Photo by Robert Hood / Fred Hutch News Service
It’s a tradition to celebrate the anniversary of a lifesaving bone marrow transplant as a rebirth. By that measure, today marks the 10th “birthday” of one of the world’s best known transplant survivors: Timothy Ray Brown.
On Feb. 7, 2007, Brown underwent a last-ditch effort to cure his life-threatening acute myeloid leukemia after chemotherapy failed. But what sets him apart from the million-plus transplant survivors worldwide who have been reborn free of leukemia and other blood cancers is that he became the first person in the world to also be cured of HIV.
A decade later, scientists at Fred Hutchinson Cancer Research Center and other institutions are working hard to make sure he will not remain the only person cured. Their challenge is to show that what once was thought impossible can be repeated and also to find a cure that is less risky and toxic than the one Brown endured. Finding a cure now commands a place on the agenda of every major scientific meeting on HIV, including next week’s Conference on Retroviral and Opportunistic Infections in Seattle.
“Cure is challenging because of the very special nature of HIV: how it attacks the body, how it integrates into our cells, and how the immune response, unlike for virtually any other virus, is inadequate,” said Dr. Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, at a recent international AIDS conference.
But, Fauci added, “We now have a cohort of dedicated scientists who are working in this field.”
The NIH helped foster this cohort. In 2011, it funded three public-private research groups, including the Fred Hutch-based defeatHIV, to focus on curing HIV. Last summer it awarded an additional $150 million over five years to be divided among the original partnerships as well as three new groups. All are led by U.S. researchers and based at U.S. institutions but each draws from academia and industry across the nation and abroad. This is an overview of the work they are undertaking.
Robert Hood / Fred Hutch News Service
For the first 15 years of the worldwide AIDS pandemic, an HIV diagnosis was essentially a death sentence. Since 1996, combination antiretroviral therapy — considered one of modern medicine’s great victories — has transformed it into a treatable disease for those who have access to and can tolerate the drugs for a lifetime.
But early hope that antiretroviral therapy, if taken long enough, would actually cure the infection was dashed when scientists learned that the virus integrates itself into the DNA of some of the longest-lived cells in the body. These reservoirs of latent cells lie dormant, undetectable and untouched by the drugs. Stop treatment, and HIV roars back like a kicked hornet’s nest.
Except in Brown’s case, it didn’t.
The Seattle-born Brown was diagnosed with HIV in 1995 and went on antiretroviral therapy the following year. It was not until he developed leukemia and needed the bone marrow transplant in 2007 that his doctor in Berlin, where he was then living, attempted to cure both diseases at once by finding a marrow donor with a rare gene mutation that blocks HIV’s entry.
In 2008, the cancer returned and Brown required a second transplant. But he has not taken antiretroviral medicine since the first, and today he still shows no signs of either leukemia or HIV. He was known only as “the Berlin patient” until 2010, when he revealed his identity to help promote cure research.
No one considers a high-risk, high-cost transplant appropriate for the vast majority of people with HIV who don’t also face a deadly blood cancer. But research groups see Brown’s case as a starting point and “proof of concept” that an HIV cure is possible.
The three research groups funded during the first round of grants in 2011 — dubbed defeatHIV, CARE and DARE — took distinctly different approaches to an HIV cure.
DefeatHIV’s strategy: cell and gene therapy, immunotherapy
At Fred Hutch, defeatHIV co-directors Drs. Keith Jerome and Hans-Peter Kiem focused on cell and gene therapy. The goal was to genetically engineer resistance in an HIV-infected person’s own blood stem cells rather than, as in Brown’s case, using immune cells from a matched donor with the rare HIV-resistant mutation.
Kiem’s lab successfully modified blood stem cells in an animal model using a gene editing technique called zinc-finger nucleases and returned the resistant stem cells to repopulate the immune system. (Research into this approach will continue under a separate five-year grant from the National Heart, Lung and Blood Institute.)
DefeatHIV will use its second round of HIV cure funding to tackle three approaches that build on its earlier work. They include:
- Exploring CAR T-cell therapy, a type of immunotherapy that already is being hailed as a potent anti-cancer weapon, against HIV in partnership with Seattle-based biopharmaceutical company Juno Therapeutics.
- Using gene therapy to induce production of a synthetic “super antibody” to target HIV.
- Adding a therapeutic vaccine to boost the proliferation and function of genetically modified HIV-resistant cells.
All three tactics focus on using the immune system to eradicate or at least control HIV, just as immunotherapies are beginning to revolutionize cancer treatment. As with cancer, Kiem said, “It’s not going to be one particular approach. It’s going to be a combination” — a belief echoed by all of the research groups.
CARE’s strategy: ‘kick and kill,’ immunotherapy
CARE, based at the University of North Carolina, Chapel Hill, and led by Dr. David Margolis, focuses on the viral reservoir. Its “kick and kill” strategy looks for drugs that can wake the virus from its latency stage so that antiretroviral drugs might then find and wipe out the hidden reservoirs.
The challenges are formidable, beginning with how to measure the reservoirs or even find all the places in the body where latently infected cells hide, much less find which agents or combination of agents — many of them cancer drugs — can best “kick” them awake.
CARE will continue to develop and test these latency-reversing agents and also begin to look at ways to boost the immune system to recognize and clear the virus after it's awakened. It will also study the optimum window for targeting reactivated cells.
Robert Hood, Fred Hutch News Service
DARE’s strategy: reservoir barriers, checkpoint inhibitors and a CMV-vectored vaccine
In its first round of funding, DARE, led by Drs. Steven Deeks and Mike McCune of the University of California, San Francisco, focused on the role of the immune system, especially chronic inflammation, in establishing and maintaining the reservoir.
Under the second round, Deeks and his collaborators in Oregon, Australia and elsewhere will continue studying the reservoir of latent cells and ways that the body’s own immune system can eradicate HIV once reawakened. Among their goals:
- UCSF researcher Dr. Timothy Henrich will look at how HIV circulates differently in blood and tissues and develop new ways to search for latently infected cells. At a Fred Hutch cure symposium in 2015, Henrich had likened finding latent HIV to finding Waldo in the children’s book, “Where’s Waldo.”
- Dr. Louis Picker, assistant director of the Oregon Health & Science University Vaccine and Gene Therapy Institute, will, in animal models, try to figure out the optimal combination of immunotherapies to reduce, eliminate or control the latent reservoir.
- Dr. Sharon Lewin of the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia, will study checkpoint inhibitors — another anti-cancer immunotherapy — to see if they can shock, kill and control HIV in people with both HIV and cancer.
- And, Deeks will focus on developing a therapeutic vaccine using cytomegalovirus as a vector to provoke the immune system into responding.
The three new groups: BELIEVE, BEAT-HIV and I4C
If the three original groups each took a distinct approach — with the understanding that a cure may likely require a combination of all three — the newly funded groups build on the most promising strategies from the first round, including cell and gene therapy and immunotherapies.
Based in Washington D.C., BELIEVE involves 18 public and private research institutes across the United States, Canada, Mexico and Brazil, led by George Washington University researcher Dr. Douglas Nixon. At a November NIH cure conference, its researchers said they will focus on:
- An experimental drug developed to treat advanced tumors that also has been shown to not only “wake up” latent HIV but enhance the ability of the immune system to kill the awakened cells, thus both “kicking” and “killing.” Called ALT-803, the drug candidate was developed by Altor Bioscience Corporation, a BELIEVE partner, and is already in clinical trials for cancer.
- Nanoparticle “backpacks” developed by Torque, a biomedical engineering company and one of the group’s research partners, to deliver T cells that specialize in killing virus-infected cells.
The Philadelphia-based BEAT-HIV, co-led by Dr. Luis Montaner, director of the HIV Immunopathogenesis Laboratory at the Wistar Institute, and Dr. James L. Riley, research associate professor at the Perelman School of Medicine at the University of Pennsylvania, will focus on combination immunotherapy. At the NIH cure meeting, the two said that BEAT-HIV would:
- Identify where and how HIV hides by figuring out how to access new areas of the body that have not been studied before and finding a way to track infected cells.
- Combine two immunotherapy strategies that independently have been shown to reduce HIV: highly potent antibodies and pegylated interferon alpha 2b, a drug used to treat hepatitis C and melanoma.
- Combine two promising gene therapies that have been independently tested in humans, similar to one of the approaches under study by defeatHIV. The plan is to engineer CAR T cells to target HIV while also engineering them to resist attack by HIV.
And the sixth group, called I4C or Immunotherapy for a Cure, is led by Dr. Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center in Boston. The focus is on creating a vaccine that can both prevent or cure HIV, building on separate vaccines developed by Barouch and by Oregon’s Picker, who also works with DARE. (A number of institutions and individual researchers work with more than one group.)
What ‘cure’ means — and why it matters
Scientists continue to tease out how, exactly, the transplant cured Brown — including whether the gene mutation or some other factor made the difference. Meanwhile, several attempts to replicate his cure, with and without an HIV-resistant donor, have failed to show the same results.
Why pursue a cure when combination antiretroviral therapy keeps the virus in check? As Fred Hutch’s Kiem recently explained, as much as treatment has done to allow people with HIV to live a near-normal life span, it does not fully restore health. Physicians who treat those on long-term therapy see accelerated aging, cardiovascular problems, bone loss, kidney disease and higher cancer risks, much of it due to higher levels of inflammation that persist despite treatment. And although the drugs are becoming more available in low-income countries, almost half of those with HIV aren’t on treatment. Even in the United States, fewer than half of those diagnosed with HIV are on regular enough treatment to keep the virus suppressed, according to the U.S. Centers for Disease Control and Prevention.
But treatment matters, even beyond extending life and limiting transmission now. Researchers over the past five years have learned that if cures or remissions are to be achieved, they will probably come easier for people whose immune systems are healthiest and who have lower levels of the virus to begin with — which early and consistent use of antiretroviral therapy can achieve.
“Getting people on treatment is part of the cure agenda,” said UCSF’s Deeks at the international AIDS conference in Durban.
Many HIV researchers have set their sights on what they term “sustained virologic remission” as at least a first step toward a cure. If cure means eliminating the reservoir entirely, sustained remission means being able to control or contain the infection without antiretroviral therapy. At a minimum, HIV doesn’t rebound and isn’t transmittable to others. (In a very small subset of people with HIV, the immune system does just that; called elite controllers, they are heavily studied by researchers.)
“The biggest regret at this point is we don’t have a second cure,” said Fred Hutch's Jerome. “We’ve tried to be open and honest that this is going to be a long road. At the same time, we’ve learned a tremendous amount about the virus, the reservoir, the challenges that we face, and a lot of what we’re learning is coming out of the collaboratories. As a field, we have a better sense of what are the most promising strategies.”
Mary Engel is a former staff writer at Fred Hutchinson Cancer Research Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.
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