October 7, 2013 8:15 am by Allday, Erin | MedCity News
In the race for a cure for HIV, the wins are stacking up.
We have the Berlin Patient and the Mississippi Baby. There's the Visconti Cohort -- 14 patients in France -- and most recently, two men in Boston who were declared to be HIV-free just this summer.
Through a variety of mechanisms and treatments, all of these people were able to shake the virus and stop taking the drugs that HIV-infected patients ordinarily need to survive. They represent possibility -- that modern science is capable of curing a deadly infection.
But possibility and reality aren't in the same place just yet. And the hunt has taken off to find a cure that won't just halt the disease one patient at a time, but put up a global blockade to HIV. Scientists are searching for a cure that's affordable and safe, and will shut down the epidemic entirely.
In the Bay Area, the Gladstone Institutes this summer has collected more than $12 million in funding from the National Institutes of Health for research aimed largely at exploring untapped avenues toward finding a cure.
UCSF is one of three institutions nationally to start research programs -- again, with NIH funding -- specifically focused on developing cures. Conversations about curing HIV have dominated locally and globally, from last year's International AIDS Conference in Washington, D.C., to a town hall meeting in San Francisco on Tuesday night.
"There have been anecdotal cases of individuals who have been for all intents and purposes cured, or whose disease has been put in remission," said Dr. Mike McCune, chief of the UCSF division of experimental medicine. "Now you have a groundswell for an effort to come up with interventions. It's a high-risk venture, but a lot of us are taking it up now because we think it's doable."
HIV under control
HIV has for more than a decade been a treatable disease. With daily antiretroviral drugs, patients can keep their infection under control, and stave off death from AIDS, for decades. But the drugs aren't a cure, and the virus lingers in a latent state, from which it can reawaken and wreak havoc if patients don't keep on medication.
Plus, the latent virus, even when kept under control by drugs, appears to cause subtle but constant damage that leads to premature aging and early death from heart disease and other age-related illnesses.
So while antiretroviral drugs have been a boon to the millions suffering from HIV and made a huge dent in the global epidemic, they aren't a permanent solution -- they aren't a cure.
The word "cure" itself is tricky when applied to HIV infection. Scientists for the most part don't expect to find an absolute cure any time soon -- a cure in which the virus is wiped out entirely. Instead, they are looking for a "functional" cure, which would mean patients could live, and stay healthy, with a small amount of virus that's kept under control either by the body's own immune system or with the help of cheap, easy-to-access drugs.
The first cure, functional or otherwise, came in 2008 with the Berlin Patient -- a man since identified as Timothy Brown who was treated in Germany and now lives in San Francisco. Brown was given a bone marrow transplant to treat cancer, but the therapy also killed off his HIV infection. Since then, a similar bone marrow treatment appears to have cured two HIV patients in Boston.
Meanwhile, scientists have 15 documented cases -- a baby in Mississippi and the 14 patients in France -- of people being cured of HIV by taking high-dose antiretroviral drugs immediately after becoming infected. All of those patients have, so far, been able to avoid the drugs long term and stay healthy.
These cases are thrilling and all cause for celebration, doctors and scientists say. But the treatments behind them aren't practical for stopping the HIV epidemic. In the case of bone marrow transplants, the therapy is too expensive and risky, and it would require finding donors for every HIV patient -- impossible on a global level.
Early antiretroviral therapy may be a reasonable treatment for many cases, but it would require a huge effort to get people tested and treated almost immediately after infection, and it isn't an option for the millions already sick.
Unusual angles
That's why scientists are tackling HIV from some unusual angles these days in their hunt for a cure. At Gladstone, for example, the recent NIH funding has gone toward three projects: looking at genetically engineered mice, hijacked viruses and suicidal cells.
"These proposals, some of them are really a shot in the dark," said Leor Weinberger, a Gladstone scientist who on Monday won an NIH grant for his work in hijacking viruses. "But you have to diversify your portfolio, you have to have some high-risk products you're invested in, if you're going to find solutions."
Weinberger's research is in harnessing bits of HIV and using them to attack the virus itself. The therapy would involve replacing some of the genetic material in the virus and disrupting its ability to replicate.
If it works, it might require a one-time injection, and while it wouldn't kill off all the virus in the body, it would render it essentially harmless, said Weinberger.
'Cellular suicide'
Dr. Warner Greene, director of the virology and immunology division at the Gladstone Institutes in San Francisco, has uncovered a surprising explanation for the deaths of certain immune cells that are associated with HIV infection. He's found that "bystander" cells -- those that haven't been infected by the virus -- appear to self-immolate when they're exposed to HIV but not yet taken over by it.
The cellular suicide is probably a protective gesture meant to prevent spread of the virus, but in fact it sets off a chain of events that leads to widespread destruction of the immune system, Greene said.
He's exploring whether anti-inflammatory drugs could halt that self-destructive process and even destroy some or all of the HIV reservoirs. Patients might still have to take regular medication, but perhaps not antiretroviral drugs, which can have tough side effects, and they might avoid the long-term damage done by latent HIV infection.
"We're looking at cell death by an intensely inflammatory response," Greene said. "It turns out the dying cells, because of inflammation, attract new cells to come to their aid, and they fall prey too. It starts a vicious cycle. Now the question is, what can we do about that? How can we interrupt this cycle?"
A popular thread of cure research is in the viral reservoirs, which are still largely undefined -- in fact, scientists aren't entirely sure where those reservoirs are located in the body.
But if doctors can find those reservoirs, or prevent them from forming, that might mean the end to HIV. The focus of UCSF's cure team is on finding the reservoirs and understanding how they're created.
Turning to mice
At the same time, Gladstone scientist Shomyseh Sanjabi, who also won NIH funding this week, is developing a strain of mice whose immune systems have been removed and replaced with human systems. These mice will be engineered to reflect both humans with normal immune systems and humans who are knowns as "elite controllers" -- able to stave off HIV infection without any treatment.
Elite controllers are rare, but scientists have recognized them as priceless for research into how the body can naturally fight HIV. Sanjabi hopes her mice will help other scientists finally unravel some of the mysteries behind HIV.
She has her own theories on HIV latency and the reservoirs, she said, but "we're just really excited by the idea that no matter what we find, whether our hypothesis is right or not, we're going to get a lot of information out of our work."
"We have to first know the beast that we're trying to kill," she said.
Erin Allday is a San Francisco Chronicle staff writer. E-mail: eallday@sfchronicle.com ___
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