BioEd Online

A study showing how HIV could prevent the brain from making new neurons offers an explanation for why some AIDS patients get dementia — and suggests a possible treatment.

Dementia due to HIV is the leading cause of cognitive decline in people under 40 years of age, says Stuart Lipton, a biologist at the Burnham Institute for Medical Research in La Jolla, California, who led the study in Cell Stem Cell¹. Researchers aren't sure what causes the condition, which afflicts 10-30% of people with HIV and causes symptoms including forgetfulness and leg weakness. If untreated with antiretroviral drugs, sufferers can turn comatose.

Biologists have two theories to explain AIDS-related dementia. It could be that when HIV infects a type of white blood cell called a macrophage, the cell pumps out inflammatory chemicals to battle the infection that also, unfortunately, wipe out neurons.

Or HIV could inflict its damage more directly. One previous study showed that a protein in the virus's shell — called gp120 — can stop brain stem cells from dividing². Such new stem cells are needed to make new neurons.

Undivided

To investigate, Lipton and postdoc Shu-ichi Okamoto studied a strain of mice genetically engineered to make the virus's gp120 protein. Under the microscope, the mouse brains look just like those of humans with AIDS-related dementia, says Lipton.

When the team studied the mice more closely, they found many of their neural stem cells were stuck in the cellular equivalent of 'neutral', unable to divide and make new cells.

Neural stem cells in the transgenic mice also contained more of a protein called p38 than normal mice. In healthy cells, p38 guards against cancer by halting cell division when DNA strands get broken. If HIV prompts so much p38 that it stops normal cells from dividing, "it's the opposite of cancer", says Lipton. The researchers also found other proteins linked to p38 in the neural stem cells of the gp120-expressing mice.

"This is the first hint at how HIV can co-opt stem cells and cause them to dysfunction," says Lipton.

Chemical cure

Drugs that block p38 are already in clinical trials for autoimmune diseases such as rheumatoid arthritis, and Lipton's team is currently testing one such drug in mice as a possible treatment for AIDS-related dementia.

At present, antiretroviral drugs are sometimes helpful at preventing dementia, but some do a better job than others, and patients eventually become resistant to the drugs. A different way of treating the condition would be useful patients who don't respond to antiretrovirals, says Francisco Gonzáles-Scarano, a neurologist at the University of Pennsylvania in Philadelphia. "At this point there really aren't any [such treatments]," he says.

But Gonzáles-Scarano wonders whether there is really enough viral protein in the brain of AIDS patients to cause dementia. If not, some other, less direct mechanism could be to blame for the problem.