How HIV Becomes AIDS

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 Doitsh, showed that HIV actually tries 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 called apoptosis. 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.

Instead, Doitsh, together with student Nicole Galloway, showed that they die through a more violent process called pyroptosis. They swell instead of shrinking. Their membranes rupture, and their innards leak out through the holes.

These escaping molecules include interleukin-1 beta (IL1β), which summons more CD4 cells to the site of infection. The result is a massive amount of inflammation, and a vicious cycle—emphasis on vicious. HIV tries to infect a few CD4 cells, which go through pyroptosis in response. Their leaked remains summon more CD4 cells, which also get abortively infected, and also go through explosive suicide. Their deaths summon yet more cells, and so on.

“We think this is the major driver that depletes the CD4 T-cells,” says Greene. “It’s at the heart of AIDS.”

“The two papers provide substantial insights into how HIV depletes CD4 T-cells,” says Dan Barouch from Harvard University. “We didn’t have a clear mechanism for how that happened before, and it’s a central aspect of HIV pathogenesis.”

Greene thinks that pyroptosis (or the lack of it) could explain why HIV usually causes AIDS in humans but its relatives, the SIVs, barely sickens the apes and monkeys that they infect. SIVs can kill CD4 cells directly, but they can’t trigger the same pyroptosis response in other primates. They kill a few cells but the majority survive, and the immune system stays strong. “That’s the evolutionary solution—not to control the virus but to control the host response,” says Greene. “I think if we had another million years, we’d evolve in the same way.”

Thankfully, his team is working to a tighter schedule. They’ve already found a molecule that can stop pyroptosis, at least in lab-grown cells.

The whole messy process depends on a protein called caspase-1. Without it, you don’t get any mature IL1β, and without that, you don’t trigger the vicious cycle of CD4 cell death. Caspase-1 plays many other roles in the body, and several pharmaceutical companies have tried to make drugs that block it, for the purposes of treating other diseases. One of these, VX-765, was developed to treat chronic epilepsy and autoimmune diseases.

Greene’s team showed that it completely prevents HIV from killing the bystander CD4 cells. No caspase-1 activity. No IL1β signals. No inflammation. No mass cell death.

No AIDS? That remains to be seen. These are only lab experiments, after all, and the drug still needs to be tested in actual HIV patients.

Encouragingly, it has already gone through early phase II clinical trials, which means that we know it’s safe and well-tolerated. “Maybe it could be repurposed for HIV infection,” says Greene. He imagines a joint attack: current antiretroviral treatments would target HIV itself, while caspase-1 blockers would stop the patient’s immune system from overreacting to the virus.

Greene is now in talks with the drug’s manufactuer—Vertex Pharmaceuticals—about launching a proper HIV trial. There are other options too—several other caspase-1 inhibitors have been developed, although they haven’t done enough in their respective diseases to justify taking them to market and seeking FDA approval. If Greene can’t get the go ahead for VX-765, he’ll just look somewhere else.

He also wants to see if caspase-1 blockers could have other benefits. Since they target the host rather than the virus, he thinks it’s less likely that you’d get resistance to them. They could also give people more time while they wait for antiretrovirals. “For every 10 people we put on antiretrovirals today, 16 more become infected,” says Greene. “There are 16 million people who should be on these drugs but aren’t, and are progressing to AIDS and dying. Maybe these caspase-1 inhibitors could be used as a bridge therapy while they wait.”

And, in the lab experiments, the caspase-1 blockers also prevented the inflammation that goes hand-in-hand with CD4 cell death. Greene suspects that this inflammation accelerates the ageing process in HIV patients. “It’s why they’re dying of heart attacks, liver diseases, dementia and cancer at an earlier age than anticipated,” he says. “Maybe we could restore their normal lifespan or improve their quality of life?”

Meanwhile, other scientists have discovered more cellular sensors that detect HIV in other types of cells. Nabel’s team showed that a protein called DNPK-1 senses HIV DNA once it has been inserted into a CD4 cell’s genome, which triggers a different self-destruct sequence. But this only happens in the small proportion of CD4 cells where the infection process is truly underway.

Another protein called cGAS can also detect HIV DNA, but in a different group of white blood cells. It’s not found in the CD4 cells that Greene examined.

This baffling variety comes as no surprise to Andrew Bowie from Trinity College Dublin, who studies how the immune system detects viruses. He was the one who discovered that IFI16 is a DNA sensor back in 2010. “Since then, we suspected that these sensors would have very cell-type specific roles in sensing viruses,” he says.

And scientists have made tremendous strides in understanding these roles just this year. The cGAS discovery was announced in February, DNAPK-1 in June, and now IFI16 in December! “We’re seeing a Renaissance of our understanding of the fundamentals of HIV infection,” says Nabel. “The more we know, the better off we’ll be with controlling it.”

References: Monroe, Yang, Johnson, Geng, Ditosh, Krogan & Greene. 2013. IFI16 DNA Sensor Is Required for Death of Lymphoid CD4 T Cells Abortively Infected with HIV. Science. Tbc.

Doitsh, Galloway, Geng, Monroe, Zepeda, Yang, Hunt, Hatano, Sowinski & Greene. 2013. Pyroptosis drives depletion of CD4 T cells in HIV-infected lymphoid tissues. Nature. Tbc.