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How HIV 'burns out' the human immune system
 
 
  18:00 20 August 2006
NewScientist.com news service
Andy Coghlan
 
Detailed studies of white blood cells have revealed how HIV relentlessly wears down the immune cells by exploiting the body's built-in protection against autoimmune diseases.
 
The new understanding should lead to ways to overcome this "Achilles heel" and treat HIV infection.
 
As HIV accumulates in the blood, specific immune cells that target viruses - called CD8 - begin to over-produce a receptor molecule called Programmed Death-1. As this PD-1 builds up on the surface of the CD8 cells, the immune cells became weaker and produced fewer virus-killing chemicals, such as cytokines.
 
Instead of functioning as sentinels of the immune system, the CD8 cells gradually burn out, becoming clogged-up with PD-1. "The immune cells are there, but they have been turned off in persons with high viral loads," says Bruce Walker at Massachusetts General Hospital in Boston, US, who led the research.
 
Tandem changes
 
The biological function of PD-1 is not fully understood, but it is thought that it may be involved in preventing autoimmune reactions - where the white blood cells attack the body's own cells.
 
Walker and his collaborators examined CD8 cells from 71 untreated HIV-positive patients in Durban, South Africa. They found that the more virus the patients had in their bodies, the more PD-1 they had on their CD8 cell surfaces.
 
But when Walker massively suppressed the amount of virus circulating in their blood by giving the patients antiretroviral drugs, the amount of PD-1 on their CD8 cells went down too, suggesting that the two rise and fall in tandem.
 
The same phenomenon was demonstrated in 19 North American individuals by a team led by Rafick-Pierre Sekaly at the Central Hospital of Montreal in Canada.
 
Mutual confirmation
 
In lab experiments, though, Sekaly showed that even after antiretroviral drugs were given, the CD8 cells continued to weaken despite the fact that the drugs drove down the amount of PD-1. "The drugs didn't correct the dysfunction, and the cells got more and more tired and burnt out," he says.
 
But the two teams were able to help the cells to recover using antibodies that block the PD-1 receptor molecules. In cell culture, these CD8 cells resumed their normal activity when exposed to HIV, producing chemicals such as interferon gamma, for example, which targets viruses including HIV.
 
And experiments in mice treated with similar antibodies also blocked the production of PD-1.
 
The teams, whose results were both published at the same time, in the journals Nature and Nature Medicine respectively, are delighted that each others' findings have been mutually confirmed.
 
Now, Sekaly wants to try the same thing in people. "We need to start a clinical trial as soon as possible," he says.
 
Total block
 
Sarah Rowland-Jones, director of research at the UK Medical Research Council's Labs in Fajara, Gambia, says that it would be interesting to know if the virus itself somehow triggers the CD8 cells to overproduce PD-1. "It wouldn't surprise me in the slightest," she says.
 
However, Rowland-Jones, who wrote a commentary piece accompanying the two studies, in Nature, warns that blocking PD-1 altogether could be dangerous. She says that in experiments on mice bred to lack the gene, the mice developed severe autoimmune disease.
 
This suggests that the protein plays an important role in stopping the immune system attacking itself. Perhaps, she says, HIV exploits this to blind the immune system to its presence.
 
Elite controllers
 
Walker and Sekaly, meanwhile, are keen to follow up an additional project which could reveal new ways to tackle the virus. The two are part of an international project, launched on 16 August at the International AIDS Congress in Toronto, to identify and study so-called "elite controllers", individuals who appear to keep HIV in check without having to take drugs.
 
They estimate that up to 2% of HIV-infected individuals are elite controllers, but have put out the call to identify at least 1000 (see Bid to solve riddle of natural resistance to HIV).
 
Journal references: Nature (DOI: 10.1038/nature05115), Nature Medicine (DOI: 10.1038/nm1482)
 
 
 
 
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