August 18, 2006
Bonnie Goldman interviews noted HIV researcher Bruce Walker, M.D., about his efforts to recruit patients for a study on HIV-positive "elite controllers," and long-term nonprogressors. Dr. Walker hopes his research can open a new door to the development of an HIV vaccine. Also see The Body's interview with Loreen Willenberg, one of the elite controllers Dr. Walker has recruited for his study.
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The study is the "HIV Controller Consortium Study." What we're trying to do is to understand why some people are able to control HIV and have it not be a problem. The basic, bottom line is that we're ultimately looking for a vaccine that will protect people from becoming infected. We don't have that [right now]. The next best thing would be a vaccine that protects against disease progression. There are some animal model data that suggest that this is a realistic goal.
The next question is: What viral load would we be aiming for, if people are going to [continue to] become infected? If you think about what you want from a vaccine -- in order to end the epidemic -- you want people who are infected not to progress; you want them not to transmit to anybody else.
Then, the question is: Is there a [certain] viral load that would predict non-progression and non-transmission? That viral load is about 2,000 copies. There's a much-diminished, although by no means zero, chance of progression with viral loads that low. There's also a much-diminished risk of transmission to somebody else. Again, by no means zero, but much less. This suggests that 2,000 copies is what we should aim for.
Now, it turns out that there are people walking around that are doing just that [on their own] -- some of whom have been doing it for 28 years and counting.
Is 28 years the longest that someone has been what you call an HIV controller?
It's the longest that we know of -- this is going back to banked specimens in San Francisco from the late 1970s. The first documented sero-conversions of patients that we're still following come from around 1978, 1979. A very small fraction of those individuals are actually alive, well, have never been treated and have normal CD4 counts. What we're trying to do is understand what it is about this select group of people that can control the virus. We're not talking about long-term non-progressors. Long-term non-progressors are probably about somewhere between two and five percent of HIV-infected individuals. It's always been a very variable definition, based on duration of infection and CD4 count.
What we're talking about here is something that's based on viral load. We're asking: Who is it out there that can control the virus to a very low level that predicts non-progression and predicts non-transmission? That's really the focus of the study. We term these people "elite controllers." They are people that have viral loads of less than 50 copies, persistently, without therapy. And the other [group], we call "viremic controllers," people with viral loads of less than 2,000, persistently, but greater than 50.
In Boston, we already have, with the help of TheBody.com and other organizations, physicians in private practice; we have [also] recruited about 100 such individuals. What we know from our studies thus far is that the things that we're measuring right now are not giving us the answer. That prompts the question of: How do you formulate the question differently? What else can we do to try and understand this extraordinary outcome? What we can do is to basically capitalize on the advances that came from the human genome project, to take a much broader look at this and understand what the genetic basis of this is, by doing a haplotype map.
What does that mean? That means we need to identify about 1,000 individuals who are elite controllers, and about 1,000 individuals who are viremic controllers. The reason for the large numbers is that there's a lot of genetic heterogeneity [differences] in the human population, so there's a lot of noise in the system. You have to get to large numbers [to find the similarities].
We're collaborating with the Broad Institute [of Harvard University and MIT], and with dozens of institutions across the country, plus institutions in Canada, South America, Australia, Africa, Europe, as well as hundreds of health care providers, to help identify these patients.
Plus, we're trying to get patients to self-identify themselves to us in a confidential way, because many of these people are not in care right now. They have never been sick. They have normal CD4 counts. We think that most of them probably know their viral loads. In fact, we estimate that there are at least 2,000 [elite controllers] in the United States, the frequency being about one in 300 infected individuals. We want to find half of those.
We have [started to find them] through our collaboration. Through this HIV Controller Consortium, we now have 100 [people] from Boston, 50 from Dr. Steven Deeks [from University of California] in San Francisco, and probably at least another 50 from other collaborators that have come on board. We're going to need to find about 800 [additional] patients that are not currently part of any cohort. It makes sense, actually, that most of these patients wouldn't be part of [any] existing cohorts because they are not sick, they haven't qualified for any studies, and so we're faced with the challenge of trying to identify people.
Where are they? Well, they would not have necessarily gotten referred to an academic center. They'd still be with their primary care doctors who, in large part, have said to the patients that we've recruited, "I don't know what's going on, but count your blessings and I'll see you in a year. We don't need to worry about the HIV infection." We're asking those people now to help us answer this question.
What's the process? How would somebody get involved?
The process of getting involved would be to basically contact the Consortium through myself, or Rachel Rosenberg, who's here with me. We would then get in touch with them. They could either do this through their doctor or through their nurse. We send a box with all the materials [needed] to get informed consent and blood specimens. Those get Fed Ex-ed back to us and we do the work in our laboratory. We're trying to make it relatively painless for patients.
How many blood specimens are required?
Only a one-time blood draw. If people want to be involved in a longitudinal way, we welcome that, because we'd like to look at this over time, as well. But really, they only need to do this once. And it's entirely confidential. People do not need to disclose their status [to the world] in order to be part of this. They have to disclose it to us, and we need to have some clinical information, in terms of what their viral loads and CD4 counts are. We require a documented year-long period with no treatment, and viral loads that fall into these categories.
What are you going to do once you get the specimens? What's your plan?
Our plan is to do a study where we link functional genomics -- where we basically do functional genomics. This means that we're going to do a haplotype map [a mapping of alleles in the human genome], where we try and understand what is the signature genetic sequence that predicts this outcome [of someone being able to control HIV naturally]. [We'll] try and understand the function of whatever that gene, or genes, may be. Then, at the same time, look at the immune function in these individuals to try and link the baseline genetic code with actual functional measures of immunology.
How come it has taken so long for someone to decide to do this kind of study?
I think a lot of us have already been involved in these studies. We thought initially that we would get an answer by studying 10 or 20 patients. What we realize now, from studying close to 100 patients, is that we're not getting an answer.
At the same time, there's been tremendous evolution in the scientific field with the publication of the human genome, with the development of high-throughput genome sequencing mechanisms. We really have come to a new and unprecedented opportunity here to ask the question about HIV disease in a very different way.
I understand there's going to be a Nature magazine article published about this. Is this something that you have written?
This [article] is embargoed. Yes. There is something that's coming out in Nature next week that relates to this story, in terms of beginning to understand what is going on that's allowing some people to coexist with the [human immunodeficiency] virus, the way we coexist with many other viruses.
How many people are in the consortium in the United States?
We have probably 25 different institutions that have signed up now, and probably at least 100 providers -- probably closer to 200 providers -- that are part of it.
What does it mean to be part of it?
To be part of it means to be involved in finding patients, recruiting them or to be involved, actually, in specific studies related to this.
How long do you think it will take to recruit your desired 2,000 patients?
Well, we want to set the bar high for ourselves, so I would hope that we could recruit these patients in six months. That's going to be a huge challenge, but there's no reason -- if we can get the word out, and if there really are 2,000 people walking around in the U.S. that know their status, we have now ramped up to where we can do this in six months. Time is really of the essence, given the epidemic and where we are with it, and where we are with [the] progress thus far, in terms of bringing the epidemic to an end.
Thank you very much for taking the time to talk to me!
If you are a person with HIV or a medical professional interested in participating in the HIV Elite Controller Study, please contact Rachel Rosenberg, Research Assistant, at 617-726-5536, or click here to send an e-mail. You can also click here to visit the study's Web site.