Cure Research: Marching on-but over uneven terrain

A recent symposium captured the growing sense among researchers that HIV infection can be cured. But it also exposed the many challenges that lie ahead.

Just before this year’s International AIDS Conference (IAC) kicked off on July 22 in Washington, D.C., scientists met there for a two-day symposium named “Towards an HIV Cure.”

The event was held just after the release of a research plan by the International AIDS Society (IAS)—which also hosts the IAC. Released on July 19 and titled “Global Scientific Strategy Towards an HIV Cure,” the plan identifies seven priorities for cure research. It is the creation of a group of 34 scientists and clinicians worldwide led by HIV co-discoverer and Nobel laureate Françoise Barré-Sinoussi of the Institut Pasteur in Paris, and Steven Deeks of the University of California, San Francisco. 

No such coherent set of internationally vetted priorities previously existed to guide the burgeoning field, explained Barré-Sinoussi, who has since been named IAS president. It was important, she noted, that scientists—and not the agencies funding them—developed the plan. “I proposed to start [with] the researchers and to go to the funders and to say, look, this is the priority,” she said. “The scientists are the ones who know the priorities.” Another important purpose of the plan, Deeks added, is to avoid redundancy in both research and funding.

As the IAS observed in a statement, the plan comes at a time of “renewed optimism in the search for an HIV cure.” Part of that optimism derives from research inspired by the case of Timothy Brown, also known as the “Berlin patient,” who is thought to be the first and so far only person to have been cured of HIV.

Some of the findings reported at the symposium, which was also co-chaired by Barré-Sinoussi and Deeks, were indeed cause for optimism. There has, for example, lately been some progress towards replicating Brown’s cure. Further, researchers now have a better understanding of the types of cells that harbor the HIV reservoir, which could spawn more efficient strategies to eradicate latent HIV. There is also growing evidence that starting antiretroviral therapy (ART) early, during acute infection, could result in a smaller HIV reservoir that is more easily contained by the immune system.

But not all news was positive. For example, researchers have found that the HIV reservoir can be established in hitherto unknown ways; and there is evidence that reactivating HIV replication in latently infected cells, so that the host cells may then be eradicated, may prove more difficult than anticipated.

Building on the Berlin case

Timothy Brown was cured of HIV after he received two allogeneic bone marrow transplants from a donor who was missing both CCR5 co-receptor genes, which made his cells resistant to HIV infection. Researchers have since sought to replicate his cure in other patients, and attendees heard of promising results from one such attempt.

Timothy Henrich, an infectious disease doctor at Brigham and Women’s Hospital in Boston, reported that two HIV-infected patients who, like Brown, received allogeneic transplants from HIV negative donors, appear now to be free of viral reservoirs, at least in their blood cells. But unlike Brown, these patients received their transplanted cells from donors who had both CCR5 co-receptors. Therefore, while Brown was taken off ART after receiving the transplant, Henrich and colleagues kept their transplant recipients on ART continuously, hoping this would protect the donor cells from becoming infected with HIV until they completely replaced the HIV-infected cells in the recipients.

And indeed, that seems to have happened: While the researchers could still detect integrated HIV DNA in their patient’s blood cells two to three months after the transplant, by eight months, after of the donor cells had taken hold in the two recipients, that DNA was gone, and there was no outgrowth of viral particles from those cells. This is still the case now, four years after the transplant. “What I think is happening is that when the new cells are taking over, they are being protected by the ART,” Henrich said, adding that the level of HIV-specific antibodies has also been declining in the transplant recipients.

Henrich noted that this is the first clear evidence of a significant reduction of the HIV DNA reservoir following transplant and treatment for several years, at least in blood cells. There was also no HIV RNA in the blood, indicating that there was no viral replication, but Henrich cautioned that it remains to be seen whether viral replication will rebound once ART is stopped. “The ultimate test would be to take these patients off their medications and see what happens. That’s something that we are thinking about doing,” he said, adding that before stopping ART, he plans use highly sensitive assays to make sure that there is no HIV RNA or DNA in blood cells and other tissues such as gut and cerebrospinal fluid of the patients.

If the treatment succeeds, it would suggest that Brown’s cure can be replicated even if the donor has a normal set of CCR5 genes. Finding a donor who lacks both genes, as was the case with Brown, is difficult, especially in non-Caucasians. It also remains to be seen if the approach would work if the recipient has the full set of two CCR5 genes because, like Brown, both of Henrich’s patients had only one copy of CCR5. Henrich said he has yet to check whether two additional patients who have volunteered to try out his experimental treatment carry both CCR5 genes.