Sheehy and other HIV activists were part of that conversation over the last two days. Since the HIV/AIDS epidemic’s earliest days, when there was no known treatment and infection meant a death sentence, people with HIV have organized to be active participants in both research and policy-making. This is still true today, almost 20 years after combination antiretroviral treatment turned HIV into a chronic, manageable disease for those who have access to and can tolerate the drugs.

“This is the one [conference] that I’m aware of that the people who are working on cell and gene therapy come together,” said Jeff Sheehy , a long-time HIV/AIDS activist who is on the governing board of a California agency that funds stem cell research.

No one, including the Seattle-born Brown, believes that such a risky cure should be attempted unless the person with HIV needs it to treat a life-threatening cancer. But scientists at Fred Hutch and elsewhere are looking for less toxic ways to build from that success by genetically engineering resistance in an infected person’s own immune cells.

The second annual Conference on Cell & Gene Therapy for HIV Cure was hosted by defeatHIV , a Fred Hutch-based research consortium investigating using genetically modified stem cells to cure HIV. The approach is based on the case, first reported in 2008, of Timothy Ray Brown , who underwent two grueling bone marrow transplants to treat his acute myeloid leukemia. In what proved to be a successful attempt to also cure Brown’s HIV infection, his doctor in Berlin found a stem cell donor who carried two copies of a rare gene mutation that confers natural resistance to the virus.

From across the country, HIV experts and cancer researchers who have devoted their careers to improving stem cell transplants came together at Fred Hutchinson Cancer Research Center Thursday and Friday. Their goal? To talk about how to translate the world’s only known HIV cure into a cure or long-term remission that is less risky, less costly and broadly applicable to the millions worldwide now living with the virus.

Nobel Laureate Dr. David Baltimore gave the keynote speech at the second annual Conference on Cell & Gene Therapy for HIV Cure held at Fred Hutchinson Cancer Research Center in August 2015.

What we’re up against

A so-called “sterilizing cure” – or eliminating all virus from the body, as is believed to be the case with Timothy Ray Brown – is the holy grail of HIV cure researchers. But scientists had some useful metaphors for what a challenge that is. HIV lies dormant in long-lived cells, untouched by antiretroviral therapy, which is why the therapy controls but doesn’t cure HIV and why the virus comes back if therapy is stopped.

One approach to curing HIV is called “shock and kill” – using drugs to shock the latent viruses awake, then using other drugs or a patient’s own, genetically modified immune cells to kill them. As few as one per million HIV-infected cells are latent, scientists said, and – as with cancer cells – missing just one of them would allow HIV to return.

So how hard is it to find that one in a million cells?

Dr. Jerry Zack, a UCLA professor of microbiology, immunology and molecular genetics, turned to football to answer that – specifically (as a Southern Californian), the Rose Bowl.

The Rose Bowl seats 92,542. To find that one latent cell that would cause HIV to roar back would be like finding one person in 11 Rose Bowl stadiums.

Dr. Timothy Henrich, a professor of medicine at the University of California San Francisco, puts the challenge another way: He has all of his lab assistants read the children’s book “Where’s Waldo” because, as he put it, “that’s what we’re doing here.”

He then showed a slide from a Where’s Waldo book with a single hidden HIV virus in it … somewhere. He once showed the slide to an audience that included Timothy Ray Brown. And guess who was the only one in the room to find it?

Brown.

“The irony in that,” said Henrich.

Zack had one more number to offer. Antiretroviral therapy could, theoretically, eventually eliminate every latent HIV virus in the body, given the rate at which such viruses “wake up” naturally. The time it would take to do so?

Using mathematical models, scientists have come up with a depressing estimate: 73.4 years.

OK. So now what?

The reservoir – and the challenge of eliminating it – is one reason many researchers talk instead about a “functional cure” similar to a remission in cancer. “Cures are great,” Zack said. “But we’re also looking at long-term remissions.”

Or, as Nobel Laureate Dr. David Baltimore put it in his keynote talk, if cure means no detectable virus and no probability of the virus returning, “I don’t think we’re likely to see that for some time. But if we can treat patients so that they no longer have to take medications, are free from the dangers of HIV-inducing disease and have limited ability to transmit the virus, I would consider that a win even if it isn’t a cure.”

Researchers talked about several ways to do this. One is to try to recreate the mutation found in Brown’s HIV-resistant donor cells, which prevents T cells – infection-fighting white blood cells that HIV targets – from developing a receptor, called CCR5, on their surfaces. HIV uses this receptor as a “door” to enter the cell. Without it, it’s as though HIV is left standing at the cell’s doorstep without a key to get in.

“CCR5 is the Achilles’ heel,” said Dr. Paula Cannon, a University of Southern California stem cell researcher and a member of defeatHIV. “You can take out people’s cells, take out CCR5 and pop the cells back in – their own cells, but an improved version that’s now resistant to HIV.”

How do scientists do that? For now, most are using a viral vector – a harmless virus that can act as a gene-delivery system. They have also developed several types of “genetic scissors” made up of specialized cutting enzymes called nucleases. Figuring how best to use this new technology – and developing new versions, including the newest kid on the block, called CRISPR/Cas9, is one focus of cure research.

“Targeted nucleases are cool,” Cannon said. “They potentially allow us to do safer gene therapy, more controlled site-specific gene editing or gene insertion.”

Can engineering resistance duplicate Brown’s sterilizing cure? Scientists don’t believe it will, entirely, in part because they are still trying to understand all of the factors that played into that cure.

In addition to the HIV-resistant genes, Brown received not one but two stem cell transplants, both of which included punishing pre-transplant “conditioning” radiation and chemotherapy treatments to destroy his old immune system and make room for the new one to grow. He developed graft-vs.-host disease, a common side effect of transplantation.

“The impact of each of these – the relative contributions of each – on cure is unknown,” said Dr. Leslie Kean, a researcher with Fred Hutch, Seattle Children’s and the University of Washington who is also researching a possible “graft vs. reservoir” effect.

Still, researchers are – cautiously – hopeful. Dr. Matt Porteus, a Stanford pediatric stem cell transplant expert, pointed out that not every CCR5 receptor would have to be eliminated to have an effect.

“Selective pressure means only a small number of cells need to be modified to have therapeutic effect,” Porteus said. “HIV would continue to kill [non-resistant] cells, leaving the resistant cells to fill the [void] and hoisting the virus on its own petard.”

Broadly neutralizing antibodies

Other researchers discussed engineering cells using genes to encode broadly neutralizing antibodies rather than to delete the CCR5 gene.

As with other infections, the body naturally develops antibodies to HIV. And some people even develop highly potent proteins that are effective against many strains of HIV. The trouble is, they develop them too late to do any good. As Baltimore put it in his keynote talk, “There’s a continual battle between two Darwinian systems – the immune system evolving to capture the virus and the virus evolving to escape. In that battle, [HIV] seems to win all the time.”

But if such broadly neutralizing antibodies could be engineered to be readily available earlier in the evolutionary battle, they may be able to either block infection or treat people already infected, said Baltimore.

Dr. Michael Farzan, an infectious disease specialist at the Scripps Research Institute in Florida, has developed an engineered molecule that outperforms the action of the best naturally occurring broadly neutralizing antibodies in a preclinical model. The researchers have developed it with the goal of preventing HIV infection but the molecule could play a role in cure efforts.

Where are we in the cure process?

Many of these approaches have been tested only in mice or other preclinical models. But some small, early clinical trials of vector-induced genetic changes in T cells or stem cells have taken place or are about to open.

“What I like about this field is nobody is rushing to say ‘Yay, it’s working’ or ‘It’s not working,” said USC’s Cannon. “The trials are being done very cautiously. This is a new type of therapy. It’s going to take several years.”

But that said, Cannon added, “I think it’s looking pretty good.”

Both Cannon and Fred Hutch stem cell researcher and defeatHIV co-director Dr. Hans-Peter Kiem are now enrolling patients in clinical trials.

One of the things that excites activist Sheehy about cell and gene therapy is the possibility of interim benefits, such as improved immune response overall.

“This may be the bunt single, but it counts,” he said. “The ability to get intermediate outcomes is a potential benefit from cell and gene therapy that I’m not sure we’re seeing in other avenues of research.”

Veteran HIV activist Matt Sharp, who has been living with HIV since 1988, is an example of that benefit. In 2010, he took part in a small clinical trial in San Francisco, one of the first to test gene therapy for HIV. His blood was drawn and his T cells were filtered out and genetically engineered to have the CCR5 mutation, then returned to his body. The goal of the trial was simply to see if altering and returning the genes worked and could be done safely, but Sharp received an unexpected benefit: His persistently low T-cell count more than doubled and remains high, relieving him of the regular bouts of pneumonia he used to suffer despite being on antiretroviral therapy.

One of Friday’s presenters, Dr. Joumana Zeidan, a postdoctoral research fellow from Case Western Reserve University, presented an analysis of that San Francisco trial, saying that the single infusion of CCR5-modified T cells helped shrink the reservoir.

Sharp, who attended the conference, raised his hand.

“Thank you,” he said. “I was a participant in that trial. I’ve been waiting for six years to understand what happened.”