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San Francisco Forum Discusses Progress Towards a Cure for HIV

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Experts discussed the latest news on HIV cure research at a well-attended town hall forum in San Francisco on October 1, covering approaches including "shock and kill," allogeneic and autologous stem cell transplantation, and gene therapy to protect cells from infection.

Nearly 100 people attended the forum, jointly sponsored by the University of California at San Francisco AIDS Research Institute, the Gladstone Institutes, and the California Institute for Regenerative Medicine (CIRM). The town hall featured researchers from 3 collaborative efforts funded by the National Institutes of Health to work on various approaches towards a cure: the Delaney AIDS Research Enterprise (DARE), the Collaboratory of AIDS Researchers for Eradication (CARE), and DefeatHIV.

The HIV cure research 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.

"The good news is that these reports are real, but the sobering news is that making a cure that's safe and available for everyone remains a huge challenge," said CIRM board member Jeff Sheehy. "We want to clear up misconceptions and tamp down some of the hype, but we can say we have solid grounds for pragmatic optimism."

Proof-of-Concept

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, explained DARE principle investigator Steven Deeks from UCSF.

The Berlin Patient, Timothy Brown, remains free of detectable HIV without antiretroviral therapy (ART) 6 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.

More recently, a baby in Mississippi born to an HIV positive mother was started on combination ART on the day of birth due to complications during delivery. The girl was taken off treatment by caretakers and lost to follow-up, but when tracked down a couple years later was found to have to no detectable HIV. This appears to be a case of very early treatment "preventing life-long infection rather reversing it," as happened in Brown's case, Deeks said.

Other proof-of-concept cases include a group of 14 people with HIV in France known as the VISCONTI cohort who started ART within a few months after infection. Although they stopped treatment after 4-5 years, they have not experienced viral rebound. According to Deeks, these individuals do not resemble "elite controllers" who naturally maintain very low viral load, and they have experienced continued declines in HIV levels over time while off therapy. He noted, however, that the French researchers retrospectively looked at a national database and "picked the winners" who remained free of HIV after stopping ART, while 9 out of 10 other people had the expected resumption of viral replication.

Finally, at the International AIDS Society conference in July, researchers in Boston reported on 2 HIV positive people who received bone marrow stem cell transplants to treat lymphoma. Unlike Brown, their donors did not have the CCR5-delta-32 mutation and the patients remained on ART during and after transplantation. These individuals did not experience viral rebound after experimental ART interruption, but it is not yet clear why. It appears that the new uninfected donor immune cells -- protected by antiretrovirals -- rebuilt their immune system as old infected cells died off.

"One critical thing about all these [examples] is that they don't pertain to a typical person with HIV," Deeks cautioned, as they were either undergoing cancer treatment or receiving ART much earlier than usual.

Shock and Kill

The so-called "shock and kill" strategy is among the approaches receiving the most extensive interest from researchers.

"Our hypothesis is that viral persistence is driven by interactions between the virus and the immune system, so a cure may require interventions aimed not just at the virus but also at the host," said Mike McCune, also a member of the DARE team.

"Shock and kill" is the focus of CARE, led by Warner Greene, Director of Virology and Immunology Research at Gladstone. This approach involves "shocking" or forcing HIV out of its hiding place 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 cure cocktail," Greene explained. The trick is to activate T-cells harboring latent HIV, but not to trigger excessive activation that results in a "cytokine storm" or toxic shock syndrome.

Daria Hazuda and researchers at Merck, working with the collaborative, have screened 2.9 million compounds and found many new latent HIV activating agents including histone deacetylase (HDAC) inhibitors and farnesyltransferase inhibitors.

But 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," Greene added. Furthermore, latently infected cells do not necessarily die spontaneously after a shock and may need the push of a therapeutic vaccine.

"It's harder to shock and it's harder to kill," he cautioned. "At every step we're learning that it's a little more complicated than we thought it was."

Stem Cell Transplants and Gene Therapy

Hans-Peter Kiem from the Fred Hutchinson Cancer Research Center in Seattle described the work of the DefeatHIV collaboration, which is focusing on stem cell transplantation. These include both allogeneic bone marrow transplants from donors and autologous transplants, in which cells are collected, modified, and reintroduced back into a patient.

Allogeneic transplants "can probably cure HIV," according to Kiem, but it is not yet clear how this happens. The role of graft-versus-host reactions (when donor immune cells attack the recipient's body), and of chemotherapy or radiation "conditioning" that kills off existing diseased and infected cells, is not well understood. The process remains risky, so for now it is only appropriate for HIV positive people who need stem cell transplants to treat lymphoma or leukemia.

Gene therapy using viral vectors or nucleases may be used with autologous transplantation to make cells resistant to HIV or even to cut out viral genes integrated into host cell chromosomes.

CIRM president Alan Trounson described one such gene therapy approach which involves disrupting the gene for CCR5 -- one of the gateways HIV uses to enter cells -- essentially mimicking the natural CCR5-delta-32 mutation present in about 1% of people of Northern European descent.

Sangamo BioSciences has already had some success using this technique to protect CD4 T-cells, but by altering hematopoietic stem cells -- which give rise to all blood cells -- researchers hope to produce an entire protected immune system.

But ultimately the goal is not just to make immune cells resistant to HIV, but also to arm them to find and attack the virus, Trounson concluded. "T-cells shouldn’t be pussycats in this disease, they should go out and fight."

When and Where?

Asked about a time frame for cure research, the scientists were hesitant to give firm estimates.

"I don't want to give a time frame, but it will be measured in years," said Greene, recalling former Secretary of Health and Human Services Margaret Heckler's infamous 1984 prediction than an HIV vaccine would be available within 2 years.

For different populations it will likely take different amounts of time, McCune suggested. 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 where most mother-to-child HIV transmission occurs.

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 the end result, but also about incremental advances along the way.

"I think 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 -- particularly in Africa -- where HIV/AIDS is most prevalent.

This will likely require therapies that can be administered wherever patients are located and will work within the body, as opposed to current methods that require cells to be removed, modified in a laboratory, and returned to the patient.

McCune stressed the need for multi-disciplinary collaboration among academic and industry scientists, which is not how many are used to working. "It's very unlikely that one drug will be the answer," he said. "It most likely will be a combination [of therapies], probably from a combination of companies...That's only going to happen if we change our business model."

Such collaboration was a key theme of Project Inform founder Marty Delaney, for whom the NIH collaboratories are named.

"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."

10/3/13