HIV is a virus that kills by crippling our defences against other infections. It sends our immune system into a creeping decline. Germs that were once easy to fight off now become debilitating and lethal threats. A simple cold can kill. Tumours start to grow.

This is AIDS. It was formally described in 1981 and now, over 30 years later, we’re finally starting to understand why it happens.

HIV can infect many different types of white blood cell, but chief among them are the CD4 T-cells. These are the bugle-players of the immune system—they mobilise other immune cells, which actively kill viruses and other invaders. HIV prevents these troops from entering the fray, because it slowly destroys the CD4 T-cells.

Only a minority fall to the virus directly. More than 95 percent don’t seem to be infected, but die anyway. This collateral damage is what leads to the symptoms of AIDS; it’s what makes HIV so lethal. If we want to know why this virus has killed 34 million people since its discovery, we need to know why these bystander CD4 cells die… and we don’t. “In many ways, the question of why these cells die after HIV infection has been neglected, and it’s at the heart of what the virus does—it kills CD4 cells,” says Gary Nabel, Chief Scientific Officer at Sanofi.

Warner Greene from the Gladstone Institute of Virology and Immunology has been trying to solve this mystery for years, and he thinks he has finally cracked it. In two papers, published simultaneously in Science and Nature, his team lays out why HIV kills so many bystander cells and, better still, a possible way of stopping it.

In 2010, Greene’s team, led by Gilad Doitshshowed that HIV actuallytries to infect the bystander CD4 cells, but fails. Ironically, it’s their botched attempt that kills the cell.

During an infection, HIV fuses with a CD4 cell, and releases its genetic material, in the form of RNA molecules. These are converted into DNA, and inserted into the cell’s genome. When the cell divides, it copies its own genes and duplicates the hitchhiking viral DNA too. But in the bystander CD4 cells, which are in a resting state, the process that coverts RNA into DNA repeatedly stalls. Rather than producing the complete HIV genome, it churns out small fragments of viral DNA, and the infection can’t continue.

That’s great, except the cell now has bits of viral DNA floating about. Three years back, the team suggested that some sensor inside the CD4 cells detects this DNA and triggers a self-destruction programme.

Now, Kathryn Monroe at the Gladstone Institutes has discovered the sensor. She used a piece of HIV DNA to fish for molecules in CD4 cells that might stick to it. She caught several bites, but the most enticing one was a protein called IFI16. When Monroe removed this protein from resting CD4 cells, they didn’t overreact to the DNA pieces left behind by the virus’s bungled attempts at infection. They didn’t die.

IFI16 evolved as an antiviral DNA sensor. It’s meant to launch a defensive programme that kills infected cells before they can contaminate their neighbours. But when it comes to HIV, this protective response just kills the host faster. IFI16 turns into a general who gets false intelligence, panics, and pushes the big, red button anyway. “CD4 cell death is more a suicide than a murder,” says Greene.

The cells don’t go out quietly either.

In many cases, cells commit suicide through a gentle process calledapoptosis. They shrink and break up into neat parcels, which are tidied away by cleaner cells. They die with a whimper; they don’t leave a mess. Everyone assumed that bystander CD4 cells die in this way.

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