Newsday - July 7, 1998
Laurie Garrett - Staff Correspondent

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 Tcell (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 Tcells. 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 Tcell 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 Tcell clones are wiped out, Roederer says.

The result is, "total remodeling of the Tcell population," Roederer explains.

In an uninfected adult, a third of all T cells are naive CD4 cells, another third are memory CD4s. The rest are from another cell population called CD8s: 19 percent are naive CD8s, and 15 percent are memory CD8s.

When HIV is in the picture, that balance shifts radically. Only 2 percent of all surviving T cells are naive CD4s, and 7 percent are memory CD4s. The remaining 91 percent of all T cells are CD8s; 10 percent naive and 81 percent memory.

The significance, Roederer says, is that within weeks after getting infected an individual is, to use a metaphor, suddenly stuck with a lousy baseball team.

"So what we've got here is a baseball game where the manager of our team has fielded 15 shortstops and only one outfielder," Roederer said.

Dr. Bruce Walker of Harvard Medical School has done studies this year on several HIV patients - both on and off HAART. He has discovered that within the first six weeks of infection, the helper Tcell population gets completely wiped out. Without those particular types of CD4 cells, the immune system can barely manage to destroy a single HIV.

That's because, Walker said, helper T cells are "the key orchestrators of the immune system. They are command central for the defense against viruses."

In the absence of helper T cells, or virtually any effective immune response, the viruses happily reside inside tonsils, lymph nodes and the spleen, making copies of themselves and infecting passing CD4 cells, Dr. Simon Wain-Hobson of the Pasteur Institute in Paris explained, using electron-microscope pictures of tonsils and spleen tissue from autopsied AIDS patients to prove his point.

As years wear on, these viral hiding places get chewed to pieces, turned into a latticework of punched-out dead cells.

The question scientists and clinicians are now asking is whether HAART - probably with some ingenious kick in the pants - can reverse all this and be pushed to wipe out those 1 million latent, hidden HIVs.

Maybe. Or maybe not. There is evidence that argues in both directions. First, the good - or at least somewhat positive - news.

Many researchers reported last week that patients having success with HAART - keeping viruses in their blood down so low that they are technologically undetectable - do show signs of immune system improvement. First, their blood CD4 count rises, and the CD8 population size drops back proportionally. The patients don't get sick - their immune systems fight off such typical AIDS-related infections as Epstein-Barr virus and parasites that cause pneumonia.

Some researchers are seeing a rise in naive CD4 cells in some patients - a sign that for the first time after years of infection the patients are making strong new T cells.

A French team reported in Geneva that one of its HAART patients suddenly was cured of a tumor he'd had for years. It was a type of cancer often seen in gay HIV-positive men. Similarly, the purple skin cancer that afflicts many gay HIV-positive men - called Kaposi's sarcoma - often disappears with HAART. That, too, looks like evidence for a strong immune response.

Many studies suggest the bodies of HAART patients rapidly manufacture T cells, often bringing the populations closer to a normal balance. And researchers at the University of California at Los Angeles and at Tulane University in New Orleans find that - for reasons unknown - adding a chemical called hydroxyurea to HAART speeds this process markedly.

"It is suggesting that, indeed, the immune system is regenerating itself," Dr. Brigitte Autran of Hopital Salpetiere in Paris, said at a news conference. "We are suggesting these naive T cells are coming from the thymus."

The thymus? Standard immunology training says the thymus doesn't function in adults - only in children, where it is the organ that produces T cells (T stands for thymus).

That dogma was just overthrown. Dr. Joseph McCune of the University of California in San Francisco measured the sizes of thymuses, using magnetic resonance imaging, in men who were on, or off, HAART. He found that some men who had the virus under control also had enlarged thymuses. A team from the university hospital in Milan, made similar findings in adults on HAART, further noting that those enlarged thymuses were making naive CD4 cells.

But what are all these new cells? Some researchers say they represent expansion of a very narrow repertoire of T cells - a kind that is programed to recognize a rather small range of invaders, or antigens. These scientists say a big thymus and billions of CD4 cells won't do an HIV patient any good if - to use Roederer's metaphor - they're just a lot of shortstops with poor batting averages.

To get to the bottom of that question, researchers run tests that identify the characters of T cells in a person's blood. If there is a very diverse set of "characters" present, the individual has a healthy immune system. A narrow range of characters is bad news.

Rafick-Pierre Sekaly of the Institut de Recherches Clinques in Montreal, ran a series of such blood tests on HAART patients. He found that the only HIV patients whose Tcell populations were reasonably diverse were untreated longterm survivors - individuals who, for unknown reasons, have lived more than 10 years with HIV without ever experiencing HIV-related illness or taking medications. And the burst of T cells in HAART patients, Sekaly said in an interview, is of a very narrow character range. In fact, they are precisely the types of cells HIV is likely to infect, if the virus has a chance to make a comeback.

Even the optimistic Autran of Paris acknowledged in her speech that very few HAART patients can mount a decent immune response against a cytomegalovirus infection or tuberculosis.

That's why the FDA's Fogelman says the glass is half empty, half full. She developed an ingenious way to evaluate the immune responses of HAART patients, using a harmless virus called phiX174. Healthy people make a huge antibody response against phiX174, which is followed by a critical Tcell reaction that corrals a second type of antibody into the fight.

Fogelman immunized 10 HAART patients with the harmless virus, as well as seven HIV patients not on HAART. And she gave them two booster shots. She did the same procedure to 10 healthy control patients.

Some of the HAART patients never made an immune response to phiX174, Fogelman said. A few started to respond, "and then aborted. We don't know what's going on with these patients."

And even the strongest responders among the HAART patients never came close to mounting a decent response. The strongest immune response in one HAART patients was less than half that of the average healthy individual.

* * * *

Seeking Immunity

Scientists do not know why the human body fails to muster an effective immune response to HIV. Here is how scientists hope they will someday be able to prompt such an immune response:

A. Humoral Immunity (antibody-based) immunity

1. A macrophage, a cell whose job it is to scout out invaders in the body, breaks down the HIV particle.

2. The fragments are received by a CD4 "helper" T cell, a type of white blood cell.

3. CD4 T cell releases signaling molecules that promote maturation of B cells designed to combat HIV.

4. Activated B cells produce antibody molecules that mark HIV particles for destruction.

5. Another macrophage senses the antibodies and destroys the HIV particle.

6. Some of the B cells become memory cells that can react quickly to a future exposure of HIV.

B. Cellular immunity

1. HIV-infected macrophage displays viral fragments that are recognized by CD8 T cells.

2. CD4 "helper" T cells prompt the CD8 T cells to destroy other HIV-infected cells. The CD8 T cell finds these infected cells by looking for short pieces of protein that the infected cell displays on its coat.

3. Some of the T cells become memory cells that can react promptly to future exposures of HIV.

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