Monkeys provide new clues toward elusive HIV vaccine, cure
Despite enormous efforts over more than 30 years, Human Immuno-deficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS) researchers have yet to develop either a vaccine or cure for the disease. But they have made progress in monkey experiments, and two studies reported this week at the largest annual United States (U.S.) HIV/AIDS conference created serious buzz.
Several AIDS vaccines have had some success in monkey models, which typically use Simian immunodeficiency viruses (SIV), a simian cousin of HIV that causes AIDS in rhesus macaques. But one vaccine has long stood out from the pack. Designed by Louis Picker and colleagues at Oregon Health & Science University’s Vaccine and Gene Therapy Institute in Beaverton, the vaccine stitches SIV genes into a harmless Trojan horse, cytomegalovirus.
Picker’s team has given the vaccine to more than 200 monkeys and then “challenged” them with injections of a particularly nasty strain of SIV. All told, 55 per cent of the animals became temporarily infected and then completely controlled the virus for years or even cleared it. Two stubborn questions remain, however: Picker and co-workers have yet to nail down the immune responses that explain the vaccine’s success, and they also can’t explain why it frequently fails.
At the meeting this week—the Conference on Retroviruses and Opportunistic Infections—immunologist Michael Gale Jr. of the University of Washington in Seattle described how his group explored these questions by taking a big picture view of active genes in the protected and unprotected animals. Specifically, the researchers identified and compared clusters of genes in the two groups of animals that were turned on high or tamped down low. These clusters control the production of various interleukins (biochemicals that communicate messages between immune cells), cell growth, and inflammation. They drilled down to 234 genes that had different expression levels in the two groups at day three and found that by looking at these alone, they could predict with 91 per cent accuracy whether the vaccine injection would protect an animal. “This is the most interesting talk at the whole meeting,” says Mario Clerici, an immunologist at the University of Milan in Italy who long has focused on why some humans handle the virus better than others.
Picker says these findings offer him new ways to tweak his vaccine. “Obviously the vaccine is tickling something, and maybe the critical issue is tickling a certain pathway a little bit stronger,” he says. As an example, he points to the genes that collectively control interleukin-10 production, which were turned on much higher in protected animals. “If that signal turns out to be critical, I can manipulate it,” he says. Picker has co-founded a company, Vir Biotechnology in San Francisco, California, that plans to start testing the vaccine in humans next year.
On the cure front, immunologist Dan Barouch, who directs the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center–Harvard Medical School in Boston, threw the kitchen sink at the virus. His team first infected 44 monkeys with a hybrid of SIV and HIV called SHIV. One week later, the scientists began treating all the animals with antiretrovirals (ARVs) and continued for two years. In all 44 monkeys, the virus dropped to undetectable levels on standard blood tests. The researchers then divided the animals into four groups that received either nothing (the controls), a potent HIV antibody, a drug that binds to toll-like receptor 7 (TLR7) that studs innate immune system cells, or the antibody plus the TLR7 drug. Sixteen weeks later, they stopped all ARVs.
In humans who control HIV with ARVs to the point that researchers cannot find the virus in their blood or tissues, the virus always comes screaming back, usually within a few weeks, once they stop taking drugs. That’s precisely what happened in all 11 control animals. In the monkeys given the TLR7 drug or the antibody, 20 of 22 no longer could suppress the SHIV. But in the group that received the antibody plus the TLR drug, five of 11 animals did not see the SHIV return after 6 months (the experiment is ongoing) and the others have low levels of the virus. “We’re very encouraged by this preliminary proof of concept study,” Barouch says.
A key obstacle to curing an HIV infection is that even when people have undetectable levels of virus, a reservoir remains of cells that hold chromosomes laced with “latent” viral DNA, which doesn’t produce progeny and thus lies under the radar of the immune system—but can suddenly kick into gear and cause mayhem. Earlier monkey studies showed that the TLR7 drug can “shock” lately infected cells to produce the virus, setting them up for elimination. Many groups have attempted “shock-and-kill” experiments in monkeys and humans. “This is the first evidence that shock-and-kill works,” Picker says.
Picker and others stress several important caveats. It’s possible that the virus will return in these five monkeys—humans presumed to be cured have had HIV show up more than two years after stopping ARVs. And in this experiment, ARV treatment was started a week after infection; it rarely happens that soon in people. SHIV is also easier for monkeys to naturally control than the SIV used in Picker’s studies. With all that in mind, Jeffrey Lifson, who does SIV studies at the U.S. National Cancer Institute in Frederick, Maryland, says the findings are “interesting, provocative, and potentially important.”
Steven Deeks, a clinician who does cure trials at the University of California, San Francisco, says he soon plans to test a similar combination of a TLR drug and a potent antibody in patients who have been fully suppressed for several years. “There’s no clear mechanism here, but as a clinician, I don’t really care,” he says. “It’s all a big black box: You have something that goes in and something that goes out. What comes out here is no virus.”
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