Body’s Vicious Guest : AIDS Virus: Scientists’ Baffling Foe

All disease-causing organisms, in order to flourish, must find a special niche somewhere in the human body. But few have mastered that technique with the sinister effectiveness of the deadly AIDS virus.

The organism kills its victims by finding shelter inside the very immune-system cells that are supposed to repel such invasions. At the same time, the virus--like some vicious, selfish guest--borrows the cell’s machinery to replicate in huge numbers before going on to destroy its dwelling and, finally, the human host that has served it so well.

The baffling AIDS virus, in short, possesses all the attributes of the “pathogenic personality,” in the words of Stanford microbiologist Stanley Falkow.

And despite periodic flurries of publicity about some seemingly promising AIDS drug, the U.S. Public Health Service estimates that it will be 1990 before a safe and effective drug or vaccine may become available. Many AIDS researchers, sobered by how little is known about the virus and the way it works, will not even hazard a prediction.

In the meantime, public health officials agree, the only viable containment strategy is more effective education programs, because AIDS can be expected to continue spreading until the year 2000--even if an effective drug treatment or a protective vaccine becomes available four or five years from now.

At least six antiviral drugs are undergoing clinical trials, involving several hundred patients at medical centers across the nation. But such drugs, experts warn, would not be a cure-all; instead, they are seen only as potential steppingstones to more sophisticated solutions.

In the race to find a cure, the federal government’s double-pronged effort aims at developing drugs that will kill the virus without disrupting normal cells, and still other drugs that will repair a patient’s immune system.

Mutates Frequently

And much will depend on how quickly researchers gain new insights into the complex biochemical and immunological properties of both the virus and the cells it attacks. The job is all the more difficult because of growing evidence that the AIDS virus mutates frequently--making it a moving target even while it ravages its victims.

The AIDS virus, known variously as HTLV-III, LAV or ARV, invades and eventually destroys a key component of the immune system called T-4 cells. T-4 cells are responsible for initiating and regulating essentially all immune system functions. Their destruction leaves the patient vulnerable to a wide variety of infections and cancers, which usually are what kill AIDS victims.

Little is known about what happens to T-4 cells after an HTLV-III virus invades, according to Dr. John Fahey, a UCLA authority.

Particularly puzzling, for example, is why the virus initially infects only some of a person’s T-cells while leaving the majority untouched. Other questions that perplex researchers such as Fahey include: Why do only some infected T-cells die while others initially appear to be unharmed? Does the virus spontaneously disappear in some individuals? Or does the virus simply remain in an inactive state? Do infections by other kinds of viruses activate the latent AIDS virus?

Ideally, an effective AIDS drug must rid the body of all the virus. But achieving that may not be so simple.

For one thing, T-4 cells, once damaged, may never regain their normal function. So another challenge is to restore the damage that the virus has already inflicted on T-4 cells. At least four additional experimental compounds are being tested for their ability to repair T-4 cell damage.

Several of these so-called immune enhancers are natural body chemicals that can be manufactured in large quantities through techniques of genetic engineering. They are alpha interferon and interleukin-2. Two others are IMREG-1 and Isoprinosine, two synthetic compounds that stimulate the body to make more interleukin-2.

Twin Goals

But experts say that accomplishing the twin goals of killing the virus and restoring the immune system--not to mention finding an AIDS vaccine--will not happen quickly. Some researchers suspect that a complete restoration of the immune system may even require a bone marrow transplant.

As of Nov. 18, according to the federal Centers for Disease Control, there have been 14,862 reported cases of AIDS in this country, including 7,628 deaths. In all, as many as 1 million Americans are believed to have been exposed to the AIDS virus--virtually all of them members of the high-risk groups such as sexually active male homosexuals, intravenous drug users and hemophiliacs.

Of the 1 million, according to health officials, about 10% eventually will develop full-blown AIDS, another 20% will show some of the symptoms of the disease and the remaining 70% will be symptom-free. Because the 70% may unknowingly be carrying the virus for years--and spreading it to others through sexual contact--public education programs are considered vital.

The six antivirals being tested in this country are Ansamycin, azidothynidine (formerly called Compound S), phosphonofornate, HPA 23 (the drug Rock Hudson went to Paris to receive), ribavirin and suramin. Experimental drugs undergoing clinical trials in Los Angeles centers are suramin, at County USC and UCLA medical centers, and ribavirin at County USC. Researchers at both USC and UCLA plan additional studies later this year with several of the other drugs.

Most of these drugs, as well as others being considered for testing, work by inhibiting an enzyme called reverse transcriptase, which is essential for the replication of the HTLV-III virus after it invades a cell.

Being able to block the enzyme is a major advantage, but the dosage needed to knock out the virus is proving to be toxic to many already-weakened patients and thus frequently must be lowered or stopped altogether.

Nevertheless, some of those test patients have gained weight, said they feel better and even been rid of the virus in their blood for periods of time, researchers report. But none of the drugs is seen as the answer.

“Antivirals offer promise. But, so far, none has been found to have a significant effect against AIDS in humans,” the Public Health Service says.

Dr. Samuel Broder, chief of clinical oncology at the National Cancer Institute near Washington, is among those most optimistic that treatments and a vaccine can be developed.

“When the isolation of the HTLV-III virus was announced in April of 1984, many scientists felt that not much could be done to intervene with the virus. There was not a great deal of enthusiasm. But now there has been a shift,” he said.

Broder attributes the new attitude to an unusually close collaboration between the National Cancer Institute and private pharmaceutical companies to speed development of a cure. The institute is supplying the expertise gained from years of research on viruses, including the isolation of HTLV-III, while the drug companies are concentrating on their own forte of synthesizing new compounds.

Some Optimism

“We have now screened more than 120 compounds. I am optimistic that some of them will be improvements over what we now have,” Broder said.

Because many AIDS patients may have to take an antiviral drug for life, such medication must be less toxic than existing drugs. Researchers also hope that such a drug can be taken orally, to avoid the inconvenience of taking such medication intravenously in a medical setting, according to Broder.

In addition, any such new drug must also have the capability of getting at the virus hiding inside cells other than those of the immune system.

Of growing concern among AIDS researchers is the recent discovery that the virus may be attacking brain cells as well as the T-4 cells.

At first, reports that a high percentage of AIDS patients were also severely depressed and showed signs of dementia were ascribed to the shock of learning that they had the disease.

However, several researchers have recently isolated the virus in brain cells and in the spinal fluid of patients who died of AIDS. According to Dr. Joseph Gibbs of the National Institutes of Health, 40% to 45% of all AIDS patients have signs of degenerative brain disease.

Evidence that the virus attacks the central nervous system as well as the immune system means that a good anti-AIDS drug must be able to get into the brain if it is going to eliminate the virus from the body altogether.

But getting into the brain may not be easy. The drug would have to get past a natural phenomenon called the blood-brain barrier, which is supposed to protect the brain from foreign substances that enter the bloodstream.

Drugs that fail to cross the barrier may rescue the patient from the immune deficiency, only to leave them victims of serious neurological disorders.

Whether a drug is able to eliminate the virus in the brain may be of special concern to those who have had a blood test indicating that they have been exposed to the virus but who have no symptoms of the disease.

“The virus may be there for life and do nothing. Or it may produce a slow neurological disease eight or 10 years from now,” said Dr. Leon Epstein, a pediatric neurologist at the University of Medicine and Dentistry of New Jersey who is working on the problem with the National Institutes of Health.

“How many of the 70% who are asymptomatic have virus in the brain?” he asked. “We don’t know, but it is likely that a significant number do. Then the question becomes how many years it will be before the virus does what it will do.”

Concern Shared

Other prominent AIDS researchers share that concern. Dr. William A. Haseltine, a pathologist at the Dana-Farber Cancer Institute in Boston, predicted that the damage inflicted by virus to the brain eventually will kill more people than now die from the infections and cancers.

Gibbs, the NIH researcher with whom Epstein works, is studying chimpanzees who have been infected with the human HTLV-III virus. If the virus has gotten into their brain cells, it would offer researchers an opportunity “to learn how to get the drug past the blood-brain barrier in dosages that would not be toxic,” Gibbs said.

Scientists are now working on a number of different approaches to knocking out the virus, according to Dr. Dani P. Bolognesi, a Duke University researcher. One possibility is to use monoclonal antibodies--highly specific “guided missiles”--to zero in on the specific receptor sites on the surface of T-4 cells to which the virus must attach itself before it can enter the cell. Blocking the receptor site presumably would deprive the virus of a “landing field.”

A novel approach to therapy suggested by Bolognesi is to give patients a competing virus that would be as attracted to T-4 and brain cells as the AIDS virus is but that does not cause disease. The idea is to occupy those cells with the benign virus, leaving no room for the AIDS virus to gain a foothold.

Screening Test

Along with developing new drugs to rid the body of the virus, scientists say that it will be necessary to develop a simple screening test that can be used on large populations to identify carriers of the virus. It is now feasible to do this only in special laboratory conditions on small numbers of subjects. The test being used now to screen blood donors only identifies the presence of antibodies to the virus, not the virus itself.

A simpler screening test would allow physicians to monitor the effectiveness of antiviral drugs in AIDS patients, said Dr. Carl Saxinger, a National Cancer Institute researcher who is attempting to develop such a test.

Scientists say also that they must learn more about the virus itself so they can not only devise ways to kill it but also develop a protective vaccine.

At this stage, nobody even knows whether an AIDS vaccine is possible because research for such a vaccine is far behind that for drug treatment.

One of the problems is to find a primate that responds to HTLV-III in the way that humans do and therefore can serve as a test model.

A vaccine made from a virus that causes an AIDS-like disease in rhesus monkeys is in the early stages of trial on that species, according to Dr. Patricia Fultz, a research scientist at the Centers for Disease Control in Atlanta.

Chimpanzees Infected

But researchers so far have not been able to infect rhesus monkeys with the human AIDS virus. They have, however, successfully infected chimpanzees, which can serve as a test model when a human AIDS vaccine is developed.

One reason for the uncertainty about a vaccine’s future is that HTLV-III appears to make frequent changes, or mutations, in the chemistry of its protein coating. This means that if a vaccine is composed of the viral coating as it exists at one point in time, the protection that it gives may no longer be effective against a virus that has since mutated and altered its coating. These chemicals, or antigens, on the coating are what trigger the individual’s immune system to make antibodies to neutralize the virus.

To get around some of the potential problems with an AIDS vaccine, several alternative approaches are being explored. One is to make a vaccine that consists of both the coating and the genetic material located inside the virus. This is done either by killing the virus or “taming” it in such a way as to render it non-infectious. Both approaches have been used successfully to make the Salk and Sabin polio vaccines.

But some researchers are concerned about the safety and predictability of either a killed or a tamed AIDS virus, partly because too much remains to be learned about the virus, such as just how it invades cells. So scientists are looking for ways to get around that problem.

New Vaccine Concept

According to Dr. Hilary Kaprowski of the Wistar Institute in Philadelphia, an AIDS vaccine may be possible by applying a new concept in vaccine development that involves using neither the genetic material nor the coating of the virus. The absence of any viral material means that the vaccine would be completely safe, he said.

Conventional vaccines protect against a disease-causing organism by inducing a person’s immune system to make antibodies against that organism. But the version proposed by Kaprowski consists of so-called anti-idiotype antibodies--literally antibodies against antibodies--produced through a complex process that enables them to react with the AIDS virus in such a way as to afford protection.

This type of vaccine has been used successfully in animals as protection against rabies and several other diseases, Kaprowski said. In addition to its safety, he believes that because of certain special characteristics, an anti-antibody vaccine would have the advantage of being effective against even a virus like HTLV-III that frequently mutates.

Whatever vaccine, if any, emerges in the years ahead, scientists still may face another major hurdle, according to Dr. Robert Gallo, the National Cancer Institute researcher who first isolated the HTLV-III virus. The potential problem has to do with the manner in which the virus sometimes may enter the body.

Transmission Question

The assumption has been that the AIDS virus--after entering the body through sexual intercourse or the use of contaminated needles or blood transfusion--becomes free-floating, like a leaf drifting down a stream. But, Gallo said, there is reason to believe that the transmission of the virus may occur inside cells--T-4 cells, for example--rather than as free-floating entities.

If that is the case--and it has already been shown to be so with two other viruses closely related to HTLV-III--then the antibody would not be able to come in contact with a virus inside a cell. Therefore the vaccine-stimulated antibody would be unable to deactivate the virus, Gallo said.

“I would say that optimism for a vaccine is extremely cautious if the mode of transmission is by way of infected cells,” Gallo said. “I would be very frightened.”

He added that “too little money has been put into vaccine research.”

“The money (for research) is going almost entirely to drugs. The idea is that we will talk about a vaccine someday. I think that is a mistake,” Gallo said. “I think what we need now is very healthy support of basic science. We have to learn everything about the (genetic material) of that virus, exactly how it gets into T-cells--we’re getting there--and how to block its replication. We have to fight to get a vaccine. The modes of transmission are important to understand.”

Gallo concluded: “And the brain involvement--that’s an immense problem. And it’s going to be bigger and bigger.”

THE FIGHT AGAINST AIDS

The growing AIDS problem is triggering crash programs aimed at developing cures and a vaccine that eventually could control the epidemic. Still, no real results are expected for several years. Here is a look at the problem and the directions researchers are taking:

HOW THE AIDS VIRUS ATTACKS A. Normally, a virus attack (1) is repelled by the body’s immune system. So-called T-4 cells (2) initiate and regulate all immune system functions; they tell B-cells (3) in the immune system to release antibodies to repel the virus (4).

B. The AIDS virus (1), also known as HTLV-III, LAV or ARV, attacks the T-cells (2), crippling the usual response by the immune system. The virus replicates itself (3) in huge numbers inside the host T-cells before destroying the host (4).

C. The patient, defenseless against infection, usually dies of one of a wide variety of infections or cancer or both.

D. Of growing concern is the discovery that the AIDS virus also maybe attacking brain cells, which seem similar to T-4 cells. Even if a drug could halt attack on T-cells by ridding the body of viruses, there may be difficulty getting the drug through the body’s natural “blood-brain barrier” to affected brain cells.

THE RESEARCH EFFORTS

DRUGS THAT WILL KILL THE AIDS VIRUS

The hope:

Scientists want to destroy the virus without disrupting normal cells. Six early-model experimental drugs that use various ways of doing this are now undergoing clinical tests.

The worries:

--The dosage of drugs required to kill the virus may itself be toxic.

--The drug may interfere with the normal immunologi-

cal response or be toxic to normal cells.

--Not enough is known about the biology of the virus.

--Viruses in brain cells also may be unaffected by the drugs.

DRUGS THAT REPAIR THE SYSTEM

The hope:

Scientists hope that after killing AIDS virus, they will be able to restore the immune system. At least four such drugs are being tested.

The worries:

--Once T-4 cells have been attacked, they may prove impossible to restore.

--Not enough is known about how T-4 cells react to the AIDS virus.

AN AIDS VACCINE

The hope:

Scientists hope that a vaccine against AIDS virus is possible.

The worries:

--Other primates used in testing may not respond to vaccines as humans do.

--Insufficient knowledge about the structure of the AIDS virus.

--Not enough is known about exactly how the virus is transmitted.

--This approach has the least financial backing, PATRICIA MITCHELL / Los Angeles Times