Photo by Robert Hood / Fred Hutch News Service
Editor’s note: Although best known as a cancer research center, Fred Hutch also is a hub of HIV research. This is one of a series leading up to World AIDS Day on the breadth of our work, from investigating HIV at a molecular level to searching for a cure to running the world’s largest HIV vaccine clinical trial network.
Tranisha Arzah was 4 years old when she said goodbye to her dying mother. The details are foggy, the sadness vivid. She can still picture her Seattle home and see the rooms where she played with her beloved brother, Tradell, until he died, too.
When she was 7, Arzah learned that her mother and brother had died of complications of AIDS. That’s also when she found out that she, like Tradell, had been born with HIV.
Today Arzah is 27 and healthy, a testament to one of the great breakthroughs of modern medicine. HIV had been a death sentence before combination antiretroviral therapy became available in 1996 — around the time Arzah’s foster mother and a counselor told her she was HIV-positive. Now research has shown that daily antiretroviral therapy that achieves and maintains a “durably undetectable” amount of HIV in the blood both preserves the health of the person living with HIV and prevents sexual transmission of the virus to an HIV-negative partner. Treatment also has almost eliminated mother-to-child transmission in the United States.
Now Arzah is working to bring about another HIV breakthrough: a cure.
About three years ago, she joined the community advisory board, or CAB, of defeatHIV. Based at Fred Hutchinson Cancer Research Center, defeatHIV is one of six research groups funded by the National Institutes of Health to focus on curing the chronic viral infection.
“I’m excited for the possibility of a cure,” Arzah said. “I decided to join the CAB and see if I could get other women involved and make sure they have a voice.”
An advocate finds her voice
What sparked Arzah’s interest in cure research was meeting the only known person to be cured of HIV: Timothy Ray Brown, who spoke in Seattle at an event sponsored by the defeatHIV CAB. By then she was working at BABES Network, a Seattle YWCA-based peer education and support program for women with HIV. She had found her voice as an HIV advocate.
It wasn’t easy. When she was 9, Arzah had moved to Port Townsend with her foster mom, who adopted her and whom she credits with “making sure I would have as normal a childhood as possible.” But as the new kid in a small-town school, the only African-American in her grade and the only person she knew with HIV, “normal” felt elusive.
“Moving was when I had to grapple with my identity of being HIV positive, especially in a small town,” she said. “When I was a kid, it was a secret for a while. I knew I was different. I didn’t really know if anyone else was dealing with it.”
After high school, in an adolescent bid for independence, Arzah moved to Bellingham. Her mom had been the one to insist — sometimes forcibly — that Arzah take her daily medications, which in the early days meant three times a day, three pills at a time. With help, she found a doctor, a caseworker and even other people with HIV — but most of them were older gay white men.
“No one looked like me,” she said. “I felt even more alone, knowing no one shared a single story that was like mine.”
So she stopped taking her treatment regularly. She struggled, she said, with her diagnosis. She just wanted to focus on being a young adult, which came with its own issues.
Then a confidant from her past life reached out and offered support. She brought Arzah to Seattle and introduced her to BABES. Here at last were women living with HIV, and although she was younger than they were, they soon became mentors and sisters to her. One of BABES' founders, she learned, had even been her birth mother’s caseworker and had visited Tradell in the hospital the day he died.
“I felt really bad that after I was taken to a foster home, she had had no clue what had happened to me over all those years,” Arzah said. “She was so happy to see that I turned out okay.”
Joining the conversation on cure
She has reconnected with her father, who had become HIV-infected while battling substance abuse but is sober now and on antiretroviral treatment. She also maintains a relationship with her youngest brother, who is HIV negative and who had been adopted by another family.
Arzah is so comfortable now with her identity — as a queer woman, a black feminist and a person with HIV — that she admits that a cure seems both exciting and scary.
“I don’t know a life without HIV,” she said.
But she does know that HIV is not over, that stigma still exists and that big swaths of people — some of them female, many of them young and black- or brown-skinned, like her — don’t have access to prevention or treatment or even just information on HIV.
She doesn’t want that to be the case with any future cure. Having struggled so long to find her voice, she wants to make sure others are heard too.
“That’s what I love about defeatHIV,” she said “They invite that conversation to happen. We get the opportunity to talk to the scientists. We get to tell them, ‘Women have concerns. Young people have concerns about getting involved.’”
A single cure sparks hope
Photo by Robert Hood / Fred Hutch News Service
To grasp the challenge of curing HIV, consider that more than 70 million people worldwide have been infected with HIV since the first cases were reported in 1981. Today almost 37 million people are living with HIV. The rest have died of AIDS-related causes.
And then there’s Timothy Ray Brown.
The Seattle-born Brown was not trying to cure his HIV infection when he reluctantly agreed to a stem-cell transplant in 2007 in Berlin, where he was then living. The immediate threat to his life was acute myeloid leukemia. Chemotherapy had failed, and the grueling transplant — assuming he survived it — was a last-ditch attempt to cure his aggressive blood cancer.
Stem cell transplants, pioneered at Fred Hutch, require a complex match between donor and patient. Brown’s oncologist, Dr. Gero Hϋtter, went one step further. Years earlier, he had read about a rare gene mutation that confers natural resistance to HIV by deleting what is known as the delta-32 section of the CCR5 gene, which HIV latches onto and uses to enter and infect white blood cells. With Brown’s permission, Hϋtter was able to find a matching stem-cell donor with that mutation.
Three months after the February 2007 transplant, Brown’s HIV was undetectable even though he had stopped taking his antiretroviral medication. Although curing the leukemia required a second transplant, today he is free of both cancer and HIV.
Scientists are still trying to understand which factors contributed to Brown’s cure, including the “conditioning,” or intense chemotherapy and radiation that destroyed his immune system to make room for the transplanted immune cells; the HIV-resistant donor cells; or the graft-vs.-host disease that Brown developed after the second transplant. All agree that this complex treatment would not be appropriate for the vast majority of people with HIV unless they faced a similar life-threatening cancer.
Still, proof that an HIV cure was even possible inspired scientists around the world — including those at Fred Hutch — to search for other, less toxic approaches.
Seeding cure research
Led by co-directors Drs. Hans-Peter Kiem, a Fred Hutch transplant and gene therapy expert, and Keith Jerome, a Hutch virologist, defeatHIV is using Brown’s case as a blueprint for a less harsh and more broadly applicable cure. One of the first three national groups to be funded by the NIH in 2011, it sought to genetically engineer resistance into an HIV-infected person’s own blood stem cells.
Kiem’s lab has successfully modified blood stem cells in animal models using a gene editing technique that employs molecules called zinc-finger nucleases and returned the resistant stem cells to repopulate the immune system. Research into this approach is continuing under a separate five-year grant to Kiem’s lab from the National Heart, Lung, and Blood Institute, a division of the NIH.
Meanwhile, defeathHIV got an additional five years of funding in 2016 to investigate using the immune system to eradicate or at least control HIV, much in the same way as immunotherapies are revolutionizing cancer treatment. Under the new round of funding, defeatHIV is:
- 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
DefeatHIV’s work has seeded additional HIV cure research at Fred Hutch.
Kiem, working with Dr. Anne-Sophie Kuhlmann in his laboratory, is working to genetically modify blood stem cells to deliver anti-HIV therapies — specifically, in this case, broadly neutralizing antibodies that have been shown to target HIV. Because stem cells give rise to all the blood cells in the body — and because such cells are continually replaced as they die off — modifying stem cells and thus stem-cell derived blood cells to produce broadly neutralizing antibodies would lead to a steadily replenished supply of the antibodies.
Jerome is developing a way to make sure that cell and gene therapies get to the right cells in the body: the type of T cells (a part of the immune system) that HIV itself targets. Working with co-investigators Dr. Dan Stone of the Hutch and University of Washington microbiologist Dr. Shiu-Lok Hu, Jerome is modifying an adeno-associated virus to act as a viral vector — a virus that delivers a therapy by infecting a cell but does not itself cause disease. To make sure it reaches the right cells, the team will destroy its usual way of getting into cells and then add an engineered protein called a designed ankyrin repeat protein, or DARPin, that only allows the virus to infect T cells.
Fred Hutch file photo
Jerome and a team of Fred Hutch and University of Washington virologists and bioengineers also are developing nanocarrier technology to deliver therapies to “kick” (or awaken) reservoirs of dormant, HIV-infected cells. These reservoirs are a key barrier to curing HIV because the dormant cells can’t be killed by antiretroviral therapies. But once awakened, these infected cells are vulnerable to the drugs. Nanocarriers are extremely small particles that can be bioengineered to carry drugs to specific cells while limiting toxicity to other cells.
In separate research, Dr. Josh Schiffer, a physician and mathematical modeler, and HIV expert Dr. Florian Hladik, are opening a small human clinical trial to test whether a drug already approved for another purpose can shrink reservoirs of HIV. The drug, an anti-proliferative agent called MMF (mycophenolate mofetil), is used to treat rheumatologic diseases, prevent rejection after solid organ transplants and prevent graft-vs.-host disease after stem cell transplants. MMF works by limiting T cell proliferation, and Schiffer and Hladik hypothesize that slowing the replication rate of latently infected T cells would shrink and may even eventually eliminate the reservoir. (Schiffer and Hladik also are working with Jerome’s nanocarrier project as a means for delivering MMF.)
Behind all of these efforts are community members like Tranisha Arzah, who are here to remind all of us why such research matters.
“I always appreciate people who are interested in our stories,” she said. “It’s important to make sure that’s in the forefront. It’s about people — that’s why we’re looking for a cure.”
Read our other stories in this series:
Mary Engel is a staff writer at Fred Hutchinson Cancer Research Center. Previously, she covered medicine and health policy for newspapers including the Los Angeles Times, where her editorials were part of a healthcare series that won the Pulitzer Prize for Public Service. She also was a fellow at the year-long MIT Knight Science Journalism program. Reach her at firstname.lastname@example.org or on Twitter, @Engel140.
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