Diana Finzi would never interrupt Dr. Robert Siliciano when his door was shut, but that morning — more than two decades ago — she flung it open and rushed in. She was distraught.
A graduate student in Siliciano’s laboratory at Johns Hopkins University School of Medicine, Finzi had been running important tests on blood samples of three patients who just might have been the first in the world to be cured of HIV, the virus that causes AIDS.
The trio had been taking three-drug combinations of antiviral drugs for more than a year and had no detectable virus in their blood. Siliciano (pronounced: Silla-Khanno) and his team had devised a complex test that could show whether HIV hidden in immune cells known at CD4+ T cells might ever replicate again. Should living, multiplying virus re-emerge, the test’s tiny wells of purified blood cells would turn blue.
Those were bright times for HIV research. Since 1995, thousands of patients who had been on the brink of death were being brought back to good health by a three-drug combination of antiviral drugs. Known to only a handful in the research community, those three patients were the embodiment of hope.
But that morning, the wells were turning blue.
“I understood the gravity of this immediately,” Dr. Finzi recalled, from her Bethesda, Maryland, office at the National Institute of Allergy and Infectious Diseases, where she now directs basic research for the Division of AIDS. Without the ability to mop up latent HIV infection, there was no quick cure for HIV.
Fast forward to 2019, and there is still no cure. Yet the efforts to find one continue.
This Thursday, Siliciano will deliver the keynote address at the 5th Conference on Cell & Gene Therapy for HIV Cure, hosted by Fred Hutchinson Cancer Research Center in Seattle. The conference and its Aug. 21 pre-conference community forum are devoted to current research on efforts to scrub out these persistent reservoirs of HIV infection — a task that was laid out starkly by findings of his laboratory in the 1990s.
Fred Hutch virologist Dr. Keith Jerome, co-host of the conference, said Siliciano is a giant in the field of HIV cure research. “Bob’s work over the past two decades has defined our understanding of the HIV reservoir and provides the conceptual basis for the HIV cure approaches we and others are currently testing,” he said.
Siliciano’s dispiriting results showing the persistence of latent HIV infection were published in Science in 1997, and two years later he and his colleagues would publish an even bleaker assessment. It included a mathematical model that calculated that it would take an average of 60 years of HIV antiviral therapy — essentially a lifetime of taking the drugs — to rid the body of the virus.
“It was the beginning of a pretty dark period,” Siliciano said, during a telephone interview. Still, encouraged by medical evidence that a cure is possible, he and a network of cure researchers around the globe are continuing their efforts to corner the virus once and for all.
Progress and continued challenges
Among the 34 million people living with HIV today, only two individuals are known to date to have been cured of HIV, both through transplants of blood stem cells: In 2007, Seattle native Timothy Ray Brown received the first of two transplants for acute myeloid leukemia, each one from a donor who carried two copies of a gene known to confer resistance to HIV infection. The purpose of the transplants was to cure his cancer, but in addition, the procedures rid him of HIV.
In March of this year, a second person, known as the London Patient, was found to be likely cured of HIV after a transplant to treat Hodgkin lymphoma. In the more recent case, the patient received a single transplant that also carried the HIV-blocking genes and was pre-treated with much milder regime of chemotherapy than Brown had experienced.
During the two-day conference, researchers will review the latest developments in efforts to cure patients of HIV — and eliminate the need for them to take antiviral drugs for the rest of their lives. These include variations on the transplantation of HIV-resistance genes, the use of gene editing to target infected cells, or adoption of cancer-fighting technologies such as CAR T-cell therapy that harness the immune system to kill latently infected cells.
Siliciano’s presentation will focus on the existing barriers to finding an HIV cure, which have stymied researchers since the beginning of the epidemic. His own laboratory continues to explore a technique known as “shock and kill.” The idea is to prompt resting T cells that are infected with HIV to become activated and churn out HIV, a process that typically kills those cells. Meanwhile, the viruses are blocked from infecting new cells by antiviral drugs in the bloodstream.
“Although it is kind of logical and simple — you turn on the virus and have the immune system get rid of it — there are huge problems we are struggling with now,” Siliciano said. “We just don’t have a good way to turn the virus back on.”
The problem that has proven so daunting is that scientists have yet to find a way to activate only those T cells that carry HIV genes. Such cells are relatively rare, but experimental drugs known as “latency reversing agents” cannot tell them apart from other resting T cells.
“We’re left with trying to find a way to turn on HIV infected cells without turning on every resting T cell in the body,” he said. “That would cause too much toxicity.”
Siliciano said that the problems with shock and kill are so difficult that the gene therapy approaches that Fred Hutch researchers Jerome and Dr. Hans-Peter Kiem are developing “may get there first.”
Kiem holds the Stephanus Family Endowed Chair for Cell and Gene Therapy and is a is a world leader in efforts to genetically engineer HIV resistance into blood cells as a potential cure for HIV. He has been working on a variety of gene therapy approaches that might replicate the experiences of Brown and the London patient. He is researching new techniques to transfer HIV-resistance genes to patients without having to modify the cells outside in the body in a laboratory, which could reduce costs of such procedures and make gene therapy available more broadly, including in resource-limited settings.
A co-host of the conference, he was delighted to have Siliciano as keynote speaker of the event.
“Dr. Siliciano’s research has been instrumental in defining and measuring the latent reservoir — the ability of HIV to hide in many different tissues in people — and that is a critical step for the development of novel therapies for HIV eradication,” Kiem said.
About the Conference on Cell & Gene Therapy for HIV Cure
The 5th Conference on Cell & Gene Therapy for HIV Cure will be held August 22–23 at the Residence Inn by Marriott Seattle Downtown/Convention Center. Registration is required.
At 7 p.m. on Wednesday, August 21, the Seattle Public Library Central Branch will host a free pre-conference community forum about gene therapy and its potential to cure HIV. It will feature a discussion, Medical Angels, with two HIV activists who took part in early gene therapy trials and Dr. Carl June, of the Perelman School of Medicine, University of Pennsylvania, who led the first clinical trial of the use of gene editing to confer HIV-resistance genes in immune cells of people living with HIV.
