Until about five years ago, cure was the forbidden word of the HIV world: No one said it out loud.
In the awful early years of the pandemic, researchers struggled to find treatments to stem the tide of deaths. To suggest a cure was possible, much less imminent, seemed not just naïve but cruel.
A cure remained elusive even after combination antiretroviral therapy in the mid-1990s turned HIV from an automatic death sentence to a manageable chronic disease. For those with access to it, the treatment was a life-saving breakthrough, yes, but no more a cure than insulin is a cure for diabetes. Scientists learned that reservoirs of latent HIV-infected cells hide in the body, out of reach of the drugs. Stop taking a daily pill, and the virus comes roaring back.
But today, scientists are not just using the word cure, they’re organizing whole conferences around it. A cure symposium has been added to the International AIDS Society conference on treatment and prevention, to be held in July in Melbourne, Australia. Fresh from that meeting, society president and Nobel laureate Françoise Barré-Sinoussi—who in 1983 co-discovered the virus that causes AIDS—will speak in August at Fred Hutchinson Cancer Research Center’s first Conference on Cell and Gene Therapy for HIV Cure.
To be clear, caution still prevails. Many, including Barré-Sinoussi, say that the most realistic goal may be a so-called “functional cure” that doesn’t necessarily eradicate all traces of the virus but eliminates the need to take daily pills. Scientists are also careful not to raise hopes that a cure of any kind will be widely available any time soon.
What can we expect in the next five years?
“If you’re talking about a handful or a roomful of people who have been cured of HIV—that's something we're likely to see,” said Dr. Keith Jerome, an expert in viral infections at the Hutch’s Vaccine and Infectious Diseases Division and co-host of the upcoming Hutch conference. “If you’re talking about something that’s broadly available to hundreds of thousands or millions of people, we’re much farther away from that.”
Jerome and Dr. Hans-Peter Kiem, a stem cell transplant researcher in the Hutch’s Clinical Research Division and conference co-host, lead a team that is investigating using genetically modified stem cells to cure HIV. Their approach is based on the case that first prompted scientists to dare say cure out loud when it was reported in 2008—that of Timothy Ray Brown.
The game changer
Seattle-born Brown, now 48, visited the Fred Hutch campus last year for a scientific forum and a public panel. Known in early reports as the Berlin patient, he was diagnosed with HIV in 1995 in Germany, where he was then living, and used antiretroviral therapy to control it. Then he developed acute myeloid leukemia and in 2007, needed a stem cell transplant, a procedure pioneered at the Hutch.
His German doctor decided to try to cure not just the cancer but HIV by finding a stem cell donor who carried two copies of an exceedingly rare gene mutation that confers natural resistance to the virus. The mutation deletes what is known as the delta-32 section of the CCR5 gene, which HIV latches onto and uses to enter white blood cells.
Brown’s leukemia returned after the first transplant, so he had a second in 2008 and has remained cancer-free. He has not taken antiretroviral medicine since the first transplant and his virus has not rebounded, giving him the distinction of being the first person pronounced—however cautiously—cured of HIV.
In 2013, scientists published a report of a second cure that occurred through different means: An HIV-infected newborn known as the Mississippi baby was treated immediately after birth with aggressive antiretroviral therapy. The child, now 3, went off treatment after 18 months and has not shown signs of infection. In March, researchers announced similar results with a second baby who had been born positive, but she is still on the antiretroviral drugs so it’s too early to know if she’s in remission. Efforts are underway to replicate the results in other newborns.
As for the Brown cure, defeatHIV, as Jerome and Kiem’s group is called, is not trying to re-create it exactly. A stem cell transplant using donor cells is a last-resort treatment requiring a complex match between donor and recipient as well as a brutal regimen of chemotherapy to kill off the old immune system. Both expensive and risky, such treatment would not be considered appropriate for the vast majority of people with HIV unless they faced a similar life-threatening cancer. Even then, finding a matching donor with two copies of the rare mutation would add to the challenge.
Instead, defeatHIV will use Brown’s case as a blueprint for attempting a new kind of therapy involving gene modification. The plan is to take an HIV-infected patient’s own stem cells and knock out or disable the gene that acts as the HIV doorway, mimicking the genetics of someone who has natural resistance. The modified cells would then be returned to the patient.
Reports of Brown’s cure came at a time when Kiem’s lab already had been working on improving techniques to modify and correct hematopoietic stem cells—the precursors that generate all the specialized cells of the blood and immune systems—to treat patients with cancer, genetic blood disorders and chronic infections. The new line of research is designed to answer the question: Can gene therapies generate enough HIV-resistant cells to lead to a cure?
DefeatHIV started in 2011 with a $20 million grant from the National Institutes of Health intended to foster public-private partnerships in working toward an HIV cure. Other members of the team include researchers from the University of Washington, Seattle Children’s, The City of Hope’s Beckman Research Institute in Duarte, California, and Sangamo BioSciences in Richmond, California.
“Timothy Brown’s cure launched the cure effort in the United States,” said Kiem. “It’s quite remarkable to think that one person has had such an influence on research direction and on the NIH.”
The Hutch-led collaboration is one of three distinct approaches funded by the NIH and called the Martin Delaney collaboratories, after an early HIV/AIDS educator and activist. The University of North Carolina, Chapel Hill, is leading a team working on an approach called “shock and kill” or “kick and kill” that is looking for drugs that can wake the virus from its latency stage so that antiretroviral drugs can kill the hidden reservoirs. A group based at the University of California, San Francisco is focused on the role of the immune system and the inflammatory reaction to establishing and maintaining the reservoir.
According to Jerome and Kiem, a successful cure will likely borrow from all three. Drugs used to wake up the viruses could facilitate gene therapy approaches by making them work more efficiently, they said. Inflammation plays a big part not only in HIV persistence but in engraftment of genetically engineered cells.
“We collaborate among the collaboratories,” Jerome said. “The ultimate cure is very likely to be a combination of approaches.”
Does a cure still matter?
Neither Jerome nor Kiem are worried at the moment about whether these efforts might lead to a so-called “sterilizing cure” that actually wipes out the virus or a functional cure. Working in a cancer research center, they have a keen appreciation of interim steps. In any case, the answer to that is years away, after the therapy is developed, and ways are found to reliably measure the reservoir and clinical trials follow patients over numerous years.
“From the leukemia or lymphoma malignancy point of view, if we don’t detect any disease after about 5 years, we talk about cure,” said Kiem. “But sometimes the disease comes back even after five or six or seven years. As with cancer, long-term monitoring of patients who might be cured of HIV will be critical.”
Does a cure still matter, given what antiretroviral drugs have already accomplished?
To Jerome, Kiem and other scientists, the answer is an urgent yes. Lifelong treatment—although far better than the alternative is expensive. Not everyone can tolerate the side effects. And despite great progress in recent years in making treatment available, only about 10 million of the 35 million people infected with HIV worldwide are on antiretroviral medication.
Another reason to press for a cure is the risk that the rapidly mutating virus will develop strains that are resistant to the drugs now used to suppress it.
“The general public in the United States doesn’t see HIV as an especially urgent problem now because they don’t see people visibly dying from the virus,” said Jerome. “But if we look at the problem from a worldwide basis, it absolutely is urgent. There’s a huge worldwide burden of disease and death from this virus. So, yes, we’re going absolutely as fast as we can.”
Early-bird registration ends July 7 for Cell & Gene Therapy for HIV Cure 2014, which will be held Aug. 26-27 at Fred Hutch. The conference is intended to foster scientific relationships and collaboration among national and international scientific researchers, early investigators, post docs and graduate students. Scholarships and travel grants are available.
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.