In 2009, Martin Delaney, a leading AIDS activist and the founder of Project Inform, co-authored an article in Science calling for a new "HIV Collaboratory" to focus on cure research. The Collaboratory would be designed "to accelerate basic discovery and the clinical translation of these discoveries." Sadly, he died before the article was published.
The article echoed at least two decades of calls from AIDS activists for the U.S. to take a new approach to finding a cure for AIDS. In 1994, under pressure from ACT UP, U.S. Representative Jerrold Nadler introduced the AIDS Cure Project (HR 4370) in Congress. It would have changed the way AIDS research was conducted by bringing together a team of researchers from diverse disciplines at a primary location. Supporters claimed that the structure and bureaucracy of the NIH worked against innovative, creative research, and that NIH granting procedures drastically slowed research and diverted money to university overhead costs, rather than to the search for a cure. Proponents estimated a budget for the AIDS Cure Project of $1.84 billion over five years.
The Delaney Collaboratories
Nothing like the HIV Collaboratory or the AIDS Cure Project ever emerged, either in the amount of funding or in the coordination of the research efforts. The NIH has, however, funded three teams devoted to AIDS cure research under the name "Martin Delaney Collaboratories."
Each of the teams includes academic researchers with long experience in HIV research or clinical care, along with at least one industry partner, and will study three areas: First, basic science, such as understanding why HIV reservoirs persist in people even after decades of undetectable viral loads, why a small handful of people have undetectable viral loads many years after infection without taking HIV drugs, and whether persistent inflammation plays a role in viral persistence. Second, core technology components like developing effective models (animal and test tube) for testing different therapies, finding ways to measure the viral reservoir, and developing treatment technologies such as stem cell expansion and genetic transformation. Finally, each team will move toward testing new approaches in people.
The defeatHIV Collaboratory at the Fred Hutchinson Cancer Research Center in Seattle includes five projects to develop proteins that attack HIV reservoirs. They will also study whether CD4 cells can be made resistant to the virus. Its industry research partner is Sangamo Biosciences, which holds the patent on zinc finger nucleases (ZFNs), a type of "genetic scissors" that can precisely target genes and change them. DefeatHIV was awarded $20 million in funding by NIH over 5 years.
Cellular therapies for HIV generally involve removing white blood cells or stem cells from a patient, genetically modifying the cells, expanding them (which can take a few weeks to a couple of months), and then infusing them back into the patient. This is known as an autologous transfusion or transplant. While the procedure is complex, the basic steps (other than the genetic modification) are performed tens of thousands of time a year in people with leukemia and myeloma. The modified cells are either mature CD4 cells or stem cells (young blood cells that have not yet matured into a specific type of white blood cells).
DefeatHIV is developing two types of genetic modifications, which could be used together, separately, or in combination with other genetic modification approaches. One is modeled on the "Berlin Patient," Timothy Ray Brown. It uses autologous transfusion and ZFNs to "knock out" the gene that makes the CCR5 receptor that HIV needs.
The other approach is more experimental and uses ZFN or other "genetic scissors" to target the HIV that has already integrated itself into the DNA of infected cells. While the possibility of actually chopping HIV out of infected cells is exciting, in one form this strategy requires introducing the genetic scissors directly into a patient's body, which is less studied than the genetic modification of cells outside of the body. This technique could also possibly be used in combination with other genetic modifications to purge HIV from infected cells removed from patients before transplanting them back into the body.
Due to the expense of these procedures, there is a fear that they will never be translatable to developing nations. Principal Investigator Hans-Peter Kiem's response is: "You have to go where the science takes you. After many years of HIV research, I strongly believe that if we are ever going get a cure we have to go into the cells and modify them. A cure based only on small-molecule drugs would be preferable, but at this stage I think we need to investigate all possibilities."
DefeatHIV is focusing on techniques to address three problems common to all genetic modification therapies: genetic transformation efficiency, cell expansion, and conditioning as mentioned above. Because all of these techniques are new and involve risk, the team is putting substantial effort into developing a nonhuman primate model to test the techniques for safety and effectiveness.
Genetic transformation efficiency refers to the percent of cells that are actually transformed by the genetic agent or vector. Of all the cells exposed to the modification agent, only a portion of them will be genetically modified.
Cell expansion describes the ability to multiply the modified cells outside the body. Since the total number of transformed cells returned to the body will greatly affect their benefit, both high efficiency and expansion are needed to give a patient the greatest number of modified cells.
Conditioning refers to drugs taken to "make room" for the new cells. Earlier experiments have shown that just infusing stem cells does not allow the cells to engraft into the bone marrow. Conditioning drugs are cancer-chemotherapy drugs that kill off or suppress parts of the immune system. Researchers are studying whether mild versions of chemotherapy will be enough to allow the new cells to engraft.
Independently of defeatHIV, Sangamo is conducting a Phase II clinical trial using autologous transplantation to remove the CCR5 receptor on CD4 cells. Company spokesperson Elizabeth Wolffe states, "Our goal as a company in this research is to give people a therapy that will allow a patient to keep HIV under control without drugs -- in other words a functional cure." Sangamo reports that the Phase II trials are progressing well and expects to present preliminary data early in 2013.
The CARE Collaboratory at the University of North Carolina at Chapel Hill is working to understand HIV latency more fully and develop treatments to eliminate latently infected cells.
"Latency" refers to HIV that is integrated into the DNA of infected cells but which infrequently produces new virus. Some small fraction of these cells persist even after decades of effective anti-HIV drugs and are a chief reason viral loads rise when HIV drugs are stopped. Researchers have long looked for an effective way to activate latent virus and cause the cells to die either because of their HIV infection or because the cells are recognized and killed by the immune system. CARE includes 15 scientific projects at four facilities.
One approach for activating these cells in order to remove their latent HIV is the use of "small-molecule" drugs that will activate resting cells and reverse HIV latency. The benefit of using small molecules over the cellular therapies described above is that they are cheaper and much easier to implement across the globe. Several existing drugs approved for other uses have been shown to activate resting HIV-infected cells in test tubes, but it's been difficult to replicate this in people.
In July 2012, CARE team leader David Margolis of UNC and Daria Hazuda of Merck published results of a study they said was the first to demonstrate that a drug can reverse HIV latency in humans. The team used the drug vorinostat, a drug used to treat lymphoma. In the trial, eight men on HIV drugs took vorinostat and within hours all eight had a significant increase in HIV RNA in their latently infected cells -- indicating that the HIV in those cells had become active. "This work provides compelling evidence supporting a strategy to directly attack and eradicate latent HIV infection, a critical first step towards curing HIV infection" said David Margolis, MD of UNC at Chapel Hill, who led the study.
Robert Siliciano, another CARE researcher and a professor at Johns Hopkins, released data showing that the infected CD4 cells survive even after latent virus is activated and are killed only when other immune cells are primed before reactivation. In the lab, he tested a model of a vaccination strategy using short pieces of HIV proteins to stimulate the anti-HIV response of CD8 cells just before activation of the latently infected CD4 cells. This produced enough cell-killing CD8 cells to attack and kill the latently infected cells.
Other drugs that could potentially activate and kill latent HIV infection are being identified by scientists. Gilead Pharmaceuticals plans a clinical trial using romidepsin, another lymphoma drug, and an activator.
The DARE Collaboratory at the University of San Francisco and at the Vaccine & Gene Therapy Institute of Florida is also working on viral persistence, but with a focus on understanding and modifying the body responses that contribute to HIV persistence, such as cell-to-cell interactions and inflammation. It includes seven projects and three core facilities, and works with industry partner Merck Research Labs. DARE has three broadly defined objectives for reversing latency: first, defining the reservoirs in the body where HIV persists; second, investigating the body's mechanisms that contribute to HIV latency, such as cell-to-cell interactions that may silence HIV transcription; and finally, testing interventions to reverse HIV latency without broadly activating the immune system. DARE is performing some studies of SIV infection in rhesus monkeys. The team will also study the effects of certain anti-inflammatory compounds on the HIV reservoir.
The California Cure Rush
The California Institute for Regenerative Medicine (CIRM) was established by Proposition 71, passed by California voters in 2004, which provides $3 billion in grants over ten years for stem cell research. The CIRM board includes California patient representatives, one of whom is Jeff Sheehy, a long-time HIV activist. CIRM grants support teams of researchers preparing to move a research project to the clinic within four years and require teams to collaborate, speeding the path to the clinic.
When Proposition 71 passed, it was not clear that stem cell research was directly relevant to AIDS, but the Berlin Patient's case suggested that modified stem cells could have a role in treating or curing HIV infection. CIRM funded two disease teams, and one or both teams may be starting clinical trials in people by the end of 2013.
City of Hope In the 1990s, The City of Hope Medical Center near Los Angeles pioneered using stem cell autologous transplants (also known as bone marrow transplants) to treat people with AIDS-related lymphoma. These transplants were routinely denied to AIDS lymphoma patients at the time. City of Hope demonstrated that the transplants could be done in people with HIV and forced insurance companies to pay for the therapy.
The CIRM disease team, lead by Dr. John Zaia, is working to develop a therapy using Sangamo's ZFNs to target the CCR5 gene in a way similar to the approach that led to a cure in the Berlin patient. Paula Cannon of the Keck School of Medicine of USC has shown that this therapy appears to work effectively to clear HIV from mice that have been modified to have a human immune system.
The team will further refine the therapy to improve its effectiveness in creating stem cells that can produce HIV-resistant CD4 cells and is developing manufacturing methods that can produce the volume necessary for clinical use.
Dr. Zaia is also involved in a different gene modification strategy with David L. DiGiusto, inserting genes for three different molecules to resist HIV infection. One of the molecules disables the CCR5 receptor, the second hides the tat/rev protein that HIV needs to replicate, and the third knocks out TAR -- a key piece of genetic machinery that HIV needs. The results showed that the modified cells survived in the patients for over two years and were resistant to HIV. But because the standard conditioning for the transplant is so risky, they have so far been performed only on HIV patients who needed the transplants to treat their lymphoma. The goal is ultimately to make the procedure safe and affordable for widespread use.
UCLA CIRM is also providing $20 million to a UCLA team headed by Dr Irvin Chen. Working with California biotech company Calimmune, the researchers are studying a technique called "RNA interference" as a method to block CCR5. RNA interference is a mechanism that our body naturally uses to block the function of various genes. When RNA that interferes with HIV is introduced into a stem cell or CD4 cell through gene modification, its blocking activity should be present throughout the lifetime of that cell and all cells arising from it -- theoretically the lifespan of a human being. Chen and CalImmune are planning to use this therapy in combination with other gene therapies.
Calimmune states that its "singular purpose" is to "provide HIV-positive patients with a similar type of genetic resistance to HIV that occurs naturally in 1% of the European population. By treating a patient's own stem cells and T cells, we aim to protect patients from the ravages of AIDS and eliminate the need for daily medication."
Calimmune plans to begin Phase 1 human trials of a dual gene therapy in 2012 and expand those trials eventually to comprise multiple studies at different locations worldwide. This trial will genetically modify both stem cells and CD4 cells by adding two genes using autologous transplants. One gene blocks the creation of CCR5 receptors through RNA interference. The other gene instructs the cell to create a molecule (C46) that acts as an HIV fusion inhibitor, similar to the drug Fuzeon.
In addition to the five teams discussed above, many other researchers are conducting AIDS cure research, including clinical trials. The ACTG has also recently expanded is efforts toward finding an AIDS cure, and a handful of its sites are either recruiting subjects or are planning to do so soon.
One technique tested uses "nanoparticle" lipid bubbles containing antibodies that specifically match up with CD4 cells. The nanoparticles deliver two drugs to the cell: bryostatin, to activate the cell, and a protease inhibitor to prevent HIV from assembling more virus once the cell is activated. Jerome Zack, director of the UCLA Center for AIDS Research, led the research and reported that the nanoparticles did not trigger toxic inflammation, a concern in all activation strategies. Scientists are also working on liposomes that bind only to CD4 cells that are latently infected with HIV.
The Money to Get There
But funding for AIDS cure research remains extremely low. The AIDS Policy Project, a group of activists focused on promoting AIDS cure research, documented in 2010 that NIH spends only about $75 million on cure research annually, less than 3% of total NIH AIDS research spending. By way of comparison, NIH spends $625 million annually for HIV vaccine research and $692 million annually for HIV drug development.
The AIDS Policy Project has called for a substantial increase in NIH AIDS cure funding to at least $240 million annually. Other treatment and research activists groups, such as Project Inform, TAG, amFAR, the International AIDS Society, and ACT UP have also long pushed for substantial increases in AIDS cure research funding. People concerned about an HIV cure should continue to push for a dramatic expansion in funding so approaches that can lead to a cure will quickly be identified and tested.
As described above, the complexity of the cure approaches taken, the substantial overlap in work done by different research groups, and the large number of different ways to solve common problems, suggest that there is still a need for a centrally coordinated, fully funded Manhattan/Apollotype project to cure AIDS as envisioned by Martin Delaney and by the ACT UP AIDS Cure Project. The early science is promising enough that it is reasonable to think that an intensified effort could produce some type of cure in five years, rather than the 20 years currently predicted. Some people are saying that President Obama needs to put forth a "grand vision" for his second term. I have a suggestion.
Join the Search for a Cure
Researchers are looking for people with HIV who want to take part in trials that may someday lead to a cure. To find them, search for HIV gene therapy or HIV reservoirs at the NIH clinical trials database: clinicaltrials.gov. You can use the Advanced Search feature to find only trials that are open near you. TAG maintains a list of trials and other HIV cure information at: treatmentactiongroup.org/cure. The University of Pennsylvania has an active info line for HIV-related gene therapy research at (215) 349-8092, and anyone within a two-hour drive to Philadelphia is encouraged to contact them. UCLA also has an HIV gene therapy information line at (310) 557-9062. The Delaney Collaboratories will post information about clinical trials as they open for enrollment.
Stephen LeBlanc is a board member of the AIDS Policy Project and an attorney practicing in San Francisco.