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The problem is that most of the molecules that make up the HAART drugs do not readily cross the blood–brain barrier, or only do so in suboptimal amounts. And whatever drugs do get into the brain do not remain there very long, as drug efflux pumps transport them back across. Furthermore, the potential exists that the drugs themselves may damage brain cells if allowed access to the CNS.

Fox and his colleagues will explore a number of new possibilities for addressing the inability to treat HIV-infected brains. There are brain-penetrating antiretrovirals, and the effect of these will certainly be studied, though Fox believes such an agent may not be necessary. "If you lower viral load [in the blood] effectively," he says, "there will be less virus entering the brain, and less of an immune response against it. Then you will have fewer abnormalities."

In one already concluded study, for instance, PMPA, a reverse transcriptase inhibitor that does not cross the blood–brain barrier, was injected in a single daily dose and shown to reverse neural abnormalities. When the treatment stopped, the abnormalities returned.

If brain macrophages are producing an inflammatory response and killing nerve cells, then the remedy may be something as simple as taking an anti-inflammatory drug, such as ibuprophen, which diffuses across the blood–brain barrier. "That’s certainly something we are going to look at," says Fox.

A New Effort at TSRI

In order to further research into the cause, prevention, and treatment of HIV infection in the brain, Fox has organized the Scripps NeuroAIDS Preclinical Studies center, funded last year through a $10 million grant from the National Institutes of Mental Health. The center will bring together researchers from across TSRI to look at all aspects of HIV brain infections and treatments as well as carrying the baton of the former Scripps AIDS Dementia center, which directed research in the area throughout the1990s.

The goals of the new center are twofold: to support the existing neuroAIDS research at TSRI and to encourage other scientists to become interested in the area. Unlike that of its predecessor, the Scripps NeuroAIDS Preclinical Studies operating mechanism will be to establish core centers to support basic research into all the important molecular, cellular, genetic, immunological, virological, neurobiological, and chemical questions. Other cores will support the cognitive, physiological, and behavioral responses to treatments in animal models. Finally, a developmental core will award grants to junior and senior faculty so that they can develop projects related to neuroAIDS.

Center scientists will develop novel in vitro molecular and cellular assays and new molecules to test. They will also support studies by producing DNA chip technology and transgenic knockout mice. They will correlate all possible therapeutics with cognitive and behavioral markers in animal models, measuring the effects of rampant chemokine and cytokine production. And they will look at immune activation markers, testing whether certain molecules interact with one another. All told, the center will support an enormous volume of research.

Fox calls the core operating model the best one possible. "To fully understand the diseases that affect the brain," he says, "one also needs to study the other systems that interact with the brain." He expects that any research supported by the center will branch off into independent, investigator-initiated research grants. Fox himself directs two such independent research grants.

"Scientists often want to try something new, but they either can’t pay for it or can’t invest a lot of time to learn how to do it," says Fox, "But we can do it. That’s one of the great advantages of [a center] such as ours. Paying a private company to do this kind of research, or trying to do it all in a single lab, would be prohibitive."

"[Researchers] still shy away from the brain," he says. "Hopefully, the center will make it more accessible."

The following TSRI researchers are associated with the Scripps NeuroAIDS Preclinical Studies center, directing cores or performing novel developmental studies funded by competitive grants from the center: Michael Buchemier, Iain Campbell, Monica Carson, Phil Dawson, John Elder, Howard Fox, Nick Gascoigne, Steve Head, Steve Henriksen, John Polich, Amanda Roberts, Nora Sarvetnick, George Siggins, Michael Taffe.

The center holds monthly meetings focussing on recent research on neuroAIDS—both at TSRI and outside of it—and its basic scientific underpinnings. Attendance is open to all who wish to find out about this field or about use of the center’s resources.

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Outwardly healthy HIV-positive individuals may experience subtle changes due to the virus's action on the central nervous system. (Proportions of a Head by Leonardo da Vinci, 1489. Brain section from the University of Wisconsin and Michigan State Comparative Mammalian Brain Collections, supported by the National Museum of Health and Medicine, NSF, and NIH. http://brainmuseum.org/ .)






See also:

The Scripps NeuroAIDS Preclinical Studies center, including meeting schedules and information about core centers

Howard Fox’s home page