Runaway production of nitric oxide (NO), a gas with effects as varied as nerve cell communication, control of blood vessel action and male erections, may contribute to AIDS dementia, according to Johns Hopkins researchers.
In the December 13 issue of Science, the researchers report an abnormally high production of the enzyme that makes NO in the brains of some people with AIDS. This increase in enzyme activity destroys brain cells. The problem affects 20 percent of all people with advanced HIV infection, they say.
The team showed that a tiny piece of the AIDS virus attaches to immune cells trying to fight HIV infections and, once on board, triggers a series of reactions that increases production of the enzyme that makes NO. High levels of the enzyme called NO synthase, used by immune cells to produce NO, raise production of this gas to six times normal in the brains of affected patients.
"Our findings hold promise for helping physicians develop a way to block this source of NO and reduce the number of AIDS patients who develop dementia," says Valina Dawson, Ph.D., associate professor of pathology. "This is especially important because increasing numbers of people with AIDS are surviving long enough to develop dementia." she says.
"Until now the dogma was that the chance of an AIDS patient developing dementia didn't directly relate to the level of HIV-1," says Dawson. "But we showed that the levels of gp41, a protein that makes up part of the AIDS virus coat, were highest in those AIDS patients with severe dementia."
In addition, the destructive effect of NO shows a "threshold" effect, Dawson says. That is, the destructive effect appears only after the level of the gas reaches a certain point.
Justin McArthur, M.D., associate professor of neurology and a co-author of the paper, says the team already is studying whether protease inhibitors can block the rise in gp41 in the brain. These HIV medications when used in combination with other drugs have greatly reduced the burden of HIV-1 in infected persons, McArthur points out. He says his group also is trying to develop drugs to block production of the enzyme (called iNOS) in brain cells.
The Hopkins team measured the amount of genetic message for iNOS and iNOS itself in brains of four HIV-negative patients who had died, as well as in 25 HIV-positive patients with no dementia, mild dementia or severe dementia. Increased levels of iNOS in brain tissue reflect increased production of NO. The genetic material represented pieces of RNA, the decoded form of DNA, which makes up chromosomes.
Brain tissue from four HIV-negative control patients and 10 HIV-positive patients with no dementia or mild dementia contained insignificant amounts of iNOS. However, the brains from the four HIV-positive patients with severe dementia had levels of iNOS up to six times that of non-infected control patients. In addition, the levels of gp41 also were significantly higher in the brains of AIDS patients who had had severe dementia, but not in the other patients.
In test-tube studies using rat brain cells, the researchers also found identical importance of NO in the chain of events leading to brain dysfunction. When cells called macrophages and microglial cells become infected with HIV-1, gp41 becomes lodged on their surface. When these infected cells make contact with uninfected cells in the brain, the gp41 stimulates those uninfected cells to make NO. The stimulated cells may be macrophages, microglial cells, or another type of cell called an astrocyte, according to Dawson.
The research was supported by the U.S. Public Health Service, Clinical Investigator Development Awards, American Foundation, for AIDS Research, the Charles A. Dana Foundation the American Health Assistance Foundation, International Life Sciences Institute and a Paul Beeson Physician Scholars in Aging Research Program.
Other authors include D. Cory Adamson, Brigitte Wildemann, Masayuki Sasaki, Jonathan D. Glass, Vesselin I. Christov and Ted M. Dawson.
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