Buoyed by a show of support from the Bill & Melinda Gates Foundation, more than 150 of the world’s leading experts in the use of gene therapy to cure HIV gathered in Seattle last week to vet their research and advance a bold idea: to make these potentially curative therapies low-cost and accessible to patients everywhere.
Hosted by Fred Hutchinson Cancer Research Center and defeatHIV, the 5th Conference on Cell & Gene Therapy for HIV Cure drew an international corps of researchers who are addressing this challenge: Antiviral drugs can stop HIV infection, but because the virus hides quietly inside a patient’s immune cells it will roar back if treatment stops.
The goal is to rid the body of these reservoirs of latent viruses, once and for all. The prospect that technologies might eventually do this economically led the Gates Foundation to support part of this year’s conference.
The gene therapy conferences were inspired by living proof that humans can be cured of HIV. In 2007, Seattle native Timothy Ray Brown, who had HIV and was battling cancer in Berlin, received the first of two blood stem cell transplants for leukemia. The stem cells were chosen from donors who carried two copies of a gene mutation that confers natural resistance to HIV. The transplants not only cured his leukemia, they made Brown the first person in the world to be cured of HIV.
Twelve years after stopping antiviral drugs, he still shows no sign of the virus. This year, two more HIV-positive cancer patients in Europe were deemed to be in remission after similar transplants containing HIV-blocking genes. A patient in London has been safely off antiviral drugs for 22 months, while another in Dusseldorf, Germany, shows no sign of viral rebound after stopping treatment eight months ago.
Those successes remain a far cry from making a gene-therapy cure accessible to the 38 million people living with the virus — a majority of whom live in poor regions across Africa — but they have fired up scientists who have held this dream for decades.
“I don’t think this is pie in the sky,” said conference co-host Dr. Hans-Peter Kiem, a transplant physician who holds the Stephanus Family Endowed Chair for Cell and Gene Therapy at Fred Hutch. “I think it can be done.”
His dream is to have HIV-fighting genes delivered to patients by a single injection. The genes might be ferried inside the body by harmless viruses that could target the patient's immune cells. Their gene cargo would essentially reprogram these cells to block or destroy reservoirs of HIV. Like Brown, these patients would no longer need to take antiviral drugs, and for all practical purposes, they would be cured.
It will take a string of major breakthroughs to make an affordable HIV cure possible, but it is a vision that has been reinforced by tantalizing advances in the lab and clinic, which is stirring interest in a handful of companies and caught the attention of the Gates Foundation.
“There is a commercial drive to take the science that is coming out of this room and to put it into the field so that people with HIV can be cured,” said Dr. Mike McCune, who joined the Gates Foundation last year as its senior adviser for Global Health.
As an HIV/AIDS researcher at the University of California, San Francisco, he was involved during the bleakest days of the AIDS epidemic there in the 1980s and was among the first to work on a gene-therapy treatment for HIV.
“There are a lot of advances that have been made in cell and gene therapy for HIV in the past 30 years,” he said. “And now there are companies forming, thinking they can come up with a business plan, which was not possible until recently.”
McCune said that business-sector interest is essential for translating lab discoveries into patient therapies. He believes that gene-therapy approaches to curing blood disorders such as sickle cell disease — which are building a track record of success in clinical trials — will lay the groundwork for greater commercial interest in HIV cures. Until that happens, he believes the Gates Foundation can make a difference.
“The goal of this meeting is to ask how we can do that in resource-limited parts of the world where the reimbursement to those companies won’t be available,” McCune said.
On the second day of the conference, the foundation sponsored a highly technical workshop devoted to “in vivo” gene therapy. That is where the action of gene engineering to fight HIV takes place inside the patient’s body, rather than in a laboratory vial or an operating room suite. This is the technology — highly experimental today — that could eventually fulfill that dream of delivering an HIV cure, inexpensively, from a single shot.
One approach, under development by University of Washington protein designer Dr. David Baker, involves building nanoscale protein carriers of HIV-suppressing genes. Infinitesimally small, they can be custom made to seek out immune cells, penetrate their cell surface, and release their cargo into the nucleus, where the cell’s genes are housed.
Baker conceded that that this technology would not be competitive today with other methods discussed at the conference. However, he said that because these proteins are easy to produce, and very chemically stable, they could — after clearing significant technical hurdles — become an affordable way to bring gene therapy to remote areas of the globe.
“Don’t get your hopes up much,” Baker said. “It’s still early days.”
Closer on the horizon are technologies that package HIV-fighting genes within the protein shells of viruses, which take advantage of nature’s preferred method of slipping foreign DNA in a cell’s genetic machinery. In numerous presentations, a family known as adeno-associated viruses, or AAVs, emerged as the most-favored vehicles, and researchers are busy reengineering these particles to make them more efficient at carrying their cargo, delivering it to the right places and less likely to provoke a patient’s immune system to attack them.
“You have to tailor and optimize,” said Dr. Hildegard Büning, from Hannover Medical School in Germany. “We have to teach the viral vector to do its job.”
AAVs are harmless viruses, but researchers are also looking at using stripped down versions of nastier bugs, such as Nipah and measles viruses, as vehicles for delivering therapeutic molecules instead of diseases.
University of Washington researcher Dr. André Lieber showed an alternative approach using adenovirus, which causes cold-like symptoms in people. Using only the shell of the virus as a container — the microbe emptied of its genes — he is able in preclinical studies to transport genes to immune cells in the body and treat blood cell disorders and cancer. These modified viruses can be freeze-dried and shipped, and they have another advantage: lower cost.
“It is very simple to make these vectors,” Lieber said. “The procedure takes six hours, and the cost per patient based on my lab estimates would be about $3,000.”
During the two-day conference, scientists presented their work on a wide variety of strategies to identify and destroy latent reservoirs of HIV — a problem identified more than two decades ago by the Johns Hopkins University lab of Dr. Robert Siliciano, the event's keynote speaker. They include continued work to make transplantation of HIV-resistance genes simpler and safer, and explorations of different techniques to edit the genes of immune cells to make them resistant to HIV.
T-cell therapy, in which immune cells from a patient are selected or genetically reprogrammed to target cancer, is being explored as a technique to target reservoirs of latent HIV. Fred Hutch immunotherapy scientist Dr. Aude Chapuis noted that she began her career as an HIV scientist exploring ways to get T cells to target cells infected with HIV. It didn’t work, but she described how her current work in fine-tuning T cells as “serial killers” of Merkel cell carcinoma might inform the latest research in coaxing such cells to target HIV. “It’s nice to see that things are coming back,” she said.
Among the challenges facing HIV cure research is how to recruit volunteers for the essential early trials of these gene therapies, which may rival in complexity to transplant treatments for cancer. Given the control of the virus afforded by antiviral drugs, potential participants must weigh the risks and benefits of joining a trial. Laurie Sylla, a member of the defeatHIV community advisory board, discussed a Seattle focus-group study that found considerable wariness on the part of potential patients.
“People were afraid to change what they felt was already working for them,” she said. Another focus group comment she related was, “Give it to Magic Johnson, and then we’ll see how I feel about it.”
One of the studies presented used a technology called zinc-finger nuclease, a kind of DNA-cutting tool, to modify the genes of immune cells. It was the first human trial ever to use gene editing to block HIV and was designed to confer the same sort of HIV resistance found naturally in the donors of cells given to Brown and the patients in London and Dusseldorf.
Eight HIV-positive patients had their immune cells removed, genetically altered in a laboratory with this cutting tool and then restored to their bodies at City of Hope in Duarte, California. The study found the procedure was safe, but it edited only about 2% of the cells — a disappointment.
“For a cure strategy, it is not ready but it is a start,” said City of Hope researcher Dr. John Zaia.
Matt Chappell, a San Francisco social worker who was one of the eight participants in the trial, attended the conference and spoke at a preconference meeting about his experience. Although the experiment did not cure his HIV, he chose to remain off his HIV drugs ever since the trial, and his health is stable.
“Trials are not treatment,” Chappell said. “You might get a benefit, and you might not. I participated because this question needed to be answered in HIV — not with the expectation that I’m somehow going to be cured.”
Fred Hutch virologist Dr. Keith Jerome, a co-host of these five conferences since the first one was held in 2014, noted that the technologies of gene editing that may work against HIV can also be applied to address other health issues. His own Fred Hutch lab is using gene-editing technologies to root out pockets of latent infection with human herpesvirus.
Jerome was pleased by the turnout and enthusiasm of the scientists at the meeting, and by the opportunity to discuss these technologies with like-minded researchers.
“Hans-Peter and I once perceived a lack of emphasis on cell and gene therapy for HIV,” Jerome said. “I’m grateful to see the field gravitate toward our vision.”
Sabin Russell is a former staff writer at Fred Hutchinson Cancer Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and he wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT and a freelance writer for the New York Times and Health Affairs.
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