Science 6 March 2015:
Vol. 347 no. 6226 p. 1056
HIV/AIDS researchers call it “shock and kill”—a way to obliterate the final reservoir of latent virus that stands between an infected person and a cure. Last week at a major HIV/AIDS conference here (see main story, p. 1055), a team reported new results from a monkey study that move a few steps toward that grand but elusive goal.
Strong cocktails of antiretroviral (ARV) drugs can knock down blood levels of HIV to undetectable on standard tests, but they have not cured anyone. That's because small “reservoirs” of long-lived cells have viral DNA sleeping in their chromosomes, where it is impervious to drugs and invisible to the immune system. So cure researchers have hunted for ways to shock these cells into producing the virus, causing them to self-destruct or be killed by the immune system.
Most cure strategies have focused on the first step: waking up the virus. But virologist James Whitney of the Beth Israel Deaconess Medical Center in Boston described a drug that appears to deliver a one-two punch: It both wakes up the virus sleeping in immune cells and then, as an added bonus, revs up the immune attack against the infected cells. “It's a magic combination effect,” says Steven Deeks, an HIV cure researcher at the University of California, San Francisco.
Gilead Sciences of Foster City, California, is testing the drug, known as GS-9620, in people who have hepatitis B. GS-9620 works by binding to immune cell surfaces through what is known as toll-like receptor 7 (TLR7), triggering a response that includes inducing CD4 white blood cells to make copies of themselves. These are the same white blood cells that HIV favors. Because HIV-infected CD4s produce the virus when they replicate, a team at Gilead led by Romas Geleziunas wondered whether their TLR7 drug might help eliminate HIV reservoirs.
The researchers infected 10 rhesus macaques with SIV, a simian AIDS virus, and treated them with ARVs to suppress the virus to undetectable levels. Then they gave four of the animals repeated injections with an analog of GS-9620. Blood levels of SIV rose to high levels in the four treated animals, indicating that the drug had prodded reservoirs to produce virus. Other attempts to shock cells harboring latent HIV have led only to tiny blips of virus. “You don't need binoculars to see these blips,” Geleziunas said.
The experiment did not cure the monkeys of SIV. But later analysis showed that after the shock with the drug, SIV DNA levels dropped in the blood, lymph nodes, and colons of three of four animals. That suggested the reservoir had shrunk, although the precise mechanism of cell killing is unclear.
Geleziunas says small studies of GS-9620 in HIV-infected people are about to begin.
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Science 6 March 2015: 1055-1056.