In 2007, a young American man living in Berlin became a marvel of modern medicine when, 12 years after he was diagnosed with HIV, the virus suddenly disappeared from his body. Timothy Ray Brown had been diagnosed with leukemia and received a stem cell transplant treat it. His stem cell donor, it turned out, had a rare genetic mutation known as CCR5-delta 32 that gave Brown resistance to HIV infection. Brown became known as "the Berlin patient." Ten years later, he is still the only person to have ever been cured of HIV.
Despite incredible advances in biomedicine, a true cure for HIV has remained elusive. Antiretroviral drugs have transformed HIV into a manageable condition instead of a death sentence. But HIV permanently integrates into the genome of an infected cell and then hides, dormant, in the body, making it nearly impossible to eradicate. Since the 1980s, researchers have been hopeful that gene therapy, in which the body's genetic material is altered, could provide a new route to treating HIV, and maybe even a cure. Brown's case made many in the field optimistic, but scientists are still stumped as to exactly how his cure worked.
A new study published Thursday in PLOS Pathogens shows a new potential route to curing HIV — though it also highlights the extreme difficulties facing researchers.
"We've effectively only cured one patient," Scott Kitchen, the lead author on the UCLA study, told Gizmodo. "But that provides a lot of hope."
In the new study, researchers took a page from Brown's treatment, hoping to stimulate the body's immune system with engineered stem cells to fight off HIV. First, blood-forming stem cells were engineered to carry genes that transform the cells into targeted killers, capable of detecting and destroying HIV-infected cells when they show up in the body. The technique works by hijacking the same molecule, CD4, that allows HIV to bond to a cell's surface, using the molecule as a signal to bind to HIV and kill it. Then those stem cells were put into the bodies of two primates via a bone marrow transplant. It's a form of treatment known as CAR-T immunotherapy.
"HIV damages the cellular immune response - that's what makes it so effective," Kitchen said. "So in order to effectively clear it, we need an effective immune response. We're providing that."
CAR-T has shown promise in treating HIV before, but with this new approach, researchers found that the primate's bodies kept producing the CAR-expressing cells for more than two years after the initial infusion without any adverse effects. This suggests the potential for a long-term solution that could reduce a person's dependence on antiviral medications and potentially even completely eradicate HIV from the body, attacking even HIV lurking dormant in the body's reservoirs whenever it comes roaring back to life.
"We believe it is a component to a cure, used in combination with something like antiretroviral therapy," Kitchen said. "This shows a cure is effectively possible."
Recently, there have been some other promising breakthroughs in eliminating HIV, but so far, researchers have mainly succeeded in curing HIV in mice. Earlier this year, scientists at Temple University used CRISPR to edit HIV DNA out of mice. A handful of clinical trials are under way attempting to cure humans with HIV through combinations of gene and stem cell therapies, but it's unclear whether these will actually work long-term. (Earlier this year, a biohacker also injected himself with a DIY HIV cure, though it's highly unlikely that his approach will work.)
Technologies like gene editing have made finding a cure for HIV seem possible, but there are still many technical hurdles in the way. A true cure may still be a long ways off.
The biggest hurdle in creating a cure is making something that lasts long enough to battle the persistent reservoirs of the virus in the body. This is the problem that the UCLA research was trying to solve. But to get there, scientists will have to improve the ability to edit cells within a patients body, rather than removing them, editing them in a lab, and then reinserting them back into the patient. There is also room for improvement in our ability to locate the genes that need to be manipulated, which are scattered throughout the body. And to further complicate things, because HIV is known to develop resistance to treatments — even CRISPR — a combination of therapies will likely be more successful.
"The availability of tools and targets suggests that designing a gene therapy intervention to cure HIV is arguably a question of technology rather than discovery," Rowena Johnson, the foundation's director of research, wrote in a paper at the time. "However, the feasibility of the approach is still a major hurdle. The timeline, cost, and complexity of testing gene therapy in the clinic are formidable."
So far, there has been much more optimism in using gene therapy to make the body's cells immune to HIV instead. In these approaches, the virus is prevented from entering a cell in the first place. It's an easier task, because it doesn't require dealing with the problem of a dormant virus that flares up over a long period of time. Several clinical trials for these kinds of therapies are also under way.
"Brown was just an extraordinary case," Kitchen said. "He went through two bone marrow transplants. That would normally kill someone. And we still don't know exactly how it worked."
In the case of the new UCLA research, the biggest hurdle is figuring out the most effective way to transplant the smallest number of stem cells possible into the body of an infected patient. Ideally, he said, they would like to develop something like a vaccine that doesn't require an invasive procedure like bone marrow transplant, but for now, that thought is mostly "science fiction." Still, Kitchen said, clinical trials for their new approach are likely just two or three years away.
A cure might not be right around the corner. But for the first time, it's starting to appear on the horizon.