing a different approach — gene therapy. It aims to re-create the Berlin patient's cure, without a risky and expensive bone marrow transplant.
Gregg Cassin is a human guinea pig in an experiment sponsored by Sangamo Biosciences, a California-based company. His experience provides a tantalizing clue that gene therapy against HIV might work.
Cassin thinks he got HIV in the early 1980s. He didn't start antiviral treatment until his immune cell counts plunged to near-zero. He's watched many friends get sick and die from AIDS while he's remained healthy.
Last year Cassin volunteered for the gene therapy experiment. "I wanted to get into the next exciting thing in research," he says, "and completely by accident, I found out I had one of these mutations, the CCR5 mutation."
That's the same mutation that Brown's bone marrow donor had — the genetic quirk that makes him immune to HIV. But Cassin has only one out of two possible mutations, while the Berlin patient's donor has both. So Cassin is only partly protected. But it may explain why he has survived so many years of HIV infection without treatment.
In the gene therapy trial, researchers took out some of Cassin's immune cells and treated them with a chemical called a zinc-finger protease that knocks out both CCR5 genes. Then they grew billions of these engineered cells and injected them back into Cassin.
After a few weeks, according to plan, Cassin stopped taking anti-HIV drugs. He was off therapy for several weeks. But then he panicked.
"This is the part I feel a little bit bad about, a little embarrassed about," Cassin says. "But my viral load shot up, and I got nervous. So I went back onto treatment."
He may have panicked too soon. Two weeks later, Cassin got the results of his latest blood test, which had been done just before he resumed treatment. It showed the amount of HIV in his blood had started to drop sharply, even without antiviral drugs in his system.
"My body was taking care of it," he says.
Scientists will never know whether his viral load, as it's called, would have continued to drop, as Brown's did after a similar initial spike. That will take many more patients who have more definite and lasting benefits.
The same goes for other would-be cures. Most researchers think in the end the answer will be a combination of approaches.
Meanwhile, Brown is still teaching scientists lessons. Recent research suggests a few of his cells may still contain traces of HIV, or rather, HIV genes. But if that's true, researcher Deeks says it doesn't seem to matter.
"The consensus on what actually happened," Deeks says, "is that he's cured clinically. Whether there's any virus left, we're not sure. But we can't detect anything that can replicate, and his immune system is no longer really responding to the virus. Which to us suggests that the virus must be almost gone."
If so, "almost gone" may be good enough — and that's an important insight. As they say, more research is needed.
I asked Brown if he's going to put up with being poked and prodded for years to come.
"I think so," he says. "Until there's a cure, I'm going to keep working for it. And well, hopefully, one day I won't have to do it any more" because he'll be just one of many cured of HIV.
"That would be nice," he says.
AUDIE CORNISH, HOST:
From NPR News, this is ALL THINGS CONSIDERED. I'm Audie Cornish.
ROBERT SIEGEL, HOST:
And I'm Robert Siegel. The world's leading AIDS researchers will gather in Washington later this week, to talk about how they plan to cure HIV. They think it may be possible to eliminate the virus from infected people, or at least reduce it to levels their immune systems can control. That would relieve patients from having to take potent antiviral drugs for the rest of their lives.
NPR's Richard Knox explains why scientists are so hopeful.
RICHARD KNOX, BYLINE: Ask AIDS researchers why they think a cure is possible, and their first response is the Berlin patient.
(SOUNDBITE OF NEWS CLIPS)
UNIDENTIFIED BROADCASTER #1: These German doctors have witnessed what could be a medical breakthrough.
UNIDENTIFIED BROADCASTER #2: Doctors in Germany believe they have cured an HIV patient, an American man...
UNIDENTIFIED BROADCASTER #3: Who now has entered the scientific journals as the first man in world history to have his HIV completely eliminated from his body.
KNOX: It was a big news story back in 2008. Doctors in Berlin announced they had rid a man of HIV, by giving him a new immune system. It came from a bone marrow donor who has a genetic mutation that makes him immune to the virus. Four years later, the so-called Berlin patient is still a rock star in the AIDS community.
TIMOTHY RAY BROWN: My name is Timothy Ray Brown, and I'm known as the Berlin patient. I come from Seattle, Washington, and moved to Berlin in 1991.
KNOX: Brown, a wiry 46-year-old who now lives in San Francisco, is still free of HIV drugs and apparently, free of HIV. Scientists regularly bleed and biopsy him, to learn as much as they can about his amazing cure. Among other things, they want to understand how the gene mutation in his new immune system is protecting him. Brown has made himself endlessly available for the research.
BROWN: I kind of have - sort of guilt feeling about being the only person in the world that's been cured so far. And I'd like to dispel that guilt feeling by making sure that other people are cured.
KNOX: Dr. Steven Deeks, at San Francisco General Hospital, is studying Timothy Brown closely. Before the Berlin patient, he says, it was almost taboo to use "HIV" and "cure" in the same sentence.
DR. STEVEN DEEKS: It was the C-word. It was something that we weren't allowed to talk about; it was something we weren't allowed to pursue - not entirely sure why it got to that point.
KNOX: One big reason is research back in the late 1990s, that showed how HIV hides out in certain immune cells. They're called memory cells because they contain a memory of all the infections we encounter in life. They stand ready to attack if a germ reappears.
DR. ROBERT SILICIANO: HIV has really taken advantage of this very fundamental aspect of the immune system and found a way to essentially, hide in these long-lived T-cells.
KNOX: That's Dr. Robert Siliciano of Johns Hopkins University. Years ago, he showed that HIV-infected memory cells hang around for 60 or 70 years - basically, a lifetime. But the virus invariably roars to life again, as soon as somebody stops taking antiviral drugs.
SILICIANO: People actually began to think that, you know, this was not going to be a problem that we could solve in the foreseeable future.
KNOX: But lately, Siliciano and others have discovered that some drugs can wake up the virus, and get it to show itself. They want to use these drugs to purge HIV from its secret hiding places. Scientists thought the infected memory cells would be killed in the process, but they were wrong.
SILICIANO: That's been one of the - sort of recent discoveries that's been a little bit discouraging. The cells don't die; nor are they readily killed by the immune system.
KNOX: But he thinks there's a way around that. Maybe a vaccine could prime the immune system to mop up infected cells, after a drug smokes the virus out. However it's done, Siliciano hopes HIV could be eliminated from the body. That would mean never having to take HIV drugs again.
Other scientists are pursuing a completely different approach - gene therapy. They want to mimic the Berlin patient's cure without a risky, and expensive, bone marrow transplant.
PRISCILLA GRACE GONZAGA: All right, so this is the only thing that I'm going to do today. I'm just going to test this.
KNOX: In a nondescript office building in San Francisco, nurse Priscilla Grace Gonzaga is drawing blood from Gregg Cassin's arm.
GONZAGA: Your T-cells went up a little bit, and your percentage went up a little bit.
GREGG CASSIN: What did they go up ...
GONZAGA: Right now, you're at 484. You're...
CASSIN: My God, it'd be nice if they'd continue going up.
KNOX: Cassin is one of several dozen human guinea pigs in one, cutting-edge, gene-therapy experiment.
CASSIN: I wanted to get into what the next exciting thing was in research. And completely by accident, I found out that I had one of these mutations.
KNOX: It's the same mutation that's protecting the Berlin patient from HIV; the one he got from his bone marrow donor. The mutation blocks a door that HIV needs to get into immune cells. Now, the important thing to know is that the Berlin patient got two of these mutations. And it takes two to bar the door completely. But Cassin only has one. In a sense, he's halfway towards a cure.
So scientists wanted to give him both mutations. To do that, they treated some of his cells with a chemical that mutates both genes. Then, they put billions of these engineered cells back into him.
Next, Cassin stopped taking HIV drugs for several weeks - that was part of the plan. Sure enough, just like earlier patients who stopped taking the drugs, the virus woke up and started flooding into Cassin's bloodstream. That made him panic.
CASSIN: This is the - a part that I'm a little - I feel a little bit bad about; a little embarrassed about. But my viral load had shot up, and I got nervous. I went back onto treatment.
KNOX: But he may have panicked too soon. A blood sample drawn just before he started taking HIV drugs again, showed the amount of virus had actually started dropping on its own before he restarted anti-viral drugs.
CASSIN: So my body was going in the direction - my body was taking care of it.
KNOX: It looked like the gene mutations were protecting him. But researchers will never know if his HIV levels would have continued to fall without treatment. In fact, Cassin's up-and-down virus level is a tantalizing clue that gene therapy against HIV might work. To find out, it'll take many more patients who have more definite and lasting benefits.
The same goes for other would-be cures. Most researchers think the answer will be a combination of approaches. Timothy Ray Brown, the Berlin patient, couldn't agree more.
BROWN: I think it's really important that the medical scientists, and drug companies, look for a cure. And I'm pretty sure that it's going to happen.
KNOX: And Brown is still teaching scientists lessons. Recent research suggests a few of Timothy Brown's cells may still contain traces of HIV. But if that's true, researcher Steve Deeks says it doesn't seem to matter.
DEEKS: The consensus on what actually happened in this patient, is that he's cured clinically. Whether there's any virus left, we're not sure. But we can't detect anything that can replicate. And his immune system is no longer really responding to the virus - which to us suggests, well, the virus must be almost gone.
KNOX: If so, "almost gone" may be good enough. And that's an important insight. As they say, more research is needed. I asked Brown if he's going to put up with being poked and prodded for years to come.
BROWN: I think so. Until there's a cure, I'm going to keep working for it. And - well, hopefully one day, I won't have to do it anymore.
KNOX: You'll just be one of many.
BROWN: Yeah, right.
KNOX: That would be nice.
BROWN: That would be nice.
KNOX: Richard Knox, NPR News. Transcript provided by NPR, Copyright NPR.