In a last-ditch effort to rid the body of HIV, droves of white bloods cells self-destruct in an explosive mass suicide that drives the progression toward AIDS, a pair of new studies has found.
These fiery deaths attract more unsuspecting cells to come over and help, initiating a domino effect of immune system destruction. The discovery of these mechanisms of cell death has solved a decades-long mystery that has plagued HIV researchers since the emergence of the disease. And researchers claim an existing drug may be able to halt this suicide cascade in its tracks.
The study in Nature identifies the chain reaction and corresponding enzymes involved. The other from Science pinpoints a protein within the white blood cell that sniffs out the viral DNA and tells the cell to pull the trigger on itself. Both were published online Thursday.
“For literally thirty years, we thought it was directly the virus killing the cell,” said immunologist Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, who was not involved in the studies. “This wasn’t a particularly satisfying explanation since many, many more cells die than were infected.”
Both findings come from the laboratory of immunologist Warner Greene of the Gladstone Institutes, a biomedical research nonprofit in California.
HIV most often targets a type of white blood cell, called CD4 T-cell. The virus latches on to some of these cells and inserts its own genetic material inside. Some of these T-cells become virus-replicating units, but other cells resist and become bystanders called resting cells.
Scientists have speculated that the virus-producing infected cells become so full of the virus they were producing that they die. Or they realize something was very wrong, and perform a clean programmed cell death called apoptosis.
The deaths of these CD4 T-cells are offset by the body producing more of them in response. But after a while, the body can’t keep up, and the T-cell count drops leading to the onset of AIDS. Then, diseases that used to be easy to fend off can take over.
“It’s really a race between production and destruction,” said Fauci.
For 30 years, scientists have thought that AIDS was brought on solely by the virus-producing infected cells, rather than the resting cells. But there weren’t enough of these infected cells to explain the huge swaths of T-cells being wiped out in patients developing AIDS.
Greene and his colleagues discovered that 95 percent of the dying T-cells were resting cells. These cells have the virus DNA in them, but unlike the cells that become virus-replicating units, the resting cells initiate a self-destruct mechanism that is downright gruesome, called pyroptosis. It causes cell swelling, membrane rupture, and leaky insides.
“It is much more a cellular suicide than a viral murder,” said Greene. “The cells are committing suicide in a vain attempt to kill the virus.”
Because of its explosive and messy nature, pyroptosis is a good way of signalling to the troops to help clean up. But inflammation of these cells during death causes the new cells to fall to the same grim fate.
“This process just becomes a gristmill for chewing up CD4 cells,” Greene said.
His team took four years to gather all the results. First, they inserted a fluorescent dye into the virus so they could identify which cells harbored HIV-replicating units. Then they waited to see which cells died. To their shock, the vast majority of cell death was among the resting, non-virus-replicating cells.
From there, they wanted to find the molecule that was the pyroptosis instigator. The team analyzed the DNA of the resting CD4 T-cells using a technique called mass spectroscopy to find every protein that was bound to it. From the original laundry list of proteins, they picked the most likely candidates and progressively knocked out each one in newly made T-cells to tease out what each protein did. When they knocked out one in particular, IFI16, the cells no longer self-destructed.
“IFI16 is like the trigger, and the pyroptosis is like the gun,” he said. “IFI16 initiates the response.”
Greene and his colleagues also describe a drug – one already cleared for human use, originally developed to prevent seizures – that could potentially prevent pyroptosis. After IFI16 recognizes the virus DNA, it triggers a series of responses in the cell, including the work of an enzyme caspase-1 that mediates pyroptosis. The drug blocks that enzyme.
“They are actually on the shelf, waiting for a disease,” said Greene, who is trying to develop a clinical trial for use of the drug in HIV/AIDS patients. “We tested that drug in our tissue culture systems, and it works beautifully.”
It differs from the antiretrovirals currently used for HIV/AIDS in that it would target the host rather than the virus. However, Fauci doesn’t believe that it will be a replacement for antiretrovirals, but instead they could possibly be used together as a joint treatment.
Greene saw his first AIDS case in 1981 — the year the disease was identified — while working at the National Institutes of Health. At the time, he was conducting research on a different human retrovirus, but found himself fascinated by the ever-unfolding mysteries of HIV.
“Every step of the way in this field of work, I have been absolutely amazed,” he said. “Each lab meeting is thrilling.”
Kim is a freelance science journalist based in Philadelphia.