Cure research: An update and a roadmap
Just before this year’s International AIDS Conference (IAC) kicked off on July 22 in Washington DC, scientists met here on July 20 and 21 for a symposium called “Towards an HIV Cure” to discuss recent advances in HIV cure research, previewing many related research announcements that were later also discussed at the main conference. (The talks were under embargo until discussed at the main conference, which is why I am only posting this now.)
The researchers met just after the International AIDS Society (IAS), which hosts the IAC, announced a roadmap called the “Global Scientific Strategy Towards an HIV Cure” that identifies seven priority areas for cure research. These include studying the mechanisms and sources of HIV persistence and the origins of immune activation and inflammation in people on long term antiretroviral therapy (ART); comparing and validating assays to measure persistent infection; finding ways to safely eliminate latent infection in people on ART; and improving the host response so it can control viral replication.
The roadmap, announced on July 19, is the result of deliberations of a group of 34 basic scientists and clinicians that was co-chaired by IAS president-elect and HIV co-discoverer Françoise Barré-Sinoussi from the Institut Pasteur in Paris and Steven Deeks from the University of California, San Francisco. The roadmap was necessary because “what was missing before was an international group [that defines] the main priorities in work on HIV cure,” said Barré-Sinoussi, adding that it was important 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,” Barré-Sinoussi said. “The scientists are the ones who know the priorities.”
Another purpose of the roadmap, Deeks said, is to avoid overlaps in terms of what different collaborations and funding agencies are doing. He said the document will be presented to an advisory board of representatives from funding organizations, who are charged with using the document to raise funds, trying to go beyond traditional funding sources such as the National Institutes of Health and instead try to raise funds from less traditional sources such as the Chinese or the Brazilian governments.
The announcement of the roadmap, the IAS said in a statement, comes at a time of “renewed optimism in the search for an HIV Cure,” given recent scientific advances such as the case of Timothy Brown who is thought to be the first person to have been cured from HIV, showing that cure is at least possible.
Some of the research updates at the two-day “Towards an HIV cure” symposium were indeed encouraging. For example, now that Timothy Brown seems to have been cured after receiving an allogeneic bone marrow transplant from a donor that was missing both CCR5 coreceptor genes (which made his cells resistant to HIV infection), researchers are working on similar approaches to see if this success can be replicated. At the symposium, Timothy Henrich from Harvard Medical School reported promising results in two HIV-infected patients who, like Brown, received an allogeneic transplant from HIV negative donors.
But in contrast to Brown’s case, Henrich and colleagues transplanted cells from donors who still had both CCR5 coreceptors. Therefore, while Brown was taken off ART after receiving the transplant, Henrich and colleagues kept their transplant recipients on ART continuously, hoping that this would protect the donor cells from becoming infected with HIV until they completely replaced the HIV-infected cells in the recipients.
And indeed, this seems to be the case: Henrich reported that once all of the donor cells had engrafted into the two recipients (which was the case two to three months after they received the transplant), he could not detect any integrated HIV DNA in, or outgrowth of viral particles from, cells taken from their blood. “What I think is happening is that when the new cells are taking over, they are being protected by the ART,” he said. He cautioned, however, that it remains to be seen if ART can be stopped in the two patients without a rebound of viral replication. “That’s one thing we are thinking of doing,” he said.
Promising news also came from Asier Sáez-Cirión from the Institut Pasteur and Charline Bacchus from the Pitié-Salpêtrière Hospital in Paris, France, who reported that it might be possible to achieve a functional cure (where virus is controlled without the need for ART) by starting ART early, at least in some patients. That’s what seems to have happened in the so-called VISCONTI cohort, a group of HIV-infected patients in France who were started on ART about ten weeks after infection. When ART was stopped after several years, they did not show any viral rebound, suggesting that they were functionally cured.
The question is why, and at the symposium, Sáez-Cirión and Bacchus reported that the early start of ART seems to have resulted in an unusually small size of the reservoir with an unusually small fraction of longer-lived CD4+ T cell types, which might at least in part explain why the VISCONTI patients can control HIV infection without the need of ART.
One reason the latent HIV reservoir persists for a long time in infected people is that some cells that harbor latent HIV persist for a long time, and eradicating especially the long-lived cells is likely an effective strategy to eradicate HIV reservoirs. At the symposium, Maria Buzon from the lab of Mathias Lichterfeld at Massachusetts General Hospital in Boston reported that one recently identified type of memory T cell that lives longer than any other memory T cell type (perhaps indefinitely) called stem cell memory (SCM) cell, seems to harbor HIV DNA in HIV infected patients on ART, suggesting that these cells contain part of the HIV reservoir.
This suggests that elimination of these cells should help eliminate much of the long-lived reservoir in HIV-infected people, Lichterfeld said. “You have to find a way to target the stem cells,” he said. “They are probably the ones where most of the long-term viruses persist.” One way to do this, he said, could be to treat patients with drugs that cause SCM cells to differentiate and develop into shorter-lived cell types; once the shorter-lived cells die, the reservoir should die with them. Lichterfeld said he is currently testing such drugs in collaboration with pharmaceutical companies.
Not all findings reported at the symposium were encouraging, however. Robert Siliciano from the Johns Hopkins University School of Medicine reported evidence that a larger fraction of the reservoir may harbor functional virus than previously thought. Siliciano and his colleagues isolated resting CD4+ T cells from the blood of patients on ART and measured which cells could produce virus particles when they were activated. Many could not produce virus particles, and sequencing of the HIV DNA in the CD4+ T cells that were not able to produce virus revealed that the HIV DNA in many of these cells had deletions or mutations.
However, to their surprise, the researchers also found that 17% of the cells that couldn't produce virus harbored complete HIV sequences that didn’t have any mutations or deletions, suggesting that in principle, they should be able to produce functional virus. While it’s still unclear why these cells don’t produce virus, this “could mean that the size of the pool of [reservoir] cells that we have to worry about is bigger” than previously thought, Siliciano said.
Researchers may also have to worry about more ways the HIV reservoir can be established than they were aware of, at least according to findings by Nitasha Kumar in Sharon Lewin’s lab at the Burnet Institute in Melbourne, Australia. One way the reservoir is thought to be established is when activated CD4+ T cells become infected and later return to a resting state. But Kumar reported that CD4+ T cells can also get infected while they are in the resting state, at least in the presence of dendritic cells, presumably by direct cell-to-cell transmission of HIV from the dendritic cells to the resting CD4+ T cells. This suggests that researchers may still have a lot to learn when it comes to understanding how the reservoir can be established. “The more we look, the more we find,” Lewin said.