The copy below is taken From the "Nashville Banner", Nashville, Tn 15 Jan 1998:

Finding `hide-out' protein may help AIDS therapy

By Bill Snyder

bsnyder@nashvillebanner.com

A natural protein that protects the body from toxic substances also may enable the AIDS virus to ``hide'' from anti-AIDS drugs, researchers at Vanderbilt University Medical Center report today.

By blocking the so-called P-glycoprotein, doctors may be able to boost the effectiveness -- and lower the cost of -- anti-AIDS drug therapy, they say.

``We're not saying this is the way to a cure,'' says Dr. Richard B. Kim, assistant professor of medicine and pharmacology who led the research team. ``But it may be an important way to further eliminate the virus.''

The Vanderbilt study was published in today's issue of the Journal of Clinical Investigation, a medical journal.

The human immunodeficiency virus (HIV) causes acquired immune deficiency syndrome by attacking and killing a type of white blood cell essential for protecting the body against life-threatening infections.

New drugs, called protease inhibitors, when combined with older medications can dramatically lower the ``load'' of HIV in the blood, and increase the number of white blood cells. But if patients stop taking the drugs, which can cost $10,000 to $15,000 a year, the virus comes back.

Kim and his colleagues have found evidence in mice that P-glycoprotein may prevent protease inhibitors from reaching HIV in the blood and in the brain -- thus creating ``sanctuaries'' for the virus to hide out.

Other Vanderbilt researchers are trying to find out if the same thing occurs in humans. If so, patients could be given drugs that block the action of the protein, thereby ``knocking down the doors'' to the HIV hide-outs.

Anti-AIDS drugs cannot shut down HIV's prodigious reproductive machinery unless they can reach and get into the cells that HIV infects. ``We're suggesting that this transport molecule (P-glycoprotein) seems to act as a barrier to prevent entry of these drugs into the cell,'' Kim says.

This is particularly true in the brain, which is vulnerable to HIV infection but which does not allow free entry of many drugs, including those used to fight AIDS.

Even if the virus was knocked out of most parts of the body, if a few viral particles remain, ``because the virus divides so rapidly it could continue to be a source of infection,'' Kim says.

``I don't necessarily think P-glycoprotein is the only way the virus is protected,'' he cautions, ``but it is clear to us that (the protein) is important in reventing entry of these important new drugs.''

In addition to Kim, the researchers included Drs. Martin F. Fromm and Christoph Wandel, fellows in clinical pharmacology; research assistant Brenda Leake; Dr. Alastair J.J. Wood, professor of medicine and pharmacology; and Dr. Dan M. Roden, director of clinical pharmacology.

Brain blockade

P-glycoprotein works by ``pumping out'' drugs and other toxins that are trying to enter cells. In the intestine, the protein prevents suspect chemicals from squeezing past the intestinal lining into the bloodstream. In the liver and kidney, it aids excretion of the substances.

This makes it difficult for some drugs, including protease inhibitors, which are given by mouth, to get into the bloodstream.

In the brain, P-glycoprotein prevents chemicals circulating in the blood from sliding through blood vessel walls into brain tissue. This blockade, known as the ``blood/brain barrier,'' keeps toxic substances -- and many drugs -- out of the brain.

The Vanderbilt researchers studied a strain of genetically engineered mice in which the P-glycoprotein function was disrupted. They found that the amount of protease inhibitor given by mouth that reached the bloodstream of these mice was two to five times higher than in mice with normal protein function.

And when protease inhibitor was injected directly into the vein, the amount that reached the brain in the genetically engineered mice was seven to 40 times higher than in the normal mice.

``Our data appears to show that far less of the drug gets into the brain because of the (protein) ransporter,'' Kim says.

This, in turn, creates a potential ``sanctuary'' for HIV, the researchers said. It may explain why some AIDS patients who have been treated ``successfully'' with protease inhibitors still develop HIV-associated nerve and brain damage.

Drugs that block P-glycoprotein, including the common heart drug verapamil, are relatively inexpensive and have few side effects. This method has recently been employed successfully to boost levels of an nti-parasitic drug in the brain.

These drugs may not act specifically on P-glycoprotein, however, but may also inhibit enzymes that break toxins into inactive forms or into forms that can be more readily flushed from the body.

``You don't want to shut down (these) enzymes totally,'' Kim warns, or the body would be unable to diffuse potentially life-threatening toxins.

1/15/98

© 1998 The Nashville Banner