Important note: Information in this article was accurate in 2003. The state of the art may have changed since the publication date.
Wall Street Journal - October 14, 2003
Tamsin Carlisle, Staff Reporter of The Wall Street Journal
While doctors have long realized that many AIDS patients who survive the disease's other ravages eventually succumb to worsening dementia, with symptoms including seizures, depression and loss of memory and motor skills, the direct cause of the brain damage wasn't known. Now, a team led by Christopher Power, a practicing physician and University of Calgary professor of neurology, has published research showing that HIV -- the virus that causes AIDS -- activates a previously unknown biochemical pathway that destroys nerve cells in the brain.
In an article appearing in this month's issue of Nature Neuroscience, Dr. Power's team of researchers from the University of Calgary and University of British Columbia describes the discovery of a normally beneficial brain protein that HIV converts into a potent neurotoxin. The protein, SDF-1, usually performs "housekeeping duties" that keep the brain healthy, says Dr. Power, but it turns deadly to nerve cells when altered by an enzyme known as MMP-2.
In an interview, Dr. Power said his team showed that white blood cells infected with HIV secrete an inert form of the enzyme, which is activated when it contacts receptor molecules on the surfaces of nerve cells. Once activated -- a process that HIV seems also in some way to facilitate -- the enzyme sets about its grim business of turning benign SDF-1 into a brain-eroding poison.
Ironically, one of the normal functions of SDF-1 is to protect the brain from viruses like HIV, says Dr. Power, which helps to explain why dementia develops late in the progression of AIDS. Possibly, he adds, HIV may simply reactivate a biochemical pathway that exists as a normal part of the brain's early development. While that's conjecture, HIV's ability to activate the neuron-destroying pathway does appear to be unique: "MMP-2 is normally relatively quiescent, but HIV turns it on. Other viruses don't turn it on," says Dr. Power.
Avindra Nath, professor of neurology at the Johns Hopkins University School of Medicine, says the Canadian researchers' discovery "opens up a brand new area of research" that could have broad implications for developing treatments for a number of intractable neurological diseases such as multiple sclerosis and Alzheimer's. Medical researchers have started to investigate only recently the role in brain function of the group of substances known as chemokines that includes SPF-1, Dr. Nath adds.
Dr. Power predicts it will be years before his research yields practical results in terms of new drugs to treat AIDS dementia. Still, in failed cancer drug Prinomastat, his researchers have already identified a compound they think is worth investigating. For a start, they have shown that Prinomastat is "very effective" in blocking MMP-2 in mice, Dr. Power says.
Pfizer Inc. abandoned development of Prinomastat after Phase III clinical trials failed to demonstrate its effectiveness as a cancer drug. Company spokesman Stephen Lederer said Pfizer is aware of a number of noncancer applications that are being proposed for Prinomastat, but it hasn't yet decided which, if any, to pursue.
Write to Tamsin Carlisle at tamsin.carlisle@wsj.com
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