[Editor's Note: Since we conducted and posted this interview in 2009, there have been many developments in the story of Timothy Ray Brown, formerly known only as the "Berlin patient." In addition to this article, we encourage you to read "Tentative HIV 'Cure' Presents a Guarded Sense of Hope" for an update on Brown's condition as of late 2010, as well as the perspectives of two of our HIV-positive bloggers -- Ibrahim (who is encouraged by Brown's story) and Thomas DeLorenzo (who remains more skeptical).]
Up until now, we've never been able to say that a person infected with HIV/AIDS has been cured. As I said, up until now.
You see, in 2006, something incredible happened in a hospital in Berlin. It was there, thanks to a unique and risky stem cell transplant, that a man may have become the very first person ever to be fully cured of HIV/AIDS.
This man's name has not been released; he's only known as the Berlin patient. But we know he's an HIV-positive American in his 40s who has been working in Berlin. In 2006, he was diagnosed with acute leukemia. In an attempt to treat his leukemia AND his HIV, the man's doctor -- Dr. Gero Hütter -- arranged for him to receive a stem cell transplant from a very special donor.
Ever since that transplant, the Berlin patient has had an undetectable viral load even though he hasn't been on HIV/AIDS treatment since before the transplant. The man has generously allowed scientists to take almost every possible biopsy and test, including the most ultrasensitive HIV tests available, but HIV has not been detected anywhere in his body. It's now almost three years since this operation and HIV still seems not to have reemerged. His story inspires new hope that some sort of gene therapy may be the key to an HIV cure.
Dr. Jeffrey Laurence, the chief scientist at amfAR, The Foundation for AIDS Research, has become the main contact in the U.S. regarding the Berlin patient, and he remains in close contact with Dr. Hütter, the Berlin patient's doctor. In September of 2008, Dr. Laurence organized a fascinating think tank of top HIV scientists to discuss the patient's case. They all agreed that the patient is "functionally cured." In this interview, Dr. Laurence tells us a little about that meeting, and about the Berlin patient's amazing story.
An HIV-Positive American Man in Berlin Needs a Stem Cell Transplant and His Doctor Tries a Daring Experiment
Welcome, Dr. Laurence.
Let's start from the very beginning. Tell us about the patient who appears to have been cured of his HIV.
I've been following this individual, trying to replicate what happened to him in others, for a couple of years now in the interests of research.1
This is a 42-year-old gentleman who's actually from Seattle, from the United States, but who is living in Germany.
He had HIV since about the age of 30, was successfully treated with a cocktail of drugs, and was doing very well with no detectable virus in his blood. His T-cell counts were over 400. He was basically a poster person for the way we can successfully treat HIV disease now. He was doing fine, with no complications.
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Then unfortunately, in March of 2007, at the age of 40, he developed a kind of leukemia -- we call it acute myelogenous leukemia, or AML -- that typically requires a bone marrow transplant. He went to a hematologist, Dr. Gero Hütter, in Berlin and was treated with the standard drugs for this type of leukemia. Seven months later, this patient experienced a relapse of his leukemia. (And that's not uncommon; that happens maybe 50 percent of the time.) This time, he was again given the standard treatment for patients with leukemia who are in relapse. But he was also given what we call a stem cell transplant. It's like a bone marrow transplant, except instead of extracting cells quite painfully, and under anesthesia, from a donor's bone marrow, we just take it from his or her blood.
What was unusual about the particular transplant done on this patient was the extra step taken when selecting the donor. Normally, when locating a potential donor for a person with or without HIV and leukemia, we would go through the worldwide registry of people who had agreed to donate stem cells or bone marrow.
There are about 13 million people who are on this computerized donor list now. The Berlin patient's physician went through the 13 million people and found 232 people who were identical tissue-type matches for this patient. Any one of those 232, if they agreed to come in and donate their stem cells, presumably would have been an excellent match for this patient. But with the patient's approval, the doctor went a step further.
It's known that if you're lucky enough to have this mutation, the delta32 CCR5, from both your parents -- something we call homozygous, technically -- you are resistant to getting infected by most forms of HIV.
The doctor had a great idea. He said, "Why don't we try to do something a little better than that? Why don't we think about curing not only your leukemia with the stem cell transplant, but also your HIV?" The thought there was, let's take all 232 potential donors and screen them for a genetic mutation that would make those cells resistant to getting infected with virtually all known types of HIV.
This is a relatively infrequent -- I wouldn't say rare -- condition, since it's found in somewhere between 1 and 2 percent of white Americans and Western Europeans; in about 4 percent of people from Scandinavian countries; and in no Africans, African Americans or Asians, which tells you something about the genetics of racial splits way back when.2
What is this genetic mutation due to?
The mutation is called delta32 CCR5, and it was discovered about 10 years ago.3 In fact, one of the groups that discovered it did so with funding from amfAR (The Foundation for AIDS Research), an organization that I work with.
It's known that if you're lucky enough to have this mutation, the delta32 CCR5, from both your parents -- something we call homozygous, technically -- you are resistant to getting infected by most forms of HIV.
The transplant was done, and it was successful. About a year later, the patient had a relapse of his leukemia and required a second transplant. Now, in this time, the patient had no HIV viral load and had good T-cell levels despite the fact that his antiviral drugs were stopped.1 His virus didn't come back and his T-cell levels remained high -- that's the miracle of this patient.
Could you explain what the purpose of a stem cell transplant is and exactly what happens during the procedure?
What we're trying to do is kill off all of the leukemic cells in a person's body. Leukemia comes from cancerous white blood cells, and the process of killing off those cells means treating the person with as many drugs that are toxic to blood-forming cells as the person will tolerate.
"And what if that virus were to pop out from hiding, from a latent state, from dormancy? It would presumably be prevented from taking over this person's body again and growing as if he had been newly infected, because the cells that he was given from the donor are resistant to infection by HIV. That's the key part of what we've done here."
In this instance, the person was 40 years old and could tolerate things very well. He was given radiation therapy to his whole body. He was given two immunosuppressive drugs. He was given a serum prepared in a rabbit immunized with human T cells -- like kind of an antibody to kill off a person's T cells. He was also given a multitude of drugs that cannot only kill leukemia cells, but can also kill immune cells.
So he was basically an empty vessel. All of his own stem cells and all of his own bone marrow blood-forming cells were utterly destroyed. If you just left him alone, he would die within a week or two. But this person obviously was rescued, as you need to be, with stem cells taken from the blood of the donor. (Stem cells can also be obtained from bone marrow.)
All of the blood-forming cells in this Berlin patient's body were replaced with donor cells. There was nothing that was genetically identifiable in terms of blood-forming cells -- in terms of T cells susceptible to HIV infection -- that looked like the recipient. It was all from the donor.
As I mentioned, this was a very special donor who had been selected. A Wall Street Journal article was written about this case.4 The article subheading was, in part, "Many Thanks, Sample 61," because of the 232 people that they could have used for this transplant, whose tissue types were perfectly reasonable to give to the Berlin patient -- and they tested every single one of them -- number 61 turned out to have the delta32 CCR5 mutation that would make the cells being put back into the body of the Berlin patient resistant to virtually any kind of HIV we know of.
To answer the question, "What if there's a virus lurking in this person's brain, hair follicle or fingernail?" Whatever you want to postulate? And what if that virus were to pop out from hiding, from a latent state, from dormancy? It would presumably be prevented from taking over this person's body again and growing as if he had been newly infected, because the cells that he was given from the donor are resistant to infection by HIV. That's the key part of what we've done here.
Why Some People Can't Get HIV and an Explanation of CCR5
Some people don't understand how HIV enters a cell. Could you explain that and why CCR5 is important?
Any virus, any bug that you get infected with only does you damage because that bug has gotten inside your cells. If it's floating around not activating anything, not harming anything, it's irrelevant and it's going to get washed out.
HIV gets into critical cells of the immune system -- the T cell, basically -- through two doors. One door is called CD4, and that's why we count CD4 cells. But the critical door is called CCR5. If you don't have CCR5 sitting on top of your T cells, it is virtually impossible for you to be infected with virtually all strains of HIV.1
So, by having this mutant given by this donor, the person's cells are resistant to being infected with HIV. You could ask, "It's a mutation that is found only in about 1.5 percent of Caucasians, 4 percent of Scandinavians. Why is it there? Where'd it come from? Is it harmful?"
We know it prevents HIV, but surely evolution didn't create this mutation just to stop one from getting HIV 100,000 years ago (or whenever it's perceived that Caucasians and Asians separated from Africans in the cradle in Africa).
Truthfully, we don't know why. The hypothesis has always been that there must have been some huge epidemic way back when that was present in Western Europe, in Scandinavia, that didn't occur in Asia and didn't occur in Africa, that wiped out so many people who didn't have this kind of spontaneous mutation.
Therefore, among the people that were left to breed, many, many more of them had this mutation. At this moment, we may never know what that catastrophe was tens of thousands of years ago that could have protected some people that had this mutation, and led to the death of so many others.
The Black Death [bubonic plague] obviously comes to mind, but people have tested the bacterium that we believe caused the Black Death in the 13th, 14th to 15th centuries and it's unrelated to CCR5, so we may never know.
Martin Delaney on a Cure for HIV/AIDS
One of the strongest advocates for an HIV/AIDS cure during the last few years was Martin Delaney, the founder and longtime director of the HIV advocacy/education organization Project Inform. Before his death in late January, we had a chance to talk to him about a cure for HIV/AIDS. He offered interesting insights into the Berlin case and discussed what he thought the chances are for a cure anytime soon.
But anyway, CCR5 is the key door for HIV to get into a cell. And the delta32 CCR5 mutation means the door ain't there. There's no way for the virus to get in. Therefore, it just kind of knocks around helplessly and eventually dies off.
I know people who were exposed to HIV repeatedly, but for some mysterious reason, weren't infected. Have there been any studies to see if such individuals have that mutation?
Absolutely. It was one of the very best things to have come out of a study that the U.S. government started a long time ago called the Multicenter AIDS Cohort Study [MACS]. MACS followed large numbers of predominately gay men in six centers throughout the United States, asking them everything about their lives and testing them at regular intervals.
It was discovered that there was not a small number of men who were having unprotected anal intercourse with people known to be HIV positive, and yet did not become infected themselves over the course of months or many years.
Their blood samples had been stored away, and with their permission, these blood samples were tested for the CCR5 mutation. In fact, some of these blood samples assisted scientists at the NIH [U.S. National Institutes of Health] in discovering CCR5 in conjunction with scientists funded by amfAR.
The disappointing news is that out of 100 people that are like that (i.e., they've had unprotected sex for many, many years and haven't gotten infected), maybe only 5 percent of them are explained by this CCR5 mutation. For the vast majority of people that are like this, we have no idea why they're protected.
So it could be another mutation?
Most of us believe it is another mutation. You can absolutely bet that there are many, many people working through these registries, trying to discover what those other mutations are. There have been a couple of hints, but so far, no slam dunk as with CCR5.
I think this is information that's going to be useful when talking about what a cure would look like and how we're eventually going to get there. It'd be nice to have more than one avenue. CCR5 is basically our major link right now. Hopefully, that kind of research will give us other links.
What Tests Confirmed No HIV Was Present in Berlin Man?
Dr. Laurence, what tests were done to confirm that there was no HIV left in the Berlin man's body?
An article was published about this patient a few months ago in The New England Journal of Medicine.1 Just before the article was published, I organized a think tank sponsored by amfAR at MIT [Massachusetts Institute of Technology]'s Endicott House, where we got together scientists from around the world, including Dr. Hütter, to talk about what additional tests could be done apart from what had already been done in Germany.
For example, in The New England Journal of Medicine article, it mentions that before that transplant, the patient had an undetectable viral load. Of course, he was on drugs. When he was taken off the drugs, he still had an undetectable viral load, but the tests that they were using are the standard kinds of tests that a person with HIV might get when he or she walks into a doctor's office (i.e., tests that can't detect less than 50 copies of virus in 20 drops of blood).
One of the scientists that I invited to this meeting said, "50 copies per 20 drops? I can get less than a third of a copy of virus in 20 drops." So we had that scientist test the patient's blood and it was negative. So there is no virus by the most sensitive ways that you could possibly look for virus.
Did you also give this man an antibody test?
That's very important. His antibody test would be positive. If you vaccinate someone, say, against the measles or polio and test them for antibodies a year or five years later, he or she will be positive for antibodies. But as you start getting on in time from that initial vaccination -- and it's why we give boosters against certain diseases -- the antibody levels fall off. And that's what's happening to this patient.
It has been about two and a half years since the patient has been off of all of his antiviral drugs and had the transplant, and he still has absolutely no detectable virus, either active virus or latent virus.
"I predict that, in a couple of years, his HIV antibody test will be negative."
His antibody levels -- we call them titers -- are declining just the way you'd expect them to if you'd given someone a vaccination against HIV and then looked at the levels of antibodies. They'd be very strong in the beginning, but would weaken if they are not re-exposed to the virus.
We believe this person has no HIV in his body and therefore there is nothing to re-expose him, so the concentration of HIV antibodies in his blood is decreasing. I predict that, in a couple of years, his HIV antibody test will be negative.
In response to the article that appeared in The New England Journal of Medicine, Dr. Jay Levy -- who's an outstanding AIDS scientist from the University of California in San Francisco [UCSF] -- wrote an editorial titled "Not an HIV Cure, but Encouraging New Directions."5 In his editorial, he said the reason he used the title "Not an HIV Cure" is that there's a lot of evidence from a lot of other studies that HIV can be "lurking" around in cells. What he means is we still wonder: "Could it be in the brain? Could it be in the liver? Could it be in the intestine? Could it be in the stomach?"
"He actually had a brain biopsy, in addition to biopsies of his intestines, liver, lymph nodes, bone marrow -- basically, every part of the body that can be biopsied. ... All were negative for virus. There is no virus in this person's body out to two and a half years off of all anti-HIV drugs."
This person, I think I mentioned, had a relapse of his leukemia and needed a second stem cell transplant in an attempt to re-cure his leukemia.1 They used cells from the same CCR5-negative donor. After that second transplant, the patient developed complications from the transplant.
He seemed to go through the first transplant with flying colors, though he had a little bit of liver upset, which resolved. But he had many problems from the second transplant itself, which are not unexpected in people who get two transplants.
One of the problems was that he started developing some mental changes. People worried, "Is it related to the transplant? Could it be related to HIV lurking in his brain?"
So he actually had a brain biopsy, in addition to biopsies of his intestines, liver, lymph nodes, bone marrow -- basically, every part of the body that can be biopsied. The best part in answering the Levy editorial was including his brain. All were negative for virus. There is no virus in this person's body out to two and a half years off of all anti-HIV drugs.
This is certainly a functional cure, in the sense that there is no need for anti-HIV drugs and no decline in the patient's immune system. But I would say that, at this point, with all the tests that have been done by scientists throughout the world that I've arranged to have samples sent to, that this patient is as close to a cure as anyone could possibly document -- apart from if the individual were to die and have every single part of every single body organ tested. There is no virus in this person's body.
amfAR Holds a Think Tank Meeting at MIT
That's amazing. Who were the 10 experts you invited? I think everyone would be curious to see that list.
The first person was Sandra Bridges. She's worked on HIV from the very beginning and helps coordinate research for the Division of AIDS, at the NIH. John Coffin from Tufts University co-discovered the ultrasensitive assay, which can detect less than a third of virus per mL of blood. Mort Cowan, at the University of California at San Francisco, has been working on the gene therapy of HIV for about a decade, and is head of a transplant program there, at UCSF. Steven Deeks, also from the University of California at San Francisco, did a baboon stem cell transplant, probably about 10 years ago, in an attempt to see whether baboon cells, which are resistant to HIV infection, could be used to help the immune system of a young man who had HIV. Dr. Gero Hütter is the physician for the patient. Judy Lieberman, from Harvard University, has spent a long period of time trying to create animal models for a way that HIV and also herpes viruses might be cured by making cells resistant to infection by herpes viruses and by HIV using gene therapy. David Margolis is head of the Department of Infectious Diseases at the University of North Carolina and a long-term AIDS researcher. John Zaia is from the City of Hope, outside of Pasadena, Calif. He heads a bone marrow transplant program there. John has also been working for almost a decade on the potential of stem cell transplants to treat HIV. Dong Sung An is from Irvin Chen's group at UCLA [University of California, Los Angeles]. He's involved in monkey studies related to the use of stem cell therapies in animals as models for curing HIV.
When we do these think tanks from amfAR, there's also staff invited. So Kevin Frost, who's our chief executive officer at amfAR, was in attendance. We always invite one journalist to cover it. The journalist was Pulitzer Prize winner Mark Schoofs. His Pulitzer Prize winning work was related to circumcision and condom use in Africa. [Click here to read Mark Schoofs' articles.]
amfAR Think Tank Attendees
|• ||Dong Sung An, Ph.D.|
University of California, Los Angeles
|• ||Sandra Bridges, M.D.|
Division of AIDS, NIAID
|• ||John Coffin, Ph.D.|
|• ||Mort Cowan, M.D.|
University of California, San Francisco
|• ||Steven Deeks, M.D.|
University of California, San Francisco
|• ||Kevin Frost|
|• ||Gero Hütter, M.D.|
Berlin patient's physician
|• ||Jeffrey Laurence, M.D.|
Senior Scientist for Programs, amfAR
Weill Cornell Medical College
|• ||Judith Lieberman, M.D., Ph.D.|
|• ||David Margolis, M.D.|
Center for Infectious Diseases
University of North Carolina
|• ||Mark Schoofs|
Wall Street Journal
|• ||John Zaia|
City of Hope
Was that a one-time meeting, or is this an ongoing think tank?
That was a one-time meeting, but due to this meeting, my editorial in The AIDS Reader6 and my commentary for amfAR, I started getting calls from transplant programs throughout the United States saying they think they have an eligible patient for this.
So, with amfAR's blessing, a core group of transplanters was created that would make certain that we had the best protocol to treat the next eligible person that had a match. Some people from the group that I just mentioned are on this panel, but I also have additional people from Johns Hopkins University and Harvard.
What's Stopping U.S. HIV Researchers From Working on Experiments Like This?
What's the status of that?
Thus far, we've had two individuals who are virtually identical twins of the Berlin patient; that is, they are 40-year-old individuals who were treated with HAART [highly active antiretroviral therapy] for HIV for many years that unfortunately developed acute myelogenous leukemia and needed, and got, treated with chemotherapy, but will need bone marrow transplants.
Unfortunately, there are two obstacles. The first obstacle is getting a match. The person I was so enthused about here at our own hospital had no matches among the 13 million adult donors that we searched. There were some acceptable matches from our cord blood program, which uses blood from the placenta where you can get stem cells. The trouble is that because you don't get a whole lot of blood from a placenta, and therefore you don't get a whole lot of stem cells, you often need to use two or three of them. The statistical improbability of finding two or three exact matches that will also be delta32 CCR5 negative is just astronomical.
Basically, we cannot find matches for the individuals that we're presented with. The hope is though that somewhere we will find a match.
Why can't you use the people in Germany?
It's a worldwide match, so the German registry's on our registry. However, the tissue-type match has to be exact. Remember, I mentioned that Dr. Hütter initially went about finding a match the way we all do, by searching among the 13 million people in the worldwide registry, and he found 232 acceptable matches.1
"This could never, ever have been done in the United States first. It could be done in Europe because they have a socialized medicine system. No one asked the question who's paying for this."
Had he not been concerned about curing the person of leukemia and curing the person of HIV, he could have used patient number one out of 232. Instead, he set out to test all 232 for the delta32 mutation and then use the person with that mutation. I mentioned before that the odds -- at least among Caucasians, and the vast majority of people who contribute to these banks are Caucasian -- are 1.5 percent.
So out of 232 individuals, statistically, Hütter was bound to find one match with the delta32 mutation, and he did. Number 61 out of 232 was not only an exact tissue-type match, but also had the delta32 mutation.
Our second problem has to do with money. This could never, ever have been done in the United States first. It could be done in Europe because they have a socialized medicine system. No one asked the question who's paying for this. Forget about HIV right now -- if you have leukemia in the United States, and you need a bone marrow transplant, most insurance companies will pay for 10 screens. Some of the more unusual ones might pay for 20 at a time. So you can search through the 13 million in the adult bone marrow registry. If you need to, you can also go through the cord bloods. You come up with a bunch of matches and insurance will pay for calling in the first 10.
The likelihood that you'll find a person who is available is very good.
Usually, we don't even need to go through all 10. But that's not going to help someone with HIV. As I mentioned, Dr. Hütter's patient had 232 matches. They could have taken the first one. He wouldn't have gotten to number 61. He wouldn't have gotten to number 10, certainly not number 20, or 30, or 40. It took him 61 tries. They would have never been able to call in patient number 61 after having had 60 other perfectly good matches.
Couldn't this be done through an NIH or academic study?
"What we really need is a new program for the bone marrow registry in the United States, if not worldwide, where we get permission initially to test for CCR5 in everyone, the way we test for tissue types and several other things that are mandated. If we had information about CCR5 status, we wouldn't have to bother calling potential matches in to test them for CCR5. We would just do this search for free on the computer."
Someone would have to pay for it. Calling the people in takes administrative money. Doing the confirmatory typing test is about 2,000 dollars a pop.
Again, all this is free in Germany. Then there's the CCR5 testing, which we could probably do in an experimental lab for maybe five or six dollars.
What we really need is a new program for the bone marrow registry in the United States, if not worldwide, where we get permission initially to test for CCR5 in everyone, the way we test for tissue types and several other things that are mandated. If we had information about CCR5 status, we wouldn't have to bother calling potential matches in to test them for CCR5. We would just do this search for free on the computer.
What we at amfAR are trying to do is raise funds to do CCR5 typing on tissues that are already in banks that are accessible to us. For example, at City of Hope, they have a registry of about 40,000 available cord bloods. They could all be tested for CCR5 if funds were available. There are many other institutions that have these registries, not all of which are actually in the worldwide registry, in terms of cord blood because it's a relatively new thing that could be tested.
I think to add CCR5 information to the list of things that a potential donor is tested for will take some political will within the transplant community itself. It would be great if we could do it. It's one of the things that we're advocating for at amfAR.
How much money do you need to do this?
To do the simplest thing, that is to just test the available cord blood stem cells that are available through these private banks like City of Hope, we're probably talking about, with administrative costs, at most 10 dollars a pop. If each of these banks has 30,000 or 40,000 samples, then we're talking about 300,000 to 400,000 dollars to screen all of them.
Can our listeners donate to amfAR to get this thing moving?
They can donate to amfAR and designate it for the cure. That would be one of the things that we're looking at. But I don't want anyone to think if they give one dollar that's going to pay for one person's testing; I can't guarantee that. It basically goes towards these kinds of studies, like typing patients for CCR5 and research into trying to move this out of just this one peculiar scenario to "How do we develop this into a cure for everyone?" That's the kind of research that amfAR's talking about and that we'd like people to donate to.
What does it say about the HIV research community in general that this experiment was done by someone who's completely outside the HIV research community? The patient's physician, Gero Hütter, isn't an HIV specialist.
He's a young hematologist. It says a lot about our health care system. It doesn't say anything about our research. Everybody and their brother who has ever heard of HIV knew that this was possible and wanted to do it.
I've had protocols available to do HIV stem cell therapies for almost four, five years. It's just that what you need is the appropriate patient. So it's not for the lack of knowledge. Everyone was waiting for someone who was HIV positive and young, who then developed a disease like leukemia, severe lymphoma or myeloma, and required a bone marrow transplant. That person just happened to walk in the door in Berlin.
That was the first obstacle. You had to actually find the person. Statistically, the likelihood of finding a person like that is one person every two years in Germany.
I've calculated that we should find about 10 people just like that every year in the United States. I've already had three such patients, in just a few months, referred to me.
So we know those people are out there to replicate. The second obstacle has to do with what I mentioned about insurance and the way we screen people.
In Germany, Dr. Hütter was able to go through all of that because he didn't have to worry about doing the extra tissue typing and whether the patient was going to be able to afford it and so forth and the patient wasn't even a German citizen.
In the United States, the way we pay for health care is very different. If you're doing a transplant to cure leukemia, it is perfectly reasonable for the insurance company to then say, "We've had a long history. We know that just paying for the first 10 matches is all you need to do." And they're right.
"Physicians in the bone marrow transplant community are trying to work around some of these rules, trying to see whether we can get CCR5 testing added to the list of other things that people are tested for. When you volunteer to be a donor, rather than just testing your blood type and your tissue type, and testing for certain infections, what if they also tested for CCR5?"
But if we're trying to cure HIV, we need to bring in everybody that's a potential donor to test them for the CCR5 mutation. I haven't tested that with an insurance company, but I'd bet they'd look at it with an askance eye because it's an experimental procedure. As you know, insurance companies don't pay for experimental procedures.
What a tragedy that one of the impediments to a possible cure is structural.
Right, but again, I should mention that this is a cure for the one-in-a-million person.
But it is structural. That is absolutely, positively correct. Physicians in the bone marrow transplant community are trying to work around some of these rules, trying to see whether we can get CCR5 testing added to the list of other things that people are tested for. When you volunteer to be a donor, rather than just testing your blood type and your tissue type, and testing for certain infections, what if they also tested for CCR5? It would add an incredibly small amount to the cost of the work. It's not going to do anything for the 13 million who are already in the registry, but wouldn't it be nice to have that information for the next 13 million that volunteer over the years? That's something we're working on.
Can activists accelerate this process?
Activists can accelerate a lot of things. The last meeting that I had with this group of transplanters was in April. I need to see where we are and how far they've gotten, and then I may ask for your help.
What Is the Most Important HIV Research Being Done Now to Address Finding a Cure for HIV/AIDS?
In your opinion, what is the most important research being done regarding curing HIV?
It's figuring out how we take this proof of concept from one patient and do it on demand.
The ideas are out there on how to do it. Basically, what you need to do is mutate this gene in every single cell that you're going to transplant into a person. What if we just took the person's own cells, or that of the next available donor that walks in the door who happens not to have the CCR5 mutation -- as statistically they won't -- and genetically give them the mutation?
Can we knock out the gene for CCR5? That's called genetic engineering. We're really good at doing genetic engineering in one cell. But the average person getting transplanted is getting a few billion cells, and we have to guarantee that 100.0 percent of those few billion cells all have their genes modified. We could take a few hundred or a few thousand cells, make certain that every single one of them has that gene modified, and then grow them into billions of cells that we can inject back into the patient, but we don't know how to do that.
Some of the physician scientists that I mentioned that I invited to our think tank in September are working on that. They're working on it in mice, and they're working on it in monkeys. With current technology, in a monkey or in a mouse or in a test tube, you can knock out the CCR5 gene in maybe as much as 90 percent of the cells. But we need 100.0 percent of cells to be CCR5 negative, because if even one little cell has the capacity to be infected with HIV and it starts multiplying in your body, that's the end of your cure.
So I think it's partly a technology problem, and that's where research comes in. We know what we need to knock out: CCR5. We have people looking, as I mentioned earlier, for other things that might account for other people being resistant to getting infected with HIV. If we find those changes, we'll have other targets to knock out.
All we need to do now is come up with better technologies than the small interfering RNAs, the zinc finger nucleases, the oligonucleotide reductases, the ribozymes and so forth. All these words for ways that we knock stuff out to get us closer to 100 percent. That's where research is so important.
"This is an important area of research that needs multiple people looking at it from multiple different angles because none of those technologies are 100 percent accurate in knocking a single gene out in 100 percent of the cells."
I have a lot of faith in this kind of research. It's going to enable us to just take cells from the first acceptable donor, as if the patient didn't have HIV, knock out that gene and give it to the patient, and replicate what happened in Berlin.
Who do you think is doing the best research on a cure today in the United States, or in Canada?
It's happening throughout all the universities that I mentioned. I obviously sought to get the best scientists from the best universities, or at least representatives from those groups.
As I mentioned, University of California at San Francisco has projects looking at this. University of California at Los Angeles has projects looking at this. Tufts University has projects looking at this. Harvard has projects looking at this, and so does Duke, and so does Hopkins, and so do we at Cornell Medical.
This is an important area of research that needs multiple people looking at it from multiple different angles because none of those technologies are 100 percent accurate in knocking a single gene out in 100 percent of the cells. We need to come up with either refinements of those available technologies or new technologies. We need as many people working at this as possible, and that's what's happening.
I've been in AIDS research forever. I was actually first author on the paper by the two Nobel Laureates Drs. Luc Montagnier and Françoise Barré-Sinoussi, in which they document their virus as the cause of AIDS.7 It appeared in the same June 1984 issue of The New England Journal of Medicine as Bob Gallo's paper documenting in a large number of people that his virus was the cause of AIDS.8
I'd gone to the Institut Pasteur with about 70 blood samples from young men with unusual diseases whom I had been following since the late '70s -- that was the group Drs. Luc Montagnier and Françoise Barré-Sinoussi tested their virus on.
I've been the first scientific advisor to amfAR since it was formed by Dr. Mathilde Krim and Elizabeth Taylor, back in 1985. So I've seen all of this and many potential hopes.
"A replication of the Berlin patient with a cheap, easily accessible method of doing gene knockouts in stem cells, I think, will be the most widely available cure. But until it can be done in a person's own cells, it's just not going to be widely applicable."
I saw the miracle that HAART therapies are, but we're not going to treat our way out of this epidemic. There's not enough money in the world -- or maybe even will in the world -- to treat every single person that needs it, although people are trying. What we really need is a cure, and with more and more people working on it, I think we're going to get there.
If you were a betting man, what would you bet would most likely lead us to a cure?
A replication of the Berlin patient with a cheap, easily accessible method of doing gene knockouts in stem cells, I think, will be the most widely available cure. But until it can be done in a person's own cells, it's just not going to be widely applicable.
I've gotten phone calls from people saying, "I have HIV. I am so tired of being on these drugs. I don't have leukemia and I don't need a bone marrow transplant, but I want you to search for a CCR5 mutation for me. I'll pay for it. I want to be cured."
I have to tell them that there is a tremendously high death rate from this procedure when you're not using your own cells, but are instead using the cells of an unrelated donor. Upwards of 15 to 20 percent of people die within the first 100 days of the procedure itself. In other words, we only do that kind of procedure, as was done in Berlin, if the person's going to die from his or her leukemia if we don't do the transplant.
So someone without leukemia, or any cancer, is still at risk for death from a stem cell transplant?
Someone who needs what we call a MUD, a matched unrelated donor transplant, has within the first 100 days a 15 to 20 percent chance of dying.
It has nothing to do with their cancer?
It has nothing to do with their cancer. It's related to all that toxic therapy that is given to them -- the radiation, the immunosuppression and the cancer drugs themselves -- that make them susceptible to infections and to other unusual immune disorders that basically kill them.
That's why this is only done in an attempt to cure someone of his or her underlying disease, such as leukemia, lymphoma or myeloma, not HIV.
Clearly, what a cure is going to look like is not subjecting anyone to anything with that kind of a risk of death. A cure is going to involve knocking out these genes in the patient's own cells to remove some of that risk of dying, because the risk of dying from what's called an autologous transplant is incredibly low, on the order of 1 percent or less. So that's the way we need to get at this. Thus far, it's still at the level of research.
So it's being done in the lab, but not in humans yet?
No, there are human studies ongoing in multiple places.
If somebody wanted to join these studies, how would he or she find out about them?
Good question. At the moment, individual universities are recruiting patients. There are cancer registries for stem cell therapies, but I don't know whether the studies that I just alluded to are actually on any national registries.
How does amfAR stay current about this man in Berlin?
Through me because I organized the think tank to describe this patient, helped announce it to the world and organized the distribution of blood samples to physicians worldwide for testing. Dr. Hütter, as I mentioned, keeps in touch with me regularly, including just last night.
Because I've now become a sort of clearinghouse for other patients throughout the United States, I'm staying on top of it for amfAR and for other people interested not only in that patient's progress, but anyone else that might be treated at another university.
You said previously that the Berlin patient is doing well. Does this mean he's working? What is he doing?
After his second transplant, because he had some mental status changes, which are now thought to be related to the transplant, he had to go to a nursing facility for a while. He left the nursing facility several months ago. He's now back home. I don't know if he's back at his job, but as of yesterday, he's feeling well. He has no complaints. For confidentiality reasons, there are certain things that I'm not supposed to know, and so I'm not certain that they're going to tell me where he works, but they might tell me whether he's working or not.
So he's not interested in being interviewed or being public about this?
I've asked that question. I've not spoken to him, but the statement that I was given is that he's considering coming to the United States, and would be willing to give interviews at that point. Dr. Hütter will keep me abreast of that. It was supposed to happen in the spring, but it didn't happen. So he's not giving interviews from where he is now, but there's the potential that he may give an interview in the future.
What Can People Do to Accelerate the Research for a Cure?
It's all very exciting. What could people do to accelerate this research?
Support research. It is the only way we're ever going to have additional treatments and eventually a cure for this disease.
"Stay knowledgeable about this disease. Don't let it fall off the radar map. Too many people think that since we have drug therapies that permit many people an almost normal lifespan, this is over and we can move on to the next cause. But it's really not like that. There are serious side effects of the drugs that we have."
Stay knowledgeable about this disease. Don't let it fall off the radar map. Too many people think that since we have drug therapies that permit many people an almost normal lifespan, this is over and we can move on to the next cause. But it's really not like that. There are serious side effects of the drugs that we have.
If we haven't stopped this disease everywhere, then we've stopped it nowhere. It's really important to eventually cure it everywhere. It's very important to advocate for a vaccine because we've never ever stopped any viral epidemic through treatment alone. It's always required a vaccine. And vaccines are going to be incredibly difficult to develop in HIV.
So stay active. Make your friends and your legislators interested and aware of the fact that you're still interested.
amfAR provides grants to researchers to continue their research?
After the discovery of this patient, did amfAR's priorities change and shift? Is more money now being allocated towards finding a cure?
Finding a cure has always been a priority for amfAR; that is one of the reasons why this think tank was formulated. The impetus was the Berlin patient, but we've had several RFPs (requests for proposals) based on the cure for many, many, many years now. So this has supported the idea that finding a cure is an important mission for amfAR and it has fortified plans that we've already had in place to seek out more and more applications looking for ways to approach the cure.
I'm not one to speak about exact dollar amounts and so forth. It's a priority of amfAR's is the best way that I can put it. And amfAR is meant to mean cure. Whenever our chairman of the board, Kenneth Cole, gives a talk about what amfAR stands for, and what amfAR does, he says "amfAR is looking for a cure," and it's true.
Given the structural problems we have in the United States, why not just have a lab in Europe do this work, and have amfAR support that? Why not just go where we could do it easily?
amfAR supports research throughout the world. In fact, in terms of looking for ways to approach the cure, a significant fraction of the grants we gave out were in Europe and Australia. We are totally international in terms of who we fund.
But it's not the lab. It's the permission to get the patients in. Germany has a health care system that'll cover German residents, not someone in New York City. The world doesn't work that way.
You could ask the question, "If I were a person with HIV and acute leukemia, and I couldn't get my insurance to pay to find a match with the CCR5 mutation, should I move to Germany, find out what their residency requirements are and have my transplant there in an attempt for a cure? But that requires the luxury to do those kinds of things. People with leukemia alone, forget about HIV, are often quite ill. You put them in remission and then you're in a race to find an appropriate donor and to treat them.
The person in Berlin had the luxury of waiting. It took three months from the time that they did the computer screen that found the 232 probable matches, to the time they found patient number 61. If the patient hadn't been able to hang on for three months, then they may not have found patient number 61.
If you're sitting here in New York, and you're ill, you may not be capable of finding a doctor abroad, finding out what residency requirements there are, meeting those residency requirements, and waiting for them to find an appropriate donor while you hang on, hoping that your leukemia doesn't come back. That's not the way it's going to work.
If this is going to work in a system as rich as the United States, you have to go back to the discussions we had earlier. If this is a priority, then why not do a CCR5 test on the next person volunteering to donate his or her blood or bone marrow (maybe donors would even be interested in finding out whether they're one of the lucky few that have this mutation), and add that information to the registry? This way we don't have to worry about moving to Europe or waiting here, instead it'll be right there in the computer system, and I can access it from my desk the way we access tissue type, blood count and everything else.
So you're one meeting away from this potentially happening?
I'm one meeting away from finding out what's happened since the last meeting where we discussed looking into uncovering what additional impediments are preventing us from finding a cure, and what we need to do to make the cure a reality. So if you call me in a couple of weeks, I'll give you an update.
Great. Thank you so much, Dr. Laurence. This has been incredibly enlightening. And thank you so much for your work in this area. I hope people listening to this will donate to amfAR and other places to help continue this very important work.
This transcript has been edited for clarity.
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