Researchers are closer to unraveling the mystery of how Timothy Ray Brown, the only human cured of HIV, defeated the virus, according to a new study. Although the work doesn’t provide a definitive answer, it rules out one possible explanation.
Brown remains one of the most studied cases in the HIV epidemic’s history. In 2006, after living with the virus for 11 years and controlling his infection with antiretroviral drugs, he learned that he had developed acute myeloid leukemia. (The leukemia has no known relationship to HIV infection or treatment.) Chemotherapy failed, and the next year Brown received the first of two bone marrow transplants — a common treatment for this cancer — and ditched his antiretrovirals. (An American then living in Berlin, Brown has been known to researchers for years as “the Berlin patient.”
When HIV-infected people stop taking these drugs, levels of HIV typically skyrocket within weeks. Yet researchers scouring Brown’s blood over the past seven years have found only traces of the viral genetic material, none of which can replicate.
Today, researchers point to three factors that might independently or in combination have ridden Brown’s body of HIV. The first is the process of conditioning, in which doctors destroyed Brown’s immune system with chemotherapy and whole-body irradiation to prepare him for his bone marrow transplant.
Second, his oncologist, Gero Hütter, took an extra step that he thought might not only cure the leukemia but also help rid Brown’s body of HIV. He found a bone marrow donor who had a rare mutation in a gene that cripples a key receptor on white blood cells that the virus uses to establish an infection.
The third possible explanation is that Brown’s new immune system attacked remnants of his old one that held HIV-infected cells, a process known as graft vs. host disease.
In the new study, a team led by immunologist Guido Silvestri of Emory University in Atlanta designed an unusual monkey experiment to test these possibilities.
Bone marrow transplants work because of stem cells. Modern techniques avoid actually aspirating bone marrow and instead can sift through blood and pluck out the stem cells needed for a transplant to “engraft.” So the researchers first drew blood from three rhesus macaque monkeys, removed stem cells and put the cells in storage. They then infected these animals and three control monkeys with a hybrid virus, known as SHIV, that contains parts of the simian and human AIDS viruses. All six animals soon began receiving antiretroviral drugs, and SHIV levels in the blood quickly dropped below the level of detection on standard tests, as expected.
A few months later, the three monkeys with stored stem cells underwent whole-body irradiation to condition their bodies and then had their own stem cells reinfused. After the cells engrafted, a process that took a few more months, the researchers stopped antiretrovirals in the three animals and in the three controls. SHIV quickly came screaming back in the three controls and two of the transplanted animals. (One of the transplanted monkeys did not have the virus rebound, but its kidneys failed and the researchers euthanized it.)
The team, which published its work online in PLOS Pathogens last month, concludes that conditioning by itself probably cannot rid the body of the AIDS virus. Silvestri explains that the monkey study was a proof-of-principle experiment that cleanly isolated the effects of conditioning alone. “There’s no way to do this in humans,” he says.
“It’s an important study, and it’s a very useful model,” says Daniel Kuritzkes of Brigham & Women’s Hospital in Cambridge, Mass., who wasn’t connected to the research.
Kuritzkes and his colleagues are particularly interested in the experiment because two of their own HIV-infected patients with leukemia received bone marrow transplants from donors who did not have HIV-resistant cells. For several months after stopping antiretrovirals, HIV remained at bay in both men, raising hopes that the resistant donor cells were not a factor. But the virus eventually returned in each patient. Kuritzkes suspects that the transplants did reduce the amount of HIV left in the patients’ bodies — known as the viral reservoir — but that the virus resurfaced because it continued to copy itself and eventually overwhelmed the immune responses against it.
Although the study shows that conditioning by itself probably cannot eliminate an HIV infection, it leaves open the possibility that graft vs. host disease played a central role in Brown’s cure. Unlike Brown and Kuritzkes’s two patients, the transplanted monkeys received their own stem cells, which did not trigger a graft vs. host response. “At the end of the day, that might be an important component,” Silvestri says. He also thinks it might help reduce the reservoir size to treat monkeys with antiretroviral drugs for longer than a few months.
Silvestri hopes to do future monkey experiments that test the different variables, including transplanting the animals with viral-resistant blood cells that mimic the ones that Brown received.
“The best scientific studies raise as many questions as answers,” says Steven Deeks, a researcher and clinician at the University of California at San Francisco, who has treated and studied Brown. “Unfortunately, the heroic efforts that went into this study failed to provide a definitive answer regarding the riddles of the Berlin patient. The model will likely need to be further optimized, and at the very least, the macaques [will need to be] treated with antiretroviral therapy for longer periods of time. But I am confident the team will figure this out.”
This story has been provided by the nonprofit science society AAAS and its international journal, Science.
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