July 15, 2013
This past March, the 20th Conference on Retroviruses and Opportunistic Infections (CROI) brought an unprecedented flurry of mainstream interest in potential HIV cure strategies. TheBodyPRO.com's Nelson Vergel sat down with leading HIV cure research activist Richard Jefferys for an update on current important aspects, and controversies, in HIV cure research. Jefferys, who coordinates the Basic Science Vaccines and Prevention Project at Treatment Action Group in New York City, is at the forefront not only of gathering data and information from different studies, but also of educating other activists on the new language of immune-based therapies. Read Part One of this conversation.
Let's go into the different issues around cure research. What do you think are the most exciting or promising areas of cure research right now? Can you explain the different concepts that are out there being explored?
Gene therapies historically have sounded kind of space age and exciting, but they have been slow to deliver on that promise. Increasingly, there are signs of progress with gene therapies in a variety of arenas. I think they remain one of the most promising-looking approaches in cure research. There is a certain amount of skepticism about them because of the fear that they would be very difficult to implement and possibly very costly. But I think that can't be used as a reason not to pursue their full potential because, obviously, if there was a breakthrough in gene therapy, then at least that would be something to work on in terms of making it more accessible and user friendly. There are approaches that people are looking at to try and use gene therapy to insert genes into cells that will protect them from HIV infection.
One of the reasons that I think this is potentially particularly important in HIV is because of the almost unique targeting of the CD4+ cell by the virus. The CD4+ cell's job is to coordinate the immune response to things like viruses. So the body is walking a really difficult tightrope with HIV, because the cells that are key to mounting a response to it and coordinating the various parts of the immune response to the virus are the cells providing the virus with a place to replicate. Even if CD4+ cells don't die, the virus is replicating in them and it inhibits their ability to do their job. Although there are approaches like therapeutic vaccines that might boost the CD4+ response to HIV, it's unclear how much benefit they can offer unless that CD4+ is also protected from infection.
So, there are things like Sangamo BioSciences Inc.'s gene therapy, which is trying to protect CD4+ cells by knocking out the CCR5 coreceptor and they are using infusions of modified CD4+ cells. There are also other researchers looking to use stem cells to transfer the modified cells, including the group of Hans-Peter Kiem, M.D., at the Fred Hutchinson Cancer Center -- also one of the Martin Delaney Collaboratories -- and Patrick Younan, Ph.D., from this group presented a very small study of just four macaques that have received a gene therapy to protect their CD4+ cells, and they seemed to do pretty well against a challenge with an SIV/HIV hybrid virus. Their CD4+ cell responses to the virus showed very high levels of the gene modification, suggesting that their ability to resist infection had actually allowed them to do their job of coordinating the immune response to the virus much better. So there's a basis to hope that gene therapies could have similar effects in people.
Although there was only one presentation that I noticed on the Sangamo gene therapy at CROI, there is longer-term data due from those studies and studies that they've done in people that might be particularly able to benefit from the therapy because they are heterozygous for the CCR5 delta32 mutation (they have one mutation instead of the two required for protection). So I think that's something to look forward to and I hope that it becomes available soon.
Any other approaches or combinations of approaches that you think are promising?
Another idea that's out there -- but nobody has actually done experiments, even in animals yet, to demonstrate whether it would work -- is this idea of combining an anti-latency approach with a vaccine that would help the immune response clear the latently infected cells that are expressing virus. That's definitely worth pursuing. There was talk about that idea at CROI, but I think studies are only just now being planned to look at how well that might work in animals and people.
What do you think are the main barriers to accelerating HIV cure research? How can a regular patient that wants to get involved help in any way possible?
I think there's reason to be concerned about the impact of the sequester on research funding and the funding that goes to networks like the AIDS Clinical Trials Group, which has a bunch of protocols in development that seem to be progressing pretty slowly, at least from an outside prospective. A further hit in terms of funding for those studies is not going to improve that situation. There are trials of molecules like the PD-1 inhibitor that might have benefits that have yet to get under way; those are going to be important studies, I think.
The other issues that people are working to address are making it easier for companies that could have uses in cure research to be able to collaborate with academic researchers to explore the potential of those compounds in ways that won't somehow negatively impact the company that needs to stay afloat to keep making the compound.
There are also regulatory issues, and I believe that the FDA is looking to have dialogues with community representatives about risk in cure research studies. There's a meeting due to be announced in the federal register, to take place in June, which will be open to people who want to weigh in on those kinds of issues.
I think animal research is another issue -- money comes into play there, also the availability of regimens that can suppress SIV, as well as the regimens that suppress HIV in people. There's still a bit of uncertainty as to exactly how best to do that and whether there should perhaps be a more coordinated, larger, systematic kind of effort to standardize animal models that will allow testing of different interventions in ways that will make it easier to compare the results because they will use the same model.
On the other hand, there are groups of people that worry a little bit about prematurely standardizing models that may not be ideal, which is something that has happened in the past in HIV vaccine research. For example, where people adopted a system that turned out to actually not be very relevant to what happens in people.
As you well know, many people are familiar with the case of Timothy Brown, the "Berlin patient." He seems to still be healthy and they haven't really seen or detected any rebound or RNA or DNA of the virus. Are there any other studies that are trying to replicate what happened to Timothy, and see whether or not other patients with malignancies or lymphoma or cancers and HIV can also be cured? Can you tell us whether or not those studies are currently enrolling and what we are expecting or hoping for from those studies?
There was one very small bit of good news about Timothy Brown at CROI. It was from a study looking at what they call lymph node fibrosis, which is something that happens in people with chronic infection. It's particularly bad in HIV where the lymph tissues become kind of scarred by the inflammation and the immune activation that's going on. Even elite controllers have more of this kind of fibrosis of their lymph tissue than uninfected people. But it turns out that Timothy Brown, in his gut lymphoid tissue, his level of fibrosis is exactly comparable to the HIV-uninfected people that they looked at in the study. So that's encouraging, because it suggests that even if those bits and pieces of viral genetic material that were reported to have been found in his system last year were real findings and there are some bits of genetic material there, it really doesn't seem to be doing the bad things that it does in people that are infected. So I think it's going to further support the idea that he really is cured of the infection.
In terms of trying to duplicate the case, there was some bad news at CROI. There's a company called StemCyte which has been banking a type of cord blood stem cells for use in stem cell transplants for people with malignancies. They've been doing that actually since 2001, way before the Timothy Brown case, and they are making those stored units of CCR5-negative cord blood available to people. At CROI, there was a poster presentation about the first two people with HIV that needed transplants for cancer that accessed those units; unfortunately, the first recipient of the CCR5-negative stem cell transplant from the repository relapsed and died from the underlying disease two months after the procedure. There was some evidence that the viral level decayed quickly, but he had complications from both the procedure and the cancer and didn't survive. So that was bad news.
There was also another individual in Madrid who received normal CCR5-positive cord blood units because there were some concerns about the viability of the CCR5-negative cells. So that individual happily is in remission for the cancer, but because it was a CCR5-positive sample, it doesn't seem to have cured the HIV infection.
There are also some patients in Boston that they keep mentioning in meetings I have attended.
Yes, the two individuals in Boston are different in that they also received CCR5-positive (not resistant to HIV infection) stem cell transplants, unlike Timothy Brown, but they remained on HAART during the procedure. They have undetectable levels of HIV reservoirs. The study about them has been published in the Journal of Infectious Diseases. There is some hope that perhaps being on antiretroviral therapy during the transplant that they received for their cancers has prevented HIV infection of their new, transplanted immune system and that they may also be cured, but there's no way of knowing for sure until the antiretroviral therapy is interrupted. They have now got permission to do those studies, but I don't think they've happened yet.
[Editor's note: The two Boston patients have since stopped antiretroviral therapy and showed no signs of detectable virus after being off treatment for eight and 15 weeks, according to data presented at IAS 2013.]
There is also a big, ongoing trial in the Cancer Trials Network in the U.S. that is being led by a doctor at Johns Hopkins, Rich Ambinder, M.D., and it's for people with HIV with cancers that need stem cell transplants. Part of the protocol is that they will search for CCR5-negative potential donors for those individuals to try and duplicate what happened with Timothy Brown. I don't know whether anybody has been successfully found a donor in that study as yet.
How about therapeutic vaccines? Anything exciting -- even in monkeys -- when it comes to actually giving somebody who is infected a vaccine to help them control the virus without drugs? I hear buzz about Louis Picker's, M.D., data a lot.
Probably the most amazing-looking vaccine in monkeys has been created from cytomegalovirus [CMV], a type of virus that's quite common in people and most of the time it doesn't seem to have obvious untoward effects, at least until old age. There's a researcher named Louis Picker who's made a vaccine against SIV using CMV as the vector, and it reliably allows half of the monkeys that receive it to control highly pathogenic challenges with SIV. At CROI, he presented evidence that -- actually, I think it was maybe five or six animals that received the vaccine and were exposed to this high dose of pathogenic virus, and they initially controlled the infection to very low levels. But over time what seems to have happened is they've actually cleared the SIV infection, which has never been reported before.
The evidence that he presented to try and support this idea that they've cleared the infection is that they took very large numbers of white blood cells, 50 or 60 million, from these animals and tried to see if they could transmit the infection to an uninfected animal. They showed that in animals that had their virus suppressed by antiretroviral therapy or in rare animals that are like elite controllers, they could take these samples and use them to infect other animals very easily. But from these vaccinated animals that seemed to have cleared the infection, when they took these large volumes of cells and infused them into uninfected animals, they did not transmit the infection. So that's really quite a remarkable result. He reported that it was associated with these very unusual CD8 T-cell responses that responded to a lot of different parts of the SIV and seemed incredibly effective at eliminating infected cells.
If that can somehow be translated into people, that would obviously be exciting. There is ongoing work now trying to develop that CMV vector so that it can be safely used in people. I believe that's in collaboration with the Vaccine and Gene Therapy Institute in Florida.
We hear some people saying, "Well, people are not monkeys. We cannot extrapolate data from a monkey SIV study to predict what would happen in humans with HIV." What do you tell those people, and how do you actually convince them that this work using SIV in monkeys is important?
I think it's a reasonable concern. There are limitations to any model. If anything, perhaps SIV in macaques seems to be harder for their immune systems to deal with than HIV, so it's a very stringent model. Really, what people are trying to use it for is to define the best approaches that are also not dangerous that can be tried in people without something disastrous happening, which is obviously not something you want.
Having said that, there are trials that are looking at approaches like therapeutic vaccination in people. There's a company called Profectus Biosciences, which is developing a trial using their HIV vaccine as a therapy. I think Tae-Wook Chun, Ph.D., one of the main reservoir researchers from the NIH, is involved in that study to look at the impact of the therapeutic vaccine on the HIV reservoir. So it's not always necessary that monkey studies precede the human trials; they can also happen in parallel and help cross-reference in terms of what's relevant and what might not be, so that people can refine the systems to make them as relevant to people as possible.
Thank you so much for being a great research activist and educator to some of us trying to learn the new language of HIV cure research.
This transcript has been lightly edited for clarity.
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