In the early days of AIDS, one of the heartbreaking features of the disease was its effect on the brain.
As they headed toward certain death, most AIDS patients also developed a type of dementia that robbed them of their ability to think and eroded their personalities.
Then came the drug regimens of the 1990s, which not only increased a patient's life span far more than some dared to hope, but also cut in half the frequency of brain dysfunction.
But the problem has not been solved. In a twist that mystifies experts, some patients who otherwise thrive on anti-retroviral drug therapy still develop trouble with remembering, concentrating, completing tasks or following directions.
These mental issues can interfere with patients' ability to function on the job or perform tasks as simple, yet necessary, as taking their medications on time.
"There is still a big gap between the success we've seen from the anti-retrovirals and the need for specifically targeted therapeutics for the brain," said Dr. Justin C. McArthur, a Johns Hopkins University School of Medicine neurologist who specializes in the cognitive problems of patients with HIV infection.
McArthur recently received a five-year, $1.5 million grant from the National Institute of Mental Health to develop new treatments for the problem. He will head a new research unit that includes other neurologists and infectious disease experts.
Most patients with cognitive impairment have less severe symptoms than their counterparts in the early days of the epidemic. "It can be a relatively subtle event," McArthur said. "They may look quite well, but if you probe their neurological functioning with tests of having complex conversations, it's pretty clear the brain is not functioning as well."
In others, he said, the effects are more pronounced - akin to replacing one of today's lightning-fast computer chips with one from a dozen years ago.
"One of the cardinal features is mental slowing. You can ask a question and literally go out and get a cup of coffee, and they're still working on it," McArthur explained.
Losing mental acuity can also have an emotional impact.
"Some patients are absolutely devastated - not only by the actual dysfunction but the fear that this will progress and they may not be able to live independently," McArthur said.
In the first decade of the epidemic, he said, 60 percent of people with the disease had significant cognitive impairment. In a third of them, the problems were severe enough to warrant placement in a nursing home.
These days, brain deficits emerge in about 30 percent of patients. Suppressing the virus apparently protects the brain in the majority of cases, but not in every case. Nobody is sure why, but theories abound.
One, said McArthur, is that the virus triggers an inflammatory response in the brain that cascades even when the virus is reduced to undetectable levels. Under this scenario, the virus lays the groundwork but does not directly cause the brain to decline.
"The virus is the fuse that ignites the fire," McArthur said. Magnetic resonance images of such patients show areas of shrinkage in the brain.
Kathy Kopnisky, chief of HIV therapeutics at the National Institute of Mental Health and overseer of the grant, said genetics probably explain why some infected patients are susceptible to cognitive impairment while others are not.
But even the notion that cognitive problems are still commonplace among patients with HIV infection is controversial, she noted.
Some researchers, such as Dr. Richard Price of the University of California San Francisco Medical Center, argue that the problem may be magnified by mental tests that tease out impairments that would otherwise be too subtle to notice.
"My prejudice - and we really don't know what the answer is - is that it doesn't seem to be as common a phenomenon as some people may think," said Price, chairman of neurology. "Earlier, we saw people with severe problems, and there's no question it was something bigger. Now, we're working around the margins with some marginal issues."
Still, he said the issue is important to study, in part because there is disagreement over how often the problems occur and what their causes might be.
The Hopkins center plans to test a variety of drugs against AIDS-related dementia. First on the list is minocycline, an old-line acne medication that is technically an antibiotic but has attracted interest for its anti-inflammatory effects.