AIDS AND IMMUNITY

Battling the Perfect Immune System Killer

"It\'s hard to tell if the glass is half full or half empty," Ilana Fogelman said, shrugging her shoulders.

She was speaking of her Food and Drug Administration research on the immune responses of AIDS patients who have been taking the powerful triple-drug combination therapy called HAART.

Pointing to her work, posted on a wall at the 12th World Conference on AIDS here, she knitted her brow and then concluded, "We\'ll have to do some more research."

An estimated 1 million people worldwide are now taking the toxic combination of one protease inhibitor drug with two older drugs to fight their HIV infections. It is now known that while HAART (highly active anti-retroviral therapy) can bring the infection to undetectable levels in the blood, HIV remains undefeated, hidden in the body.

Now there is strong interest in--and debate about--restoring the immune system. Can the ravaged systems of AIDS patients be reconstituted to take up the fight?

In every conceivable way, HIV has adapted to become the perfect immune system killer.

Dr. Rolph Zinkernagel of Zurich University aptly describes how HIV works as "immunopathology."

The virus enters the body by infecting immune system cells, the germ-ingesting white blood cells called macrophages, which carry them like Trojan horses straight into enemy territory: the lymph nodes.

"It\'s all a continuum from macrophage--the entire HIV process," says Dr. Jan Orenstein of George Washington University.

Transported to the lymph nodes, HIV can latch onto the first lymphocyte (lymph cell) it sees that has a CD4 receptor--usually a CD4 T cell (T cells help other immune system cells make antibodies and a variety of chemicals to attack an invader). Using CD4 and other receptors on the cell\'s surface, the virus enters the cell, making its way to the nucleus. And then HIV, which is an RNA virus, makes a mirror image of its genes, in the form of DNA. Since all human genes are made of DNA, this mirror switch allows the dangerous virus to insert itself into the human genetic code.

And there it may lie, for years on end, waiting for an opportunity to pop out of the DNA and make thousands of copies of itself, which can then be released from the cell to travel outward in search of other CD4-bearing cells to infect: dendritic cells, macrophages, small cells in the brain and other even smaller cell populations.

The hallmark of HIV disease is the death of massive numbers of CD4 cells. A low CD4 blood-cell count almost invariably signals trouble for the HIV patient.

New studies unveiled last week at the 12th World AIDS Conference demonstrate some seriously bad news: Most of the significant damage to the immune system is set in place within the first three to six months after infection. Few people realize they are infected during that period. They usually don\'t have any symptoms.

The immune system damage set in place during those early weeks includes:

- A pool of about 1 million latently infected cells. This pool is constantly replenished, staying about the same size for the first years of infection. And none of the currently available drugs, taken in any combination, can eliminate that pool.

- A dramatic depletion of T cells of the "naive" type. These are usually young cells, designated naive because they\'ve not yet faced an invading microbe.

- Stabilization of the pool of memory T cells. These are usually older cells that have done battle with invaders and quickly "remember" the same type of microbes or agents if they return.

- A sharp rise in antibodies against HIV, followed by a drop and then continued low-level antibody production, usually targeting parts of HIV that aren\'t significant to the virus. Therefore, the antibody response is ineffective.

- An obliteration of the helper T cell population.

When naive T cells encounter evidence of foreign material-- called an antigen--they clone themselves to make more fighters that recognize that particular antigen.

Mario Roederer of Stanford University has found that naive T cells that encounter HIV clone 10,000 copies of themselves. That ought to be plenty to counter the invasion. But it\'s not. Billions of human immuno-deficiency viruses are made every day in an infected person. So those naive T cell clones are