The Toughest Virus of All

By Joe Levine.

Of all the viruses that have plagued human beings through the ages, few have cast darker shadows or proved more formidable than the one that causes acquired immunodeficiency syndrome. The current AIDS death toll of 15,000 in the U.S. seems small compared with some of the scourges of old. But no cure or vaccine is in sight, and the figure is expected to rise to nearly 180,000 in five years. By that time, predicts U.S. Surgeon General C. Everett Koop, 145,000 Americans with AIDS will need health and other services costing between $8 billion and $16 billion annually.

It was against that grim background last week that Koop, in a dramatic report to the public (see box), warned that AIDS will spread beyond its current high-risk groups into the general population. He called for greater use of the only weapons currently at hand for controlling the AIDS epidemic: education about the disease beginning as early as the third grade and prevention. Koop's report was educational in itself. It was comprehensive and accurate, and its warnings were expressed in sexually explicit language that readers could not fail to understand.

The message seemed particularly relevant in light of another AIDS disclosure this past week. At a symposium held by the Montefiore Medical Center in New York City, two researchers who have studied the widespread transmission of the AIDS virus among heterosexuals in Haiti and Africa voiced "great concern that a similar phenomenon could happen in the developed world." Their work revealed that 89% of Haiti's AIDS victims had apparently contracted the disease through heterosexual activity -- more than double the percentage of two years ago -- while incidence of the disease among a study group of African prostitutes has jumped nearly 18-fold since 1980. Said Cornell University Professor of Medicine Warren Johnson: "We haven't identified anything different that would set Haiti or Africa apart from other countries."

Elsewhere, growing awareness of the AIDS crisis was reflected in a flurry of activity. In Los Angeles, junior high and high schools were conducting seminars and distributing pamphlets as part of Mayor Tom Bradley's October "AIDS Education Month." And in Princeton, N.J., the Robert Wood Johnson Foundation announced the donation of more than $17 million to eleven cities and counties around the country for the care of AIDS patients.

But in other parts of the country, unwarranted fears of catching AIDS through casual contact manifested themselves in the workplace and on the ballot. After pinning an antihomosexual slogan to the wall of their garage, 29 New England Telephone Co. technicians staged a one-day walkout in Needham, Mass., to protest the return to work of a colleague who has the disease. The AIDS victim had stayed away from his job for a year, awaiting settlement of his $1.5 million lawsuit against the utility. He had charged the company with revealing his condition to his co-workers, who had then begun to threaten him. In California, debate continued over Proposition 64, on the ballot for consideration by voters in November. If passed, the proposition would give health officials the right to quarantine all AIDS patients and carriers of the virus. Perhaps the best news for AIDS patients last week was that shipments of azidothymidine, the experimental drug produced by Burroughs Wellcome Co. of Research Triangle Park, N.C., were arriving at twelve medical centers around the nation. The centers are awaiting the imminent FDA approval of the drug for use on those whom it seems to help most, the 6,000 AIDS patients who have also suffered a recent attack of Pneumocystis carinii pneumonia. Interim results of clinical trials with AZT were so promising that the tests were halted in September for ethical reasons, so that the drug would no longer be withheld from a control group of AIDS patients who had been receiving only inert placebos. AZT is also the first of the experimental drugs that can successfully penetrate to the brain, where until now the virus has found refuge.

But AZT is not a panacea for AIDS. Because the original trials were terminated after only seven months, doctors cannot predict how long doses of the drug will continue to thwart the virus. They also warn that AZT has damaged the marrow of some patients' bones and could have even worse long- range effects. Moreover, says Terry Beirn of the American Foundation for AIDS Research, "we're not talking about cure. At the moment, I don't think it's in the lexicon."

No matter how effective drugs such as AZT and others currently being tested prove to be, they represent only one part of a three-pronged attack on AIDS. Bolstered in June by $100 million in federal funds, Government and industry scientists are also scrambling to develop therapies to help rebuild immune systems devastated by the AIDS attack. "The real goal," says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), should be "to simultaneously suppress the virus and build up the immune response in the patient." Other researchers are concentrating on preventing the disease, experimenting with vaccines designed to protect healthy people from infection by the virus.

But the AIDS virus has proved a tough adversary. One of its troublesome traits is its ability to mutate rapidly, apparently changing the structure of its identifying surface antigens so frequently that the immune system cannot alter its antibodies fast enough to keep up with the virus. The same characteristic will be a problem for vaccine developers; by the time they create a product designed to stimulate antibodies against one type of AIDS virus, many others, with different antigens, may show up. Also, even when vaccine-stimulated antibodies are appropriate for the invading viruses, the antibodies could prove unable to dispose of the viruses adequately. Says Researcher Opendra Narayan of Johns Hopkins: "The chance of going to a lab and creating something nature hasn't done yet is slim."

Another of the virus' Machiavellian tactics -- its apparent ability to fuse helper T cells and to move from one to another without returning first to the bloodstream -- has also frustrated vaccine- makers. Within the cells, the virus is safe from any marauding antibodies in the bloodstream, whether produced naturally or stimulated by a vaccine.

Finally, the sheer destructive power of the virus has so far stymied efforts to reinvigorate the immune systems of AIDS victims, especially those with an advanced case. The virus seems to do away with enough helper T cells to push the immune system beyond the point of no return.

Of all the approaches, drugs have been the AIDS patients' greatest objects of hope. Many of them, like AZT, are aimed at blocking reverse transcriptase, the enzyme that enables the AIDS virus to convert its RNA to DNA within the ; cell and begin reproducing. "We think reverse transcriptase is easily fooled and easily disrupted," says Samuel Broder, director of clinical oncology at the National Cancer Institute. The trick is to block the enzyme without disturbing the vital functions of the helper T cell. AZT has been only partially successful in this regard. In one of its side effects, it actually suppresses the crucial immune-system response in some patients with an advanced case of AIDS. Still, says Broder, the "side effects always have to be weighed against what the disease itself will do. And the disease itself can bring you death, which is a pretty mean side effect."

Besides AZT, the most promising of the experimental drugs that subvert reverse transcriptase are dideoxycytidine and the Swedish drug Foscarnet, both of which may eventually prove to block the enzyme at a lower dose than AZT. Other, less understood drugs may hinder the virus in different ways. Jerome Groopman, AZT project director at New England Deaconess Hospital, says the key to successful treatment will probably be "discovering at what point in the life cycle of the virus a drug will be effective."

Developing a viable vaccine will be more difficult. In theory, creating it should be simple: inject a killed or weakened virus into the body, and the immune system will promptly produce a standing army of antibody-producing B cells designed to recognize and attack the real thing when it shows up. In practice, however, most doctors feel that vaccines containing killed or weakened versions of the AIDS virus are too dangerous; if some of the creatures revive after the manufacturing process, the vaccine could infect a recipient with the very disease it is meant to ward off. As an alternative, scientists are using genetic-engineering techniques in an attempt to create "subunit" vaccines containing only portions of the virus that are harmless. If these segments have the appropriate antigens, however, the immune system may respond as if a complete virus had intruded, producing an army of B cells and antibodies to fight it. That still leaves the problem of the mutating virus and its ever-changing antigens. For a solution, researchers are examining successive generations of the AIDS virus, looking for antigens on the viral envelope that remain constant and that could serve as subunits for a vaccine that will remain effective despite the virus' rapid mutations. While they search for stable candidates, they have also been experimenting with a / surface protein that binds the virus to its target cell. Two California biotechnology firms, Genentech of South San Francisco and Chiron of Emeryville, have been able to produce rather weak antibodies to this protein in laboratory animals but only in response to about half of the handful of AIDS strains they have tested. Laurence Lasky, a Genentech scientist, is not discouraged. It may be possible to create a vaccine that can work against a number of truly divergent strains, he says, but only if that number stays in the "manageable range."

Because subunit vaccines often seem to produce weak immune responses at best, some researchers are taking a different tack. They are trying to incorporate harmless pieces of the AIDS virus into vaccinia, a live virus that serves as the smallpox vaccine and is known to be safe. Early results are encouraging. Bernard Moss, chief of the viral diseases laboratory at NIAID, reports that cells taken from monkeys treated with the AIDS-modified smallpox vaccine, when placed in a test tube with live AIDS viruses, do not become infected. "We're optimistic," says Moss, "but at this stage it's research."

In still another approach, Myron Essex, a Harvard virologist, is investigating the possibility that a recently discovered harmless African virus closely resembling AIDS could provide the "best protection against AIDS yet." There is some evidence, he says, that people infected with an apparently benign virus called HTLV-4 do not develop AIDS. Essex is conducting a study of a group of Africans with HTLV-4 who are also at risk for AIDS. If they prove to be immune to the disease, an HTLV-4 vaccine might provide the AIDS virus with its greatest challenge.

Unfortunately, only minimal progress has been reported in efforts to reconstitute the immune system after an AIDS attack. In one dramatic exception, an AIDS patient who received bone-marrow transplants from his identical twin showed signs of improvement; the donated marrow promptly began to manufacture immune cells to replace those destroyed by the AIDS virus.

Despite the money, energy and talent being devoted to research, however, scientists are all too aware that, in the words of C. Everett Koop, "there is no cure for AIDS. There is no vaccine for AIDS." For now, at least, the Surgeon General's call for an informed populace and safe sexual practices seems to be the best preventive medicine around.

With reporting by Cheryl Crooks/Los Angeles and Dick Thompson/Washington, with other bureaus