Drugs that trip cellular alarm could help clear out hibernating HIV
HIV can currently be managed with a lifelong daily drug regimen, but unfortunately the infection can’t be eliminated entirely. Now, researchers have found a potential way to trip a cellular “alarm” to alert the immune system to clear out infected cells.
An HIV diagnosis is no longer a death sentence – antiretroviral therapy (ART) can prevent the virus from replicating and spreading, letting patients live mostly normal lives. But the virus still lurks inside infected cells, ready to spring into action if the daily drug treatment is ever interrupted.
However, recent work has raised hopes that HIV might be completely curable in the not-too-distant future. Various studies have shown promise in ripping the virus from its hideout using “kick and kill” drug combos, immunotherapy, engineered stem cells, genetic “kill switches,” CRISPR gene-editing, or CRISPR and ART drugs together.
In the new study, researchers from Washington University in St. Louis identified a promising new method. They found that human immune cells have an “alarm” system called the CARD8 inflammasome, which detects a protein called HIV protease and marks the infected cell for destruction.
The problem is, HIV is crafty and it knows how to avoid detection. It silences that protein while inside cells, and usually only activates it once it leaves immune cells, where CARD8 can’t reach it.
So for the new study, the researchers found a way to activate that protein while the virus is still inside the cell, where CARD8 can detect it and alert the immune system to destroy the infected cell. Using this method, HIV could be dragged out of hiding and eliminated from a patient entirely. Better yet, one of the drugs that makes HIV protease active again is efavirenz, an antiretroviral drug already in use for HIV.
“We’ve long used this class of drugs to block HIV from inserting its genetic material into new cells,” says Liang Shan, senior author of the study. “That’s their day job. But now, we have learned they have a second job – activating HIV protease inside the infected cell. When we treat HIV-infected human T cells with this drug, the protease becomes activated before the virus successfully leaves the infected cells. This triggers the CARD8 inflammasome, and the infected cells die within hours. This is a potential route to clearing the virus that we have never been able to completely eliminate.”
In tests in human cells in culture, the team showed that the technique worked to destroy the infected cells. It even worked against a range of HIV subtypes found around the world.
Of course, it’s still early days for the study, and there’s no guarantee that the results would carry across to humans. Tests in animals will likely follow, before any trials in humans are conducted, but the method is another intriguing potential tool to add to our growing arsenal against HIV.
The research was published in the journal Science.