As people around the globe prepare to mark World AIDS Day this Sunday, nearly 38 million men, women and children are living with HIV/AIDS, a disease that still has no cure.
Thankfully, at least 24 million of them, in nations rich and poor, are keeping the AIDS virus at bay with anti-HIV drugs; but the pills must be taken daily, for a lifetime. If the pills are stopped, the infection springs right back.
However, with philanthropic and government support, scientists at Seattle’s Fred Hutchinson Cancer Research Center are working the long game. In addition to developing and testing HIV vaccines, they play a leading role in an expanding global effort to find a true cure, where the virus is stopped without the constant need for antiviral drugs.
That cure research — still a niche field in the universe of AIDS studies — relies on the notion that HIV can eventually be scrubbed out of the bodies of infected people by giving their blood cells protective genes, and that this gene therapy can one day be delivered to millions of people through just a shot in the arm.
On Oct. 23, these researchers received a significant vote of confidence when the National Institutes of Health and the Bill & Melinda Gates Foundation announced a plan to each provide $100 million in grants that will support gene-based research on cures for HIV as well as sickle cell disease, both of which are especially prevalent in resource-poor regions of Africa.
The Hutch researchers hope to win some of those grants to expand and further develop their efforts to harness the human immune system to fight HIV and sickle cell disease. The grants will be distributed over the next four years, with the hope of moving into clinical trials for such therapies in the next seven to 10 years.
“Two hundred million dollars is a lot of money,” said Fred Hutch virologist Dr. Keith Jerome. “There is no way to phrase that in any other way.” Jerome and his Hutch colleague Dr. Hans-Peter Kiem are co-directors of defeatHIV, a collaborative of researchers from many institutions that since 2011 has been developing cellular and gene-therapy cures for the disease.
“One of the wonderful things about that number is that it is enough to get the attention of the scientific community at large. What you want to do is get the attention of people who have the knowledge and ability to solve the problem,” Jerome said.
Dr. Mike McCune, senior adviser for Global Health at the Gates Foundation, said the focus of the collaboration with the NIH will be on finding ways to deliver cures for sickle cell disease or HIV in a practical manner — even by a single shot in a walk-in clinic — without the cost and toxicity associated with hospital-based gene therapy. “We want these interventions to be available to all, in all parts of the world, including resource-limited parts of sub-Saharan Africa,“ he said.
The NIH/Gates program will initially focus on sickle cell disease, where research on gene therapy has been going on longer and has advanced more quickly. Sickle cell disease arises from a genetic mutation that causes red blood cells to form in rigid crescent shapes that can bunch up, blocking blood flow and causing severe pain and anemia. It affects about 100,000 Americans — cutting life spans short by 20 to 30 years. It afflicts some 20 million people worldwide, most of them in Africa.
Preliminary results of human clinical trials for a gene therapy cure for sickle cell disease have been encouraging, and more results are expected shortly at the American Society of Hematology annual meeting Dec. 7–10 in Orlando.
“We are starting with sickle cell disease for two reasons: First, the burden of this disease in sub-Saharan Africa is enormous; secondly, we know precisely how to fix it genetically,” McCune said.
Jerome agrees that a gene therapy cure for sickle cell disease is more likely to happen before one for HIV. “It is a difficult, difficult virus,” he said.
Kiem, who holds the Stephanus Family Endowed Chair for Cell and Gene Therapy, is an oncologist who performs bone marrow and stem cell transplants on cancer patients. His HIV work is inspired in part by the case of Timothy Ray Brown, the Seattle native who, while living in Germany, became the first person in the world to be cured of HIV. He was saved by a blood stem cell transplant aimed primarily to cure his aggressive form of leukemia.
In 2007, Brown’s doctors in Berlin found a stem cell donor who carried two copies of a mutated gene that confers natural resistance to HIV in about 1% of Caucasians in Europe. The mutation blocks the ability of HIV to break into cells through a kind of trap door on the surface of blood cells. The faulty genes essentially jam a component of that trap door, known as CCR5, so HIV cannot get in. Could that protection carry over in a transplant?
As prospects improve for research on cures for HIV, advocates are urging that women and transgender people be included in any future clinical trials.
Women and girls make up roughly half of the 38 million people in the world living with HIV, but participation in clinical trials skews heavily toward males, said Brian Minalga, project manager for the Women’s HIV Research Collaborative, a National Institutes of Health-funded advisory group housed at Fred Hutch.
“A cure would be huge. It would change everything, and women and transgender people need to be involved in that,” Minalga said. “It is their human right.”
At a recent conference of the Association of AIDS Care Nurses in Portland, Oregon, Minalga presented results of an analysis by the New York-based Treatment Action Group of 128 HIV-cure studies. Of the only 44 studies that reported enrollment by sex, 18 (40%) were all male, one was all female, and 25 included males and females.
“There’s a problem here, systemically, about what research questions are asked and about how women and transgender people are enrolled,” Minalga said. “Why does this matter? It is because men and women are different, and transgender and cisgender people (those whose gender identity matches the sex they were assigned at birth) are different.”
The NIH Revitalization Act of 1993 requires that women and minority groups be included in all NIH-funded medical research, but the guidance only applies to late-stage clinical trials. As a result, Minalga said, females tend to be left out of early-stage studies, even in preclinical studies involving mice.
Brown and his doctors thought it would be worth a try. It was a brutal procedure that almost killed him, but he was cured of both HIV and leukemia. For more than a decade, he was the only person believed cured of HIV. This year, two more patients, in London and Dusseldorf, Germany, appear to have been cured with similar procedures.
Kiem and Jerome have co-hosted five scientific conferences in Seattle since 2014 to discuss research on ways to understand how and why Brown — and now two others — were cured by transplants, and how more cures could follow. The successful transplants essentially swapped out the patients’ immune systems for new, HIV-resistant ones. The long-term goal is to expand and vastly simplify the process of modifying the human immune system without transplantation by transferring genetic traits that block HIV or command immune cells to destroy other cells where HIV quietly hides.
In current gene therapy experiments, a patient’s own blood stem cells are removed and genetically modified ex vivo — outside the body — in a laboratory setting. Snippets of DNA that confer resistance to HIV, such as the CCR5 mutation, are inserted into genes of the patient’s cells. This is a cut-and-paste process called gene editing, which is made possible by new generations of precision gene-cutting tools, such as the enzyme CRISPR/Cas9. The edited stem cells are then returned to the patient.
Blood stem cells are the mother cells of the immune system, and when these modified cells divide, their HIV-resistance genes are passed down to their progeny: a whole family of diverse blood cells, including the T cells that HIV normally likes to infect. Kiem said he and his colleagues are currently studying how to modify stem cells so they are not only resistant to HIV but also generate immune cells that can seek out and destroy any remaining infected cells in the patient.
Kiem is taking this curative process one big step further. A mixture containing all the ingredients for gene transfer — DNA and the gene-editing enzymes — is packaged into a syringe and injected into the body. The gene-transfer process takes place “in vivo,” or inside the body. He calls it “gene therapy in a syringe.” It has the potential to be safe, effective and relatively inexpensive.
Dismissed as “pie in the sky” by some leading HIV researchers, the approach has nevertheless inspired a cadre of scientists who see a path forward and continue to carry out studies aimed at overcoming the many barriers that remain.
McCune said the new grants are designed to answer questions addressing those challenges. Among them:
“I don’t think it is pie in the sky at all,” Kiem said. The technique has been shown to be effective in early preclinical studies, and within the five to 10 years of the new grants, he believes it will have been tested in humans.
“The same thing we can do now ex vivo, we know we can do in vivo,” he said. “It will be a process of fine-tuning.”
Kiem recently described his vision for bringing an HIV cure to the poorest corners of the world at TEDxSeattle. He said that the research on HIV reminds him of what drew him to Fred Hutch a quarter-century ago, when Dr. E. Donnall Thomas was challenging conventional wisdom with his belief that bone marrow transplants could cure cancer. Thomas in 1990 won the Nobel Prize in physiology or medicine for that work.
Now, Kiem sees in gene therapy an unconventional path to an HIV cure. “I want to focus on making this in vivo gene therapy work,” he said, “so it can cure diseases like HIV/AIDS, sickle cell disease, and even cancer.”
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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