In a heroic act of sacrifice, HIV-infected white blood cells known as T cells self-destruct to prevent proliferation of the virus, according to a new study. Unfortunately, their sacrifice is in vain, as the mass die-off of T cells debilitates the body’s immune system, resulting in the immune disorder associated with AIDS. For decades, scientists have puzzled over why this happens, though. Only about 5 percent of T cells become fully infected with HIV, which hijacks the cells’ DNA-replicating system and turns them into factories for pumping out new copies of the virus. So why, then, do the other 95 percent — “bystander” T cells, as they’re known — also fall prey to HIV?
It turns out that these T cells are more like the walking wounded than bystanders, say researchers from the Gladstone Institute of Virology and Immunology in San Francisco, who published their findings this week in the journal Cell.
Immunologist and senior study author Warner C. Greene and colleagues pitted T cells exposed to HIV against a variety of HIV drugs that work at different stages of the virus’s life cycle. They were able to pinpoint the stage at which T cells died: after becoming infected but before turning into HIV replicating machines.
HIV can only fully hijack a T cell that’s currently replicating itself, so when it infects cells that are resting, the virus just waits dormant inside the cell. Greene and his team discovered that, rather than wait around to become HIV factories, the cells sacrifice themselves.
“The cell senses this and says, ‘Uh oh, something’s very wrong here. I need to commit suicide to protect the host,’ ” Greene said.
But the sacrifice comes at a significant cost. Massive die-offs of these infection-fighting blood cells leave the body unprepared to fend off secondary infections. What’s more, when the cells explode, they release proteins that signal for reinforcements from other T cells, resulting in a vicious cycle of partial infection and suicide. That would explain the chronic inflammation that accompanies HIV infection, Greene said.
It’s not clear how the cells sense the foreign viruses within themselves, Greene said, but identifying the mechanism could open up a new line of attack on HIV. By preventing partially infected T cells from committing suicide and recruiting ever more T cells to the infected region, HIV might not be able to proliferate throughout the body and cause a total immune system shutdown. “It’s a completely different approach,” Greene said. “It wouldn’t be attacking the virus, it would be attacking the inflammation.”
Irvin S.Y. Chen, director of the AIDS Institute at the University of California, Los Angeles, said the findings finally answer the long-looming question of how HIV kills T cells. “You would think we would have the answer by now, nearly 30 years into the epidemic, but not until this study did we begin to appreciate the answer.” he said.
Carl Dieffenbach, director of AIDS research at the National Institutes of Health in Bethesda, said he’d like to see the results replicated with different strains of the HIV virus, but he’s excited about the specific therapeutic possibilities they’ve revealed. “Some research just leaves you with more questions,” he said, “but these are very directed questions.”
