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Specialists highlight recent advances, obstacles in HIV functional cure

Recent breakthroughs in HIV have indicated that a cure is possible. Still, there are many obstacles to overcome.

Despite the successful stem cell transplant that “cured” Timothy Brown, or the Berlin patient, of HIV, researchers suggest this technique is not feasible for all patients with HIV and similar attempts have not reached the same result.

Today, multiple approaches to finding a cure are being investigated. Infectious Diseases News asked four prominent scientists in HIV research to discuss their own methods and contributions toward the eradication of HIV as well as the challenges they continue to face. The following commentaries were excerpted from videos featured on Healio.com/ID.

James A. Hoxie, MD University of Pennsylvania

“Cure” is a powerful word. I gave lectures to medical students for over 20 years, and “cure” was never in the lecture. All of this changed dramatically with Timothy Brown. We cannot think of this as a realistic approach to carry out on people living with HIV infection now, but what this amazing story and courageous man did for the field was tell us that it is no longer a question whether HIV can be cured, the question is how to do it. As one person who gave a lecture said, “You only have to hear one talking dog to know that dogs can talk.”

There are approaches to engineer the immune system to control the virus [and] approaches to use powerful new antibodies that are extremely potent in killing or preventing HIV infection and possibly even in attacking the cells that harbor the virus. Some of the big obstacles that investigators face is trying to understand where the virus is, how it’s hiding, [and] why it can lie asleep for so long. Now that we can use the word “cure” in this field, we do have a rational way to go about addressing these questions. The field, in many ways, is probing this creatively and collaboratively, which is exciting.

For those of us in this field and especially those of us who have been there from the beginning when HIV was a new disease and we didn’t have any drugs — look where we are. We feel empowered by what we’ve accomplished, and that can only make us hopeful for what is ahead.

Janice E. Clements, PhD John Hopkins University School of Medicine

Cure research is all about trying to reactivate latent genomes such that the virus doesn’t spread. By reactivating the virus, the cell would be killed either by the immune response or by the virus, and that would result in a decrease in the number of latently infected cells. The estimate is that we have to reduce the level of the reservoir by 1,000- to 10,000-fold, so it has to be beyond the level of our current technology to measure them, but we’re pushing our assays and developing assays to be able to increasingly measure smaller and smaller reservoirs.

There are many approaches to cure, and I think this is the way it has to be approached ... because we don’t know what will work. [My lab] works in animal models. In the last 6 months, we found a combination of two drugs that work at different points in the virus activation process that can activate the virus. The drugs ... activate the protein kinases and phosphokinase pathways so that the virus gets reactivated transcriptionally. When we measured the reservoir, we did see a sevenfold decrease in the viral reservoir in resting CD4 cells, so that is a real success. Sevenfold isn’t enough ... but it’s a step. We only gave [the animal models] two 1-month treatments of the drug therapy, so [we may have to] give repeating treatments and multiple different combinations of drugs. Other targets right now are altering the epigenetic status of DNA by changing histone acetylation. The strategy is to use multiple places in maintaining latency to then reverse latency and get activation.

Daniel R. Kuritzkes, MD Brigham and Women’s Hospital

One of the studies that helped contribute to our understanding of the complexities that surround the search for a cure was work we did at Brigham and Women’s Hospital with my colleague Timothy Henrich, [MD]. Two patients with lymphoma received stem cell transplants, except in their case, the cells they got were from patients who had wild-type cells. These patients continued on antiretroviral therapy throughout the course of their transplant, which is in contrast to what has been done in most centers where treatment is interrupted. We noticed after the transplant that not only was there no virus in their bloodstream, which is what we would have expected, but we couldn’t find any hints of provirus or integrated virus in their circulating cells.

We decided that it would be appropriate to attempt a very carefully monitored treatment interruption to see whether in fact the virus had completely disappeared. The first patient came off therapy and was doing fine after a couple of months, with no evidence of viral rebound ... so we went ahead and interrupted the second patient. Unfortunately, after about 12 weeks, the second patient experienced a rapid rebound in their virus [and] went back on therapy. The first patient continued to be virus-free, but also rebounded after about 8 or 9 months.

Although these results are disappointing on the surface ... we learned some very important lessons from these two patients. The most important of which is that it can be very difficult, almost impossible, without doing a treatment interruption to know you have actually eradicated HIV. The good news in the study was that it appeared that the reaction the donor stem cells had against the patients’ own lymphocytes was actually eliminating HIV-infected cells. That tells us something important about the role that the immune system could have in helping to eradicate persistent HIV.

I think what we’ve learned is that there is every reason to be hopeful, given the new tools that are being discovered and the technologies that are now available to us, that we have a real chance of developing an HIV cure, but we’re clearly just at the earliest stages of this research. I would guess it will be at least a decade before we have anything approaching a cure.

Joseph J. Eron, MD University of North Carolina School of Medicine

Much of the research that we’re doing is trying to poke the virus [to] make it show itself so that somehow the immune system can clear it. That’s a critical step. The second critical step is to boost their immune system [so that it is] a little more aware of HIV so they can clear those infected cells. We’re doing one very clever study, led by Cynthia Gay, [MD, MPH], and David Margolis, [MD], where they actually take [out] a patient’s infection-fighting cells, educate them, get them to kill HIV-infected cells better and then infuse those cells back into patients.

An issue that I’ve heard discussed quite a bit is that cure might be very expensive. It will be expensive in the beginning, and it won’t be available to everybody, but this is how medicine works. We achieve a goal by curing HIV or curing cancer and then we try to scale that. We try to learn from what we’ve gained and make it more affordable [and] more available. I appreciate the goal is not to cure a few people in a developed country like the United States or developed countries like in Europe. The goal, eventually, is to have a cure that can reach everyone ... not just people in resource-rich settings.

I think it’s important to remind people that [finding a cure] is a really long process. When I speak to patients, I like to talk about getting to the moon. We made it to the moon, but the first thing we had to do was get out of the atmosphere. That’s kind of where we are with HIV cure research. If you think about those astronauts, they knew they weren’t ever going to the moon. They knew that they were contributing to something that would take awhile to build over time. The patients who are volunteering for these studies are really doing something that is giving of themselves. Maybe in 5, 10 or 15 years, we’ll get close enough to a cure that they’ll be able to benefit, but a lot of them are volunteering their time [and] taking some risks for a process that really is going to take a long time.

Disclosures: Eron reports financial relationships with various pharmaceutical companies and is an investigator on several studies with the NIH for which he receives financial support. Kuritzkes reports consulting for HIV therapeutics development for Bristol-Myers Squibb, Gilead Sciences, Merck, Teva Pharmaceuticals and ViiV Healthcare. Clements and Hoxie report no relevant financial disclosures.

To watch the videos, click here.

Recent breakthroughs in HIV have indicated that a cure is possible. Still, there are many obstacles to overcome.

Despite the successful stem cell transplant that “cured” Timothy Brown, or the Berlin patient, of HIV, researchers suggest this technique is not feasible for all patients with HIV and similar attempts have not reached the same result.

Today, multiple approaches to finding a cure are being investigated. Infectious Diseases News asked four prominent scientists in HIV research to discuss their own methods and contributions toward the eradication of HIV as well as the challenges they continue to face. The following commentaries were excerpted from videos featured on Healio.com/ID.

James A. Hoxie, MD University of Pennsylvania

“Cure” is a powerful word. I gave lectures to medical students for over 20 years, and “cure” was never in the lecture. All of this changed dramatically with Timothy Brown. We cannot think of this as a realistic approach to carry out on people living with HIV infection now, but what this amazing story and courageous man did for the field was tell us that it is no longer a question whether HIV can be cured, the question is how to do it. As one person who gave a lecture said, “You only have to hear one talking dog to know that dogs can talk.”

There are approaches to engineer the immune system to control the virus [and] approaches to use powerful new antibodies that are extremely potent in killing or preventing HIV infection and possibly even in attacking the cells that harbor the virus. Some of the big obstacles that investigators face is trying to understand where the virus is, how it’s hiding, [and] why it can lie asleep for so long. Now that we can use the word “cure” in this field, we do have a rational way to go about addressing these questions. The field, in many ways, is probing this creatively and collaboratively, which is exciting.

For those of us in this field and especially those of us who have been there from the beginning when HIV was a new disease and we didn’t have any drugs — look where we are. We feel empowered by what we’ve accomplished, and that can only make us hopeful for what is ahead.

Janice E. Clements, PhD John Hopkins University School of Medicine

Cure research is all about trying to reactivate latent genomes such that the virus doesn’t spread. By reactivating the virus, the cell would be killed either by the immune response or by the virus, and that would result in a decrease in the number of latently infected cells. The estimate is that we have to reduce the level of the reservoir by 1,000- to 10,000-fold, so it has to be beyond the level of our current technology to measure them, but we’re pushing our assays and developing assays to be able to increasingly measure smaller and smaller reservoirs.

There are many approaches to cure, and I think this is the way it has to be approached ... because we don’t know what will work. [My lab] works in animal models. In the last 6 months, we found a combination of two drugs that work at different points in the virus activation process that can activate the virus. The drugs ... activate the protein kinases and phosphokinase pathways so that the virus gets reactivated transcriptionally. When we measured the reservoir, we did see a sevenfold decrease in the viral reservoir in resting CD4 cells, so that is a real success. Sevenfold isn’t enough ... but it’s a step. We only gave [the animal models] two 1-month treatments of the drug therapy, so [we may have to] give repeating treatments and multiple different combinations of drugs. Other targets right now are altering the epigenetic status of DNA by changing histone acetylation. The strategy is to use multiple places in maintaining latency to then reverse latency and get activation.

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Daniel R. Kuritzkes, MD Brigham and Women’s Hospital

One of the studies that helped contribute to our understanding of the complexities that surround the search for a cure was work we did at Brigham and Women’s Hospital with my colleague Timothy Henrich, [MD]. Two patients with lymphoma received stem cell transplants, except in their case, the cells they got were from patients who had wild-type cells. These patients continued on antiretroviral therapy throughout the course of their transplant, which is in contrast to what has been done in most centers where treatment is interrupted. We noticed after the transplant that not only was there no virus in their bloodstream, which is what we would have expected, but we couldn’t find any hints of provirus or integrated virus in their circulating cells.

We decided that it would be appropriate to attempt a very carefully monitored treatment interruption to see whether in fact the virus had completely disappeared. The first patient came off therapy and was doing fine after a couple of months, with no evidence of viral rebound ... so we went ahead and interrupted the second patient. Unfortunately, after about 12 weeks, the second patient experienced a rapid rebound in their virus [and] went back on therapy. The first patient continued to be virus-free, but also rebounded after about 8 or 9 months.

Although these results are disappointing on the surface ... we learned some very important lessons from these two patients. The most important of which is that it can be very difficult, almost impossible, without doing a treatment interruption to know you have actually eradicated HIV. The good news in the study was that it appeared that the reaction the donor stem cells had against the patients’ own lymphocytes was actually eliminating HIV-infected cells. That tells us something important about the role that the immune system could have in helping to eradicate persistent HIV.

I think what we’ve learned is that there is every reason to be hopeful, given the new tools that are being discovered and the technologies that are now available to us, that we have a real chance of developing an HIV cure, but we’re clearly just at the earliest stages of this research. I would guess it will be at least a decade before we have anything approaching a cure.

Joseph J. Eron, MD University of North Carolina School of Medicine

Much of the research that we’re doing is trying to poke the virus [to] make it show itself so that somehow the immune system can clear it. That’s a critical step. The second critical step is to boost their immune system [so that it is] a little more aware of HIV so they can clear those infected cells. We’re doing one very clever study, led by Cynthia Gay, [MD, MPH], and David Margolis, [MD], where they actually take [out] a patient’s infection-fighting cells, educate them, get them to kill HIV-infected cells better and then infuse those cells back into patients.

An issue that I’ve heard discussed quite a bit is that cure might be very expensive. It will be expensive in the beginning, and it won’t be available to everybody, but this is how medicine works. We achieve a goal by curing HIV or curing cancer and then we try to scale that. We try to learn from what we’ve gained and make it more affordable [and] more available. I appreciate the goal is not to cure a few people in a developed country like the United States or developed countries like in Europe. The goal, eventually, is to have a cure that can reach everyone ... not just people in resource-rich settings.

I think it’s important to remind people that [finding a cure] is a really long process. When I speak to patients, I like to talk about getting to the moon. We made it to the moon, but the first thing we had to do was get out of the atmosphere. That’s kind of where we are with HIV cure research. If you think about those astronauts, they knew they weren’t ever going to the moon. They knew that they were contributing to something that would take awhile to build over time. The patients who are volunteering for these studies are really doing something that is giving of themselves. Maybe in 5, 10 or 15 years, we’ll get close enough to a cure that they’ll be able to benefit, but a lot of them are volunteering their time [and] taking some risks for a process that really is going to take a long time.

Disclosures: Eron reports financial relationships with various pharmaceutical companies and is an investigator on several studies with the NIH for which he receives financial support. Kuritzkes reports consulting for HIV therapeutics development for Bristol-Myers Squibb, Gilead Sciences, Merck, Teva Pharmaceuticals and ViiV Healthcare. Clements and Hoxie report no relevant financial disclosures.

To watch the videos, click here.