New Research Shows Path HIV Takes Into Brain

Despite recent hopes that powerful "cocktails" of drugs can beat AIDS virus into submission, the fight isn't over yet.

Even if AIDS is driven out of the immune system entirely by heavy doses of drugs, there is always a fear it could resurge.

It has long been known that AIDS attacks not only the body, but also the brain, where it is immune to most of the drugs developed against it.

However, new research from the Dana-Farber Cancer Institute is taking strides to eliminate the threat of a resurgence of AIDS from the brain.

Associate Professor of Neurology Dana H. Gabuzda has worked in part to take the first step in determining how to eliminate AIDS from the brain.

She says that although it has never been observed--mostly because a cure has not been found for AIDS--just expunging the virus from the immune system might not be effective.

"Theoretically even if HIV were eliminated totally by other drugs from the body, it could resurface from hiding in the brain," she says.

Once it is in the brain, HIV--the virus that causes AIDS--is invulnerable to the action of all the treatments which have been developed to fight it, with the exception of AZT.

However, HIV has been shown to develop resistance rapidly to that drug in the brain.

In order to prevent the resurgence of the virus, Gabuzda and post-doctorate Jianglin He are exploring how HIV attacks the brain.

HIV only expresses itself in the brain in the late stages of the infection.

"Just as [HIV] invades the body's white blood cells, it is able to infiltrate similar cells in the brain, called microglia, quite effectively," Gabuzda says.

Unlike in the body, where HIV only destroys immune cells, Gabuzda says that the infection of microglia--the brain's counterpart to white blood cells--is responsible for the release of neurotoxins, which damage neurons.

"The resultant damage causes cognitive impairments, forgetfulness, impaired reading and slurred speech," she says.

Until now, the mechanism for how HIV enters these cells has been a mystery.

The theory has been that the virus binds to several extracellular proteins--"gates" through which the disease must pass before entering the cells.

Until recently, only one of these proteins was known--the immune cell receptor CD4.

Last year, Associate Professor of Pathology Joseph G. Sodroski found two other gate proteins that HIV uses to enter cells in the rest of the body--CCR5 and CXCR4.

Gabuzda used this discovery to try to find out if any of these proteins allowed HIV into microglia. She found that CCR5, and another protein--CCR3--are part of the complex that is the brain's gate for HIV.

These molecules had been suspected of being able to channel HIV "but this had only been suggested in recombinant DNA experiments," says Gabuzda. "This is the first time CCR3 has been shown to be the doorway."

Since the publication of this research in the Feb. 13 issue of the journal Nature, companies are already exploring its potential for therapeutic use.

"It is known that people who are deficient in the CCR3 receptor show no known abnormality, and further that they are highly resistant to HIV infection," says Gabuzda.

These facts are raising hopes that a drug which blocks the receptor could inhibit HIV's infection of the brain.

'Theoritically even if HIV were eliminated totally by other drugs from the body, it could resurface from hiding in the brain.' --Dan H. Gabuzda, Associate Professor of Neurology, Dana-Farber Cancer Insititute