HIV Cure Research Update
Experts discussed the latest HIV cure news at a “town hall” forum in San Francisco on October 1 sponsored by the University of California at San Francisco AIDS Research Institute, the Gladstone Institutes, and the California Institute for Regenerative Medicine (CIRM).
The HIV cure field has seen remarkable, if slow, progress over the past few years and has recently garnered considerable attention, in part due to some overly enthusiastic media reports.
“We want to clear up misconceptions and tamp down some of the hype, but we can say we have solid grounds for pragmatic optimism,” said CIRM board member Jeff Sheehy.
The town hall featured researchers from three collaborative efforts funded by the National Institutes of Health to work on various cure approaches: the Delaney AIDS Research Enterprise (DARE), the Collaboratory of AIDS Researchers for Eradication (CARE), and DefeatHIV.
DARE principle investigator Steven Deeks from UCSF explained that the resurgence in optimism is largely attributable to several “proof-of-concept” cases showing that a functional cure for HIV—once deemed all but impossible—is in fact feasible.
The Berlin Patient, Timothy Brown, remains free of detectable HIV without antiretroviral therapy (ART) six years after he received bone marrow transplants to treat leukemia from a donor with a natural mutation known as CCR5-delta-32, which makes immune cells resistant to HIV entry.
A baby in Mississippi born to an HIV positive mother was started on combination ART on the day of birth. She was taken off treatment and lost to follow-up, but when tracked down a couple years later had no detectable HIV.
The VISCONTI cohort, 14 people with HIV in France who started ART within a few months after infection, stopped treatment after four to five years but have not experienced viral rebound. Finally, researchers in Boston recently reported that two HIV positive bone marrow transplant recipients did not experience viral rebound after experimental ART interruption.
While these cases are promising, Deeks emphasized that all these cases “don’t pertain to a typical person with HIV.”
Shock and Kill
The CARE collaboration is focusing on “shock and kill,” an approach that involves forcing HIV out of hiding in resting cells. Once the virus is exposed, the hope is that the immune system will kill off infected cells or give them the signal to kill themselves.
This is not likely to be accomplished with a single drug, but rather with a “synergistic cocktail,” explained Warner Greene, Director of Virology and Immunology Research at Gladstone. The trick is to activate T-cells harboring latent HIV without triggering excessive immune activation that results in a “cytokine storm” or toxic shock syndrome.
Recent work suggests that the HIV reservoir is larger and more complex than previously believed, and all cells that harbor latent HIV may not be “shockable.” Latently infected cells do not necessarily die spontaneously after a shock and may need to be pushed by a therapeutic vaccine.
“It’s harder to shock and it’s harder to kill,” Greene cautioned. “At every step we’re learning that it’s a little more complicated than we thought it was.”
Stem Cell Transplants
Hans-Peter Kiem from the Fred Hutchinson Cancer Research Center in Seattle described the work of DefeatHIV, which is focusing on stem cell transplantation.
Allogeneic bone marrow transplants from a donor “can probably cure HIV,” Kiem said, but it is not yet clear how this happens. Gene therapy may be used with autologous or “self” transplants to make cells resistant to HIV or even cut out viral genes in host cell chromosomes.
CIRM president Alan Trounson described an approach which disrupts the gene for CCR5, one of the gateways HIV uses to enter cells, in blood-forming hematopoietic stem cells. Sangamo BioSciences has already had some success using this technique to protect CD4 T-cells, but by altering stem cells researchers hope to produce an entire protected immune system.
When and Where?
Asked about a time frame for cure research, the scientists were hesitant to give firm estimates.
For different populations it will likely take different amounts of time, suggested Mike McCune from the DARE team. For children treated at birth like the Mississippi baby, for example, a cure may come sooner—and this is an approach that could be feasible in developing countries.
Forum organizer and community member Matt Sharp, who participated in Sangamo’s T-cell gene therapy trials, urged researchers and regulators to not only think about end result.
“It’s important that we [look at] some of the advances that might be made from work done so far,” he said. “My trial reset my CD4 count at a higher level. Let’s see what uses we can make of iterative steps, while keeping our mind on the ultimate goal.”
Asked about their wildest dreams about an HIV cure, participants agreed that the goal is to develop approaches that can be widely implemented in resource-limited settings where HIV/AIDS is most prevalent.
“The only hope for Africa is a cure,” Greene concluded. “The world is not able or willing to put everybody on antiretroviral therapy for the rest of their lives. Whatever the cure is, it has to be safe, it has to be scalable, and it has to be usable in developing countries.”
Liz Highleyman is a freelance medical writer and editor-in-chief of HIVandHepatitis.com.