Cover Stories

INVINCIBLE AIDS Strange new cases that do not seem to be caused by the known HIV viruses. Drug treatments that no longer look so promising. New complications in the search for a vaccine. Suddenly, the AIDS outlook has become bleaker: more heterosexual transmission, more cases among women and a rising death toll well into the next century

Wars are usually launched with the promise of a quick victory, with trumpets primed never to sound retreat. And the campaign against AIDS was no exception. Soon after researchers announced in the mid-1980s that they had discovered the virus that causes AIDS, U.S. health officials confidently crowed that a vaccine would be ready in two years. The most frightening scourge of the late 20th century would succumb to a swift counterattack of human ingenuity and high technology.

But no one was making any victory speeches last week in Amsterdam, where more than 11,000 scientists and other experts gathered for the Eighth International AIDS Conference. The mood was somber, reflecting a decade of frustration, failure and mounting tragedy. After billions of dollars of scattershot albeit intensive research and halfhearted prevention efforts, humanity may not be any closer to conquering AIDS than when the quest began.

There is no vaccine, no cure and not even an indisputably effective treatment. While AIDS education has slowed the epidemic in developed countries, the disease continues to spread rapidly in many poorer nations. The World Health Organization says at least 30 million people around the world could be infected with the AIDS virus by the year 2000. Other experts think the number could reach 110 million.

Despite dogged detective work by the world's best researchers, AIDS (acquired immunodeficiency syndrome) remains one of the most mysterious maladies ever to confront medical science. The more researchers learn about the disease, the more questions they have. Human immunodeficiency virus (HIV), proclaimed to be the cause of AIDS, has proved to be a fiendishly fast-moving target, able to mutate its structure to elude detection, drugs and vaccines. No one knows for sure how HIV destroys the human immune system, and puzzled experts have debated whether the virus is the only culprit at work.

Bewilderment reached a new level in Amsterdam, where scientists reported cases of people who have an AIDS-like condition but have not been found to be infected with HIV. That frightening revelation raised the possibility that a new AIDS virus is emerging. Another theory, suggested by France's Dr. Luc Montagnier, who first discovered HIV, is that the strange cases were caused by one or more mutant forms of HIV that were altered too radically to be detected by standard blood tests.

Hardly any of the news at the conference was good. As groups of protesters staged daily demonstrations demanding more action against the epidemic, Dr. Jonas Salk suggested that vaccine researchers were on the wrong track, and the actress Elizabeth Taylor blasted President Bush for not doing enough about AIDS. Delegates heard reports on the surging costs of treatment, warnings about the threat of AIDS-associated infections such as multidrug-resistant tuberculosis, and alarming projections that AIDS will become more of a heterosexual disease. The infection rate among women is rising and will pass the rate in men by the year 2000.

"We're dealing with something that's expanding out of control," said Dr. June Osborn, chair of America's National Commission on AIDS. Dr. Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases, noted that "the science is going as fast as it has with any disease," but he admitted that "the advances over the last several years are clouded and dwarfed by the size of the growing epidemic." Mark Harrington, a member of the New York City-based Treatment Action Group, summed up the situation more simply and grimly: "It's clear we're losing the battle. We have one class of drugs that slows AIDS down by two or three years, and then people go on and die."

THE MYSTERY OF NON-HIV CASES

The biggest surprise in Amsterdam was the talk about a new kind of AIDS. Dr. Jeffrey Laurence of the New York Hospital-Cornell Medical Center described five instances of people who suffer from an AIDS-like illness and yet bear no trace of HIV anywhere in their body. When a similar case was reported at last year's AIDS conference in Florence, it was dismissed as a fluke. This year several scientists in the audience stood up to tell of other cases of non-HIV AIDS, bringing the total to about 30 -- a number that is small but impossible to ignore.

Is a deadly new microbe on the loose? Speaking in the U.S. last week, Dr. Sudhir Gupta of the University of California at Irvine claimed to have found ! one in patients with AIDS-like symptoms. But there is no proof yet that the virus caused the symptoms. It is possible that the patients don't have AIDS but have some other problem with their immune system that mimics the disease. "It's just very premature to talk, because we don't know if it's real," says Fauci. "We should know something in a matter of months."

Even if there turns out to be a new virus, people should have no reason to panic or refuse blood transfusions. Researchers think they can isolate the pathogen within months and develop a blood test. In the meantime, this unusual type of AIDS, whatever causes it, is very rare. Said Laurence: "Every major AIDS researcher is here in one place in one room, and still we're talking about only a handful of cases."

The bad news, if a new virus does exist, is that AIDS will become even harder to prevent or cure. Pharmaceutical manufacturers have already been hampered by HIV's talent as a quick-change artist. Only last year a group of promising anti-AIDS drugs had to be shelved because HIV adapted too easily to the medication. And drugs that prove effective against all forms of HIV will not necessarily knock out an entirely novel virus.

HIV is a formidable enough opponent, mainly because researchers still don't understand the method to its madness. Like all viruses, HIV is simply a strand of genetic material (in this case the nucleic acid RNA) surrounded by a protein coat. A virus lacks the tools to reproduce unless it invades a living cell and takes over the host's molecular machinery. The intruder can then produce many copies of itself, eventually killing the cell. One of HIV's favorite targets is the CD4 T-cell, an important player in the human immune system.

But there the understanding runs out. Why does HIV lie dormant in human cells, usually for years, before producing a full-blown case of AIDS? What triggers the deadly phase of the infection? How does the virus go about destroying the immune system? Even at the height of the disease, HIV particles are found in no more than 1 in 100 CD4 T-cells. And yet the cells that do not harbor the virus die off almost as fast as those that do. Some researchers think that HIV must somehow provoke immune-system cells to destroy themselves.

One prominent theory is that the virus needs an assistant assailant -- a "co-factor," in scientific jargon. But the search for co-factors has been inconclusive. Although the presence of genital sores from syphilis or other ) venereal diseases makes transmission of the AIDS virus easier, neither the sores nor the microbes that cause them are necessary for HIV to spread. Researchers have also investigated the possibility that cytomegalovirus, a common form of herpes virus, might be the elusive co-factor, but eventually they ruled it out. "It has to be something that's not too obvious," says Dr. Kent Sepkowitz at the New York Hospital-Cornell University Medical Center. "Otherwise, we would have figured it out a long time ago."

Montagnier believes that the co-factor might be a mycoplasma -- a primitive bacterium-like organism. The possible role played by this microbe may help explain one of the mysteries surrounding the origin of AIDS. Studies of blood samples preserved from decades ago show that HIV was present in Africa long before AIDS appeared. What caused the once harmless virus to turn deadly? Montagnier thinks it was a strain of mycoplasma that until recent years was confined to America. Somehow, somewhere, according to his theory, HIV and the mycoplasma got together in a group of humans, and that was the start of the AIDS epidemic.

POWERLESS DRUGS, ELUSIVE VACCINES

If HIV were an ordinary virus, designing drugs to kill it might not seem like an impossible mission. "But it is a much more difficult virus than anyone anticipated," says Myron Essex, head of the Harvard AIDS Institute. "It has many more fancy genes to determine how it replicates. It has positive and negative controls that interact with cellular controls, which allows it to crank up rapidly or remain silent for a long time. It's a very, very unusual virus."

Most important, HIV can easily disguise itself by altering the proteins in its outer coat. When that happens, the job of finding and attacking the virus becomes harder. Even AZT, the most effective drug against HIV, is nowhere near as potent as doctors or patients hoped it would be.

First approved for use in the U.S. five years ago, AZT prevents one of the viral genes from making an enzyme, called reverse transcriptase, that is critical to HIV's reproduction. This action prolongs life by postponing some of the symptoms of AIDS. But in patient after patient, HIV eventually mutates into a form that is less vulnerable to AZT. As a result, the drug's benefits generally run out within 18 months.

The only other anti-HIV drugs approved in the U.S. -- DDI and DDC -- are variations on the AZT theme. Researchers have begun examining other types, however. One variety targets the gene that codes for another enzyme, protease, that is crucial to the manufacturing of viral proteins. The research looks promising, but a breakthrough is not expected anytime soon.

The same adaptability that makes HIV so troublesome to drug designers threatens to stymie vaccine development as well. Researchers are not at all confident that they can devise a simple series of shots that would give a person lifetime protection against AIDS. To do that, a vaccine would have to ward off all of HIV's current strains as well as any future mutants.

Neutralizing HIV is especially tough because its coat is laced with sugar molecules that shield it from the human immune system. Some viruses, such as the one that causes polio, have no sugar in their protein coat. Others, like flu viruses, have only a little. It is no coincidence that the most effective vaccines have been made to fight these kinds of viruses. Never before have scientists tried to devise a vaccine against a pathogen as well protected as HIV.

Undaunted, researchers are testing about a dozen experimental vaccines. After the trials have been thoroughly evaluated, the most promising prototypes will be chosen -- probably in the next two years -- for testing to determine if they can stimulate the immune system to produce antibodies capable of blocking HIV infection. The trouble is that scientists can only guess at what constitutes an effective collection of AIDS antibodies. No one has ever survived the disease to provide researchers with any clues. Even if the experiments go well, a preventive vaccine will probably not be available before the end of this century.

In the meantime, Dr. Robert Redfield of the Walter Reed Army Institute of Research in Washington and his colleagues are trying to develop a vaccine that helps people who are already infected. By injecting a slightly modified form of the virus' protein coat, the Army researchers hope to kick-start the patients' immune systems into mounting an effective counterattack. Redfield thinks that his version of the viral coat may share enough characteristics with all the known mutant strains of HIV to overcome the variability problem. Said Redfield, a rare, unabashed optimist at the Amsterdam meeting: "I believe HIV is very simple, very straightforward, and it's going to be solved."

THE EVOLVING EPIDEMIC

One of the most baffling enigmas of AIDS is the fact that the disease spread primarily among homosexual and bisexual men and intravenous drug abusers in the U.S. and Europe but became a largely heterosexual infection in Africa. Researchers announced last week that they may have an answer. Based on a study of the newly emerging epidemic in Thailand, they concluded that HIV has shown predilections for different human host cells in different parts of the world.

Using biochemical tools that were not available at the beginning of the epidemics in Africa and the Americas, molecular biologist Chin-Yih Ou and his colleagues at the U.S. Centers for Disease Control found two distinct epidemics caused by somewhat different strains of HIV in the northern Thai city of Chiang Mai. Both epidemics started no more than four years ago, but one occurred mostly in intravenous drug abusers and the other started in female prostitutes. There was little overlap between the two groups.

The scientists discovered that the prostitutes were more often infected by a strain resembling those types found in Africa. Apparently, it preferred the moist mucosal tissue of the genital organs, making heterosexual transmission easier. The other variety, found in the drug abusers, appeared similar to strains detected in the U.S. and Europe. It thrived on immune cells in the bloodstream. As a result, transmission occurred through the exchange of contaminated blood, as might occur during the sharing of needles or in abrasive anal sex.

The rise of two or more dissimilar types of HIV could explain why AIDS did not explode among heterosexuals in the U.S. and Europe, yet spread rapidly among men and women in Africa and parts of Asia. HIV has still not evolved in the industrialized world into a form that is easily transmitted by heterosexual activity. But it probably will, given the virus' proven ability to mutate. "Over time, in the U.S., more and more strains will adapt to become more efficient at heterosexual transmission," Essex says. "So far, there haven't been a critical number of people infected heterosexually. As that happens, you will get adaptation of the virus for transmission in that route. The heterosexual epidemic in the U.S. will expand."

Already American physicians are seeing more women with HIV. In many AIDS clinics in San Francisco and New York City, women make up 30% to 50% of all new patients. About half of them became infected through heterosexual contact. They range from very well educated to barely literate, but most of them say | they had no idea that their sexual partners had engaged in high-risk behavior. In fact, because AIDS is still thought of as a gay man's disease in the U.S., many women discover that they are infected only after they have passed the virus on to their children.

Another alarming trend is that more and more AIDS patients are developing tuberculosis. Normally, they respond to the traditional treatments for this degenerative lung disorder. However, a growing number of AIDS patients are contracting a much deadlier form of TB that is resistant to standard drug therapy. In Amsterdam Dr. James Curran, head of the AIDS program at the CDC, called the combination a "double epidemic."

Since the bacteria that cause TB spread through the air, they threaten not only AIDS patients but healthy people as well. Those with an intact immune system can usually fight off the infection, but this does not hold true for people who harbor HIV. Until the resurgence of TB, medical personnel who were HIV-positive but still healthy could work on AIDS floors without jeopardizing their own or anyone else's well-being. Now they will face a greater risk of encountering and developing TB. More AIDS patients are thus likely to be treated under quarantine conditions to avoid spreading the TB bacteria.

Tragically, even as AIDS goes in ever more dangerous demographic directions, government agencies throughout the world are failing to respond. Prevention programs are stalled or being abandoned. The World Health Organization's AIDS budget for this year is $90 million, down from $110 million two years ago. In the U.S., the National Institutes of Health requested $1.2 billion for AIDS in next year's budget, but President Bush trimmed that amount to $873 million and Congress is likely to cut it even further.

By the year 2000 AIDS could become the largest epidemic of the century, eclipsing the influenza scourge of 1918. That disaster killed 20 million people, or 1% of the world's population -- more than twice the number of soldiers who died in World War I. "This epidemic is of historic scale," says June Osborn of the U.S. AIDS commission, "but the response has been far short of historic."

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CREDIT: TIME Graphic

Source: WHO CAPTION: THE DECADE OF DEATH

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CREDIT: TIME Graphic

Source: WHO CAPTION: AIDS cases by geographical region

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CREDIT: TIME Graphic

- Source: CDC 1992 figures CAPTION: Reported U.S. AIDS cases by type of transmission