Timothy Ray Brown, aka the “Berlin patient,” the only person to be cured of HIV, may finally have company. A decade after Brown became famous thanks to a stem cell transplant that eliminated his HIV infection, a similar transplant from a donor who has HIV-resistant cells appears to have cured another man, dubbed the “London patient.”
“This is a big deal,” says Sharon Lewin, who heads the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia. “It tells us that Timothy Brown wasn’t a one-off.” Although the interventions that the two patients received could only be used on a tiny fraction of the 37 million HIV-infected people worldwide, their stories point to cure strategies that could be more widely applicable.
To treat blood cancers, both HIV-infected men received stem cell transplants from people who carried a mutation in the gene for CCR5, a cell surface molecule that many HIV strains use to infect cells. Beforehand, each had been treated with toxic chemicals in a “conditioning” regimen meant to kill off their existing cancerous bone marrow cells. After HIV-resistant blood cells derived from the transplant supplanted the recipients’ vulnerable cells, the two patients stopped taking the antiretroviral (ARV) drugs that had been damping down their infections.
Brown remains uninfected as far as scientists can tell, and no HIV has been detected in the London patient’s blood for 18 months, save for one blip of viral DNA that researchers studying the man suspect was a false signal. The team also found that his white blood cells now cannot be infected with CCR5-dependent HIV strains, indicating the donor’s cells had engrafted.
Virologist Ravindra Gupta at University College London, who is scheduled to describe the London patient’s case tomorrow at the Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, Washington, and online in Nature, resists using the term “cured” for the man, who remains anonymous. Gupta prefers to say the man is instead in long-term remission, in part because the team hasn’t looked at tissues other than the patient’s blood. “After 2 years, we’ll be talking more about ‘cure,’” Gupta says.
Stem cell and bone marrow transplants haven’t cured the handful of other HIV-infected blood cancer patients who have received them. Some seemed to control the infection without ARVs for a period but later had the virus rebound or died from their leukemia or lymphoma. Gupta did not expect this transplant to work either. “It’s been 10 years since the last success, and I was totally prepared for failure of the graft or return of the lymphoma,” he says.
It’s great that I finally have someone added to my family. It’s been too long.
In some of the past transplant failures, the donor did not have a mutated CCR5, but the conditioning regimen seemed to have significantly reduced the “reservoirs” of cells in the recipient that have latent HIV infections, invisible to the immune system. Brown, who required two transplants to cure his leukemia, had intensive chemical treatment and, on top of that, received whole body irradiation. The London patient, in contrast, had a milder regimen that targeted his lymphoma.
“This case tells us that there is no magic conditioning regimen,” Lewin says. Brown and the London patient also suffered from graft-versus-host disease as the transplanted immune systems attacked other recipient tissues as foreign. That might have had the ironic benefit of further reducing HIV reservoirs, Lewin says.
To learn more about the factors that favor a cure, amfAR, the Foundation for AIDS Research, a New York City–based foundation, in 2014 began to fund a consortium of international researchers who do transplants in HIV-infected people with blood cancers. The London patient is one of 40 in the study.
Timothy Henrich, a clinician at the University of California, San Francisco (UCSF), has seen HIV bounce back in two patients who had a conditioning regimen that impressively knocked down HIV reservoirs but whose transplants came from donors with working CCR5s. “Durable engraftment” of the CCR5 mutants is key to a cure, he concludes.
The London patient and Brown may point to ways to judge the success of a potential cure short of stopping ARVs and seeing whether the virus returns, says Rowena Johnston, who directs research at amfAR. Certain HIV antibodies and proteins declined in the blood of both men, she points out, which might offer a helpful early indicator of whether a cure strategy is working prior to stopping ARVs. “That could be a fantastic way forward,” Johnston says.
Steven Deeks, an HIV researcher at UCSF, says the results could also boost cure efforts to cripple CCR5 “without the need for heroic interventions such as in the Berlin and London cases.” In one example, Pablo Tebas, an infectious disease specialist at the University of Pennsylvania, and his co-workers remove white blood cells from HIV-infected people and then knock out their CCR5 genes with a genome editor called zinc finger nucleases, a precursor to the better known CRISPR. The researchers expand the modified cells and then reinfuse them into their patients with the hope that they will engraft and populate the blood.
In their latest small study, presented at CROI, Tebas’s team showed that in 15 patients who received this therapy and then stopped ARVs, HIV did rebound, but a few weeks slower than it does in people without such transplants. It’s far from a cure, but Tebas thinks coupling this approach with other interventions “might be the way of the future.”
The news about the London patient also encourages Paula Cannon at the University of Southern California in Los Angeles. “I did a little happy dance when I read the paper,” she says. Her group has been working on a way to mutate the CCR5 gene directly in the bone marrow of a person to simulate the effect of the transplants.
“Even if we’re not going to cure the world with stem cell transplants,” Johnston says, “it’s important to have a collection of people who’ve been cured so we can put together that information to figure out how we can do a cure more broadly.”
And Brown welcomes the London patient. "It’s great that I finally have someone added to my family. It’s been too long. I think it’s a movement in the right direction and proves that cure of HIV is possible but I think lots more work needs to be done to help everyone who is living with the virus," he says.