Monday, June 4, 2001

Plumbing the Immune System

AIDS Research Sheds Light on Functions, but Vaccine Remains Elusive

Keay Davidson, Science Writer  SAN FRANCISCO CHRONICLE


In the last two decades, AIDS has pushed immunology - the science of the immune system - to the forefront of medicine.

In the process, AIDS has provided important new information on the workings of the immune system, that invisibly small army of molecular soldiers that wars against infections.

But many immunological mysteries remain, which is one reason why AIDS continues to be a devastating disease. That's also a reason why a holy grail of AIDS research - an effective AIDS vaccine - remains elusive.

"Research on HIV and AIDS has provided revealing insights into the biology of the normal immune system, how it works," said Dr. Warner Greene, director of the Gladstone Institute of Virology and Immunology at UCSF.

In particular, Greene notes, AIDS has shown what happens when a key component of the immune system fails - the CD4 "helper" T-cell. Many types of cells are involved in immunity, but the CD4 T-cell has shown a particular vulnerability to the human immunodeficiency virus, or HIV.

The increased focus on immunology also has helped "to uncover a variety of new cells that play a role in maintaining immune function and its defense against microbes," said veteran AIDS researcher Dr. Jay Levy of the University of California at San Francisco.

But do advances in our understanding of the immune system during the AIDS era constitute a scientific "revolution"? Not yet, some say.

"I don't know that there have been any real revolutions in immunology in the last 25 years. . . . I think (the progress has) been basically incremental, " said Dr. Marc Hellerstein of UCSF. But that's the way science works, he adds.

"You have to fill in the holes, and there are a lot of unknowns."

Years ago, the only people who studied immune deficiency were, for the most part, pediatricians who were interested in children with a rare congenital deficiency of either B-cells or T-cells, two of the immune system's major disease-fighting cells.

An example is the so-called "bubble boy" of the 1970s whose immune deficiency forced him to remain inside a sterile, bubble-like chamber.

Back then, "If you ever said Œimmune deficiency' at a cocktail party, you'd have to pronounce it correctly and explain what it was. Now everyone knows what it is," says Dr. William Shearer, a pediatric immunologist and member of the board of directors of the American Academy of Asthma, Allergy and Immunology.

Acts as a Trojan horse

Perhaps AIDS' most startling single lesson has been that the immune system can act as a Trojan horse: It can house an attacking infection, allowing it to survive within the body - specifically, within CD4 cells - for years before it strikes.

"Who would have guessed that years ago? Nobody!" Shearer said. "The whole notion that the immune system can actually serve as a Œreservoir' for infectious particles came out of AIDS research."

Among other AIDS-spurred advances in general immunology:

-- The realization that the thymus gland may not fully deteriorate in adulthood or after an immune system-devastating illness, as was formerly assumed.

The thymus, located behind the breastbone, plays a vital disease-fighting role. Progenitors of T-cells are produced in the bone marrow, then travel to the thymus, where a small number become fully functional.

It was once believed that when one reached adulthood, the thymus deteriorated and "would not come back again," says Dr. Mike McCune of the Gladstone Institute. Oddly, there had been anecdotal reports by doctors as far back as the early 20th century of adult patients whose thymus glands were substantially intact. But such reports were largely ignored until the 1990s.

"Studies of AIDS have opened up new vistas into the knowledge of thymic function," says Jay Levy of UCSF. "It has changed our view that this (thymic) tissue is vestigial after age 18. Actually, new cells can emerge from the thymus up to middle age."

-- A new appreciation of the so-called "innate" immune system, which traditionally received less attention than its better-understood cousin, the "adaptive" immune system.

The innate and adaptive immune systems are roughly akin to the two parts of a medieval army: the unsophisticated, club-wielding infantry and the expertly trained archers. The former is the first line of defense and attacks targets without a high degree of specificity, while the archers attack specific targets with lock-and-key precision.

Innate immune system

The innate immune system may repress HIV in the body more effectively than previously thought, recent research suggests.

"In fact, one of the most exciting developments is that we are beginning to understand innate immunity at the molecular level, and this opens up tremendous avenues," says Dr. Abul Abbas, chair of the UCSF pathology department and co-author of two textbooks on immunology.

-- New insight into how humans can acquire epidemic infections via contact with animals - in the case of AIDS, from primates. Some scientists now think that humans acquired HIV in the early 20th century from eating the meat of African chimpanzees infected with the primate version of HIV, the simian immunodeficiency virus (SIV).

This realization makes Shearer wonder: "Is there something else out there, something worse than HIV, lurking in some animal reservoir somewhere in the world? . . . (The SIV-HIV link has) pointed out the vulnerability of human beings to animal diseases."

Less glamorous - but vital - immunological questions have also been answered by improved lab techniques, developed in part because of AIDS research. For example, we now know how long CD4 T-cells live: typically 70 to 80 days in a healthy person, and only 20 to 25 days in an AIDS patient.

ŒBig Science'

AIDS has also made immunology into what science watchers call "Big Science. " The disease has diverted unprecedented amounts of federal and private cash into research on AIDS and immunology in general. This year, the total federal research budget for AIDS is $2.4 billion.

And for good reason, scientists say. Many immunological mysteries confront AIDS researchers. Among them are:

-- Exactly what combination of B and T-cell responses are required to repress HIV with maximum effectiveness over the long term? "Once we know the answer to this question, we will be in a much stronger position to create an effective vaccine," Greene said.

-- Precisely how does HIV kill CD4 T-cells? Although two decades have passed since AIDS first hit headlines, this fundamental question remains unanswered. There is much speculation about exactly how HIV damages a healthy cell, "but no one really knows for sure," Greene said.

Famed AIDS researcher Anthony Fauci observed: "Every once in a while, an experiment of nature comes along and dramatically alters the human immune system in a very specific way that allows one to Œdissect out' the regulatory mechanisms of the human immune system. HIV infection is just such an experiment of nature."

AIDS, Fauci said, is caused by "the depletion of the CD4 helper T-cells . . . so I would say it has allowed us to advance significantly our understanding of the regulatory mechanisms of the immune system, particularly with regard to the central role of the CD4 positive helper T-cell. It hasn't revolutionized the field (of immunology), but it really advances it substantially.

"It has opened up a lot of doors for us toward understanding the complexity of the human immune system in a way that no amount of ethical human experimentation would have allowed us to do."

Fighting HIV HIV attacks

As the human immunodeficiency virus (HIV) travels through the blood, it reproduces by burrowing into cells and combining its RNA with the cell's DNA to create copies of itself. RNA material combines with cell's DNA to create more HIV New HIV virus buds out of cell Body battles back

The immune system responds in two ways. In the humoral response, B-cells produce antibodies that attach to the virus and mark it for destruction by other white blood cells called macrophages. In the second defense, called the cellular response, specialized white blood cells called T-cells either help to make antibodies or kill cells already infected with HIV. The humoral response (Target: Free- floating virus) Large white blood cells, such as macrophages, engulf and degrade HIV into fragments and present them as antigens to CD4 "helper" T-cells. Helper T-cells enlarge and release molecules signaling B-cells to produce antibodies specific to HIV. The cell mediated response (Target: Infected cell) An HIV-infected macrophage or other white blood cell presents viral fragments recognized by CD8 "killer" T-cells.

Killer T-cells are prompted by helper T-cells to destroy more HIV-infected cells.

Helper T-cells release molecules activating killer T-cells. Some T-cells and B-cells shrink and become inactive "memory" cells, waiting to respond to future HIV exposures. White blood cells seek out marked HIV and destroy it. Losing the battle

The major weakness in the body's immune system is the CD4 "helper" T-cell. By binding with CD4 cells, HIV can kill them and stop production of antibodies, leaving the immune system weakened and vulnerable to opportunistic disease.

Doctors gauge the health of the immune system by counting CD4 cells. A healthy, HIV-negative adult has between 600 and 1,200 CD4 cells per cubic millimeter of blood. If the count falls below 350, the immune system has become weakened. Sources: Scientific American, University of Kansas Graphic: John Blanchard / The Chronicle