HIV (purple) mingling with a dendritic cell (purple)
((Image: AS&K VISUAL SCIENCE/SPL)
Just when all seems lost, our hero strikes back with such speed that the evil invader is vanquished. It could be the climax of a blockbuster movie, but it's more important than that. If this is how a handful of people are able to fight off HIV, we could have a route towards a blockbuster drug or vaccine.
Less than 1 per cent of people infected with HIV around the world are able to suppress its effects without taking drugs. These "elite controllers" are somehow able to keep the virus from replicating uncontrollably, thus preventing it from taking its terrible toll on their bodies.
Unsurprisingly, ever since these people were first identified, researchers have been hoping to discover their immune system's secret, in the hope of bottling it for the other 99 per cent of people with HIV.
The latest insights come from experiments on specialised dendritic cells that "teach" the immune system to destroy infected or faulty cells. We already knew that elite controllers have CD8 T-cells – components of the immune system – that react more strongly to HIV than T cells of other people, but we didn't know why, says Xu Yu at the Ragon Institute, a collaboration between Massachusetts General Hospital, MIT and Harvard set up to study these unusual individuals .
Riot, then backlash
Yu's team infected colonies of dendritic cells with HIV and compared those from elite controllers with those of HIV-negative people, people with HIV receiving antiretroviral drugs, and those that weren't.
Normally, immune cells neutralise invading viruses by destroying viral RNA and DNA as it starts to build up. This is what happened in all the dendritic cells the team tested – except those from elite controllers. In these colonies the virus appeared to run riot, producing copious amounts of genetic material. "It seemed as though the virus was escaping from detection, and that's our most paradoxical finding," says Yu.
But then came the equally unexpected backlash. When they eventually swung into action, dendritic cells from elite controllers produced large quantities of antiviral compounds called type 1 interferons. Other people's dendritic cells responded much more sluggishly.
And the elite controllers' cells were still pumping out interferons two days later, long after the other cells' response had petered out. "Both the speed and the ability to sustain the defence were what marked out the elite controller cells," says Yu.
The interferon spewing from the elite controllers' cells also triggered the rapid proliferation of CD8 T cells, priming them to attack any other cells containing HIV.
No stealthy approach
"It tells us what the difference is in elite controller cells, and it sounds pretty key, but it doesn't tell us why it happens," says Sarah Rowland-Jones at the University of Oxford. She suspects that the extra viral DNA that built up in the elite controllers' cells may have made the infection more obvious to the immune system. In contrast, other people's immune cells destroyed most but not all of the HIV, potentially allowing the infection to continue unnoticed.
Yu says her team hopes to capitalise on the discovery by seeking ways to make dendritic cells from ordinary patients mimic the HIV response seen in elite controllers. They are now screening novel molecules and adjuvants – substances given alongside vaccines – to identify any that do the trick. These could then be tested to see if they provide the extra kick needed to prime the immune system against HIV.
Journal reference: PLOS Pathogens, DOI: 10.1371/journal.ppat.1004930