Antiretroviral drugs have transformed HIV infection from a death sentence to a chronic condition for many people who carry the virus. But because HIV never truly leaves the body, the virus rebounds rapidly if patients stop taking the drugs for even a short time.
Now scientists are trying to figure out how, and where, HIV hides when blood tests show that a person’s viral load is low or undetectable. The location of this reservoir has long been a mystery, but that could soon change. Powerful new techniques are giving researchers an unprecedented look at how HIV travels though the bodies of people and animals — turning up clues to the virus’s hiding places and new targets for future therapies.
HIV is a challenging foe because it integrates into the DNA of its host cells. Some scientists argue that a true cure would require removing all traces of the virus’s DNA from the body, rather than simply preventing HIV from hijacking cells to replicate itself — and that goal may be unreachable. “We are starting to realize that getting rid of all the HIV DNA is not completely realistic,” says Sara Gianella, an infectious-disease researcher at the University of California, San Diego.
The best researchers can hope for might be to permanently silence or contain HIV after infection, says Gianella, who presented new findings on HIV’s hideouts at a meeting last week organized by the US National Institutes of Health (NIH). Antiretroviral drug cocktails (known as ART) suppress the virus in immune cells in the blood — but the first results from Gianella’s “Last Gift” study confirm that HIV can stash itself within immune cells in dozens of types of tissue.
The project examines bodies donated by people with HIV who enrol when they are within six months of death from unrelated conditions. All participants are on ART when they sign up for the study, but some are asked to stop taking the drugs. Gianella’s team collects blood samples while donors are alive, and about 50 different types of tissue after death. The samples from people who stopped ART show where HIV has rebounded, while samples from people who continued the drugs can provide information about the virus’s reservoir.
The researchers did not detect HIV in the blood of their first donor, who continued taking antiretroviral drugs until his death. But they did find viable virus in nearly all of the 26 tissues they examined after the man died.
Hide and seek
Janice Clements, a pathobiologist at Johns Hopkins University in Baltimore, Maryland, calls the project “amazing”. After a person with HIV dies, she says, researchers can rarely acquire tissue samples quickly enough to measure the level of virus present, and they usually don’t know whether the dead person had been taking antiretroviral drugs.
Clements’ research has shown that HIV tends to linger in the brain and cause neurological problems, because most antiretroviral drugs can’t cross the blood–brain barrier. At the meeting, Clements and her colleagues presented the first evidence that simian immunodeficiency virus (SIV), which is closely related to HIV, survives in the spinal cord of macaques taking antiretroviral drugs and spreads quickly after the animals stop the drugs. “This is unlike any virus we’ve cured,” she says.
Nicolas Chomont, a virologist at the University of Montreal in Canada, says that HIV’s behaviour in tissues known to be part of the reservoir is complex, with virus levels going up and down. “People will tell you the reservoir is everywhere, and that might be true,” he says. “Even if it’s true, we need to understand if [the virus] in the brain and the big toe are the same.”
Tracking these patterns over time might require researchers to detect traces of HIV in the reservoirs of living people — a daunting task. “For these very rare events, you need to know where to look,” says Thomas Hope, a cell biologist at Northwestern University in Evanston, Illinois.
At the NIH meeting, Hope presented a new imaging technique in macaques infected with SIV. The researchers inject the animals with antibodies that bind to the virus, which makes it visible in positron-emission tomography (PET) scans of the monkeys’ bodies.
The approach has revealed that SIV spreads through mucosal cells in the animals’ guts and lymph nodes within hours of infection. Hope has begun to treat infected macaques with ART to determine where and how quickly the drugs lower their levels of SIV. After six months of treatment, the researchers plan to stop the treatment and scan the monkeys to see where the virus has rebounded.
And later this year, another team will begin one of the first PET imaging studies of people with and without HIV in their blood, using a different antibody. Timothy Henrich, an infectious disease researcher at the University of California, San Francisco, who is directing the study, says that his group hopes to measure what happens when people on ART stop taking the drugs and the virus rebounds. Gianella’s team also wants to test PET imaging in Last Gift participants.
Ultimately, working out where HIV rebounds from will require more than just measuring the virus in blood, Hope says. Blood immune cells are “going to be a more minor player compared to the dark matter reservoir which we haven’t really defined yet”, he says. “We know it’s there.”
Nature 562, 472-473 (2018)