by Chael Needle

LifeGuide

[Treatment Horizons]

A new 3-D imaging technology has provided a way “to make the first map, or images, of how HIV attacks the brain,” says Paul Thompson, PhD, an associate professor of neurology at UCLA and the first author of a UCLA/University of Pittsburgh study published in the Proceedings of the National Academy of Sciences on October 10.

In the study, composite maps of people living with AIDS were produced from brain scans showing regional changes in the thickness of the cortex. This outer layer of gray matter is affected first during disease progression and therefore is a good measure of the wellness of the brain. Twenty-six patients with AIDS participated in the study; all of them had lost at least half of their T cells, none had experienced AIDS-related dementia, and thirteen were on HAART. These maps were compared to fourteen HIV-negative individuals of the same age and with the same risk factors, and the level of damage was assessed.

One of the study’s major findings is that the damage that HIV causes to the brain is more severe than once thought and highly selective, attacking regions that control motor, language, and sensory functions and leaving other areas alone. While the symptoms are very mild, and often not noticeable without sensitive testing, “it’s important that we know about them and try to resist them,” says Thompson. The researchers also found that brain tissue loss was worse in people with greater depletion of T cells, linking what was once thought to be separate phenomena. The logic of this selectivity remains a mystery. “It’s almost as if you have this lava flow of damage that kind of skips around some areas for no apparent reason and leaves them intact,” says Thompson.

The research team also found that, even if a patient’s immune system is responding to HAART, HIV in the brain may be replicating unchecked. Among the patients with AIDS, no difference in tissue loss was noted between those on HAART and those who were not. “Even though HAART therapy and neurotherapy is rescuing the immune system, we still have to be concerned about progressive damage in the brain. Although it sounds like a depressing story, there’s now a technology to map how someone’s brain is doing,” says Thompson on a positive note.

This technology, and the new measure of the disease burden—in general and on the brain—that it provides, he says, is not very costly and could easily be added to drug trials, whose goals might be revised to prevent these early changes in the brain from happening. The questions begging for answers are numerous.

Which of the drug candidates with neuroactive potential are actually saving brain tissue? Does a particular drug save brain tissue in different areas than another drug, or work more effectively at one stage of illness than at another? How does one drug stack up to another? “One drug may be terrific for the immune system, and less effective in the brain. For another drug, it may be the other way around. Part of this research entails understanding which cocktails of drugs or sequences of treatment can resist damage, as well,” says Thompson.

HIV reaches the brain within two weeks of infection, and “presents a huge challenge for any treatment design.” Most anti-HIV drugs cannot pass through the blood-brain barrier, a protective coating which plays gatekeeper to toxic substances that may harm the brain. The virus slips through via immune cells called monocytes, but the barrier prevents larger molecules, such as, say, protein-based drugs, from entering. “One drug, Merck’s indinavir, has been shown to get into the brain a little bit,” notes Thompson.

“Imaging is used a little in physicians’ day-to-day HIV/AIDS treatment design, at least in the developed world,” explains Thompson, “but really only in three situations: if a patient has a seizure, if a patient has dementia (and most do not), and, more relevant to people, if there’s an acquired persistent decline in mental ability.” But the study shows promise that a fourth application may become routine. As the study’s use of imaging “has been shown to be a very sensitive marker to early change,” says Thompson, neurologists in the past week have expressed interest in using the technology earlier than they had done so before. “In the past we imaged people with AIDS who already had a very prominent problem coming into the clinic, but brain scanning could be useful just for people living with HIV without AIDS, or for people with AIDS but no symptoms. [Knowledge of the state of one’s brain] could be very reassuring,” offers Thompson, either for people to confirm that brain tissue is not being lost or for people to identify the biological basis of the symptoms they are noting and move toward managing them.

Log on to www.loni.ucla.edu/~thompson/

MEDIA/AIDS/AIDSPressRelease.html for more information about the study.

Chael Needle wrote about vaccine candidate DP6-001 for the October issue.

November 2005