Newsday - November 17, 1991
Laurie Garrett - Staff Writer

It's been a long day, says Dr. Anthony Fauci, but then every day in the life of America's chief of AIDS research is long, filled with administrative details and meetings to plot the next step in the war against the elusive human immunodeficiency virus. He won't get home until 10 p.m., after he addresses a banquet at a major science conference in Washington. And he has to be back the next morning in time for a 6:30 strategy meeting with colleagues linked by telephone around the world.

"It's the only time this particular group can get together. We're all so busy. Six-thirty, can you imagine?" says Fauci, as he plops down into a leather armchair, his energy belying the lack of sleep and the daily stress he carries.

Ever since Magic Johnson announced he was infected with HIV, the phones have been steadily ringing as congressmen, constituents and journalists want to know what will happen to the basketball superstar. Even Vice President Dan Quayle - who at first said that sexual abstinence was the "sure cure" for AIDS - that morning said that it "would be wonderful to have a cure for AIDS in the marketplace before Magic Johnson gets AIDS."

"People ask, `Why has it taken so long to take care of HIV when we've taken care of all other infectious diseases so quickly?'" Fauci says. "They forget it took decades and decades to get rid of polio and smallpox. HIV is moving along very quickly, but we still are in the middle of an out-of-control epidemic."

As Fauci heads off to his speech, Dr. William Haseltine gets his second wind and pushes another late night at the Dana-Farber Cancer Institute in Boston where his team may have identified exactly how the virus is sexually transmitted.

Meanwhile, Drs. Gerald Myers and Flossie Wong-Staal are winding up their work days. Myers commands a vast computerized network of genetic information at New Mexico's Los Alamos National Laboratory, building a map of how the virus changes and evolves. And Wong-Staal's work on the basic biology of HIV, first at the National Cancer Institute, in Bethesda, and now at the University of California, San Diego, is aimed at finding a way to pierce the virus' formidable genetic armor.

As Haseltine parks at home, Dr. Francoise Barre-Sinoussi is just starting her day at the Pasteur Institute in Paris where she is analyzing a mysterious strain of the virus found in Zaire that seems to be an especially fast killer. It was her adept touch that finally in 1983 teased the mysterious virus out from the cells of sick Parisian men.

Meanwhile, in Geneva, researchers from all over the world are in a telephone conference call with Dr. David Heymann, who heads up the World Health Organization's effort to coordinate global AIDS drug-and-vaccine research.

All of these, and thousands more throughout the world are part of the largest medical hunt since the discovery of a vaccine for polio. Though it left millions crippled, polio rarely claimed the lives of its victims. HIV disease is almost always fatal. Up to 11 million people are already infected, WHO says, and despite expenditures of billions of dollars on treatment, prevention and research, the epidemic is expected to hit 40 million in just nine more years.

None of these scientists, nor dozens of other leading AIDS experts interviewed last week, are optimistic about finding a cure for the deadly disease because the virus acts on the most basic human level and can change its form faster than science can aim. An effective vaccine, some way to prevent the virus' spread, is probably decades away.

"It's incurable," Wong-Staal says, without hesitation, of HIV, "because it is a retrovirus and it integrates into the chromosomes of the host. And once it's there it cannot be removed."

Because there is no way to destroy the virus once it worms its way into the human cell, the search is on for what Fauci and others call a functional - as opposed to an actual - cure for AIDS. The virus would survive but would be kept at bay by a combination of drugs that is relatively non-toxic and can be taken for years. Some drug would boost the beleaguered immune systems and others would control infections by microbes that take advantage of the patient's weakened state. "That, for me, is a reasonable goal to shoot for in the next decade," Fauci says.

* * *

In the first decade of the AIDS epidemic, scientists discovered that HIV caused the disease by destroying cells in the body's immune system. As the numbers of the cells - called CD4 T-cells - declines, the body's ability to stave off opportunistic infections shrinks. People succumb to a wide range of secondary diseases such as tuberculosis, yeast infections and pneumonia.

There are few weapons in medicine's arsenal that are effective against any viruses, as seasonal flu sufferers well know. HIV is orders of magnitude more difficult to tackle than a garden-variety virus because it is one of only three known human retroviruses.

The usual viruses are essentially tiny packages of genes, usually in the form of DNA or deoxyribonuclueic acid. Human cells also contain DNA genes, which are the blueprint for growth. To make proteins - the building blocks of cells - DNA must be translated into smaller RNA blueprints.

Viruses containing DNA are usually large because their genes have to include all sorts of directions regulating their own reproduction. Their bulky size makes DNA viruses relatively easy targets for the body's immune system.

But in the mid-1960s Howard Temin and David Baltimore discovered some viruses pulled a sneaky genetic trick to evade the defenses of animals and plants they infect. These viruses, dubbed retroviruses, contain tiny pieces of RNA, rather than bulky DNA. When retroviruses infect cells, they literally insert their genes into the host DNA. Once inside, the viral genes can hide for years, or commandeer the cell's genetic and protein-production systems to make tens of thousands of more viruses. The immune system barely has a chance to see the enemy before the body is overrun.

The human immunodeficiency virus, like all retroviruses, cannot be removed from a person's DNA once it has infected the individual's cells. So, scientists say, it is incurable.

"We've learned enough about the virus to know there will be no easy cure, no magic bullet," Haseltine says. "Ultimately, the effective treatment will come from . . . an entirely new class of drugs."

So far, three drugs have been discovered - two of them licensed by the Food and Drug Administration - that offer hope of giving some patients additional months of life. All three - AZT, ddI and ddC - block the ability of the virus to reproduce. Unfortunately, their blocking effects are both fairly toxic to the body and fail after a while because the virus overcomes the drugs by mutating. HIV becomes resistant to these drugs within a matter of days in some patients, months in others.

"By now, scientists have tested almost all the drugs available and many chemicals which have the potential to be drugs," Haseltine says.

In the past 10 years, various drugs have sparked waves of enthusiasm among scientists and from patients, desperate to grasp any straw. But the history of the epidemic is littered with dashed hopes and false starts.

Until recently there was excitement about a class of European HIV-blockers called TIBOs, but clinical trials show the drugs are quite toxic, says Fauci. More importantly, Haseltine notes, TIBO-resistant HIV strains appear within three weeks, rendering the drugs useless.

"Things couldn't be worse right now," says AIDS patient and leading New York activist Larry Kramer. "Nothing is panning out; the current drugs aren't working. We also know that everything in the pipeline is turning out to be a dud. So we're in major, major trouble."

The picture is not only gloomy for people, CORRECTION: An article in Sunday's Newsday incorrectly described the medical condition of Larry Kramer, a leading New York AIDS activist. He has tested positive for the human immunodeficiency virus, which causes AIDS. (11/18/91 P 2 NS) such as Kramer, who already have AIDS, but also for those, such as Magic Johnson, who are in the early stages of HIV infection. Haseltine doubts any of the therapeutic approaches considered promising just a year ago will pan out:

Soluble CD4. Because HIV uses receptors, called CD4, as doorknobs to gain entry to cells, scientists hoped to flood infected patients with decoy CD4s that would sop up roving viruses. Clinical studies completed this year show it doesn't work.

tat inhibitors. Perhaps the most important HIV gene is tat, which controls the production of new viruses. Genetically engineered inhibitors that prevent tat from working have proven too toxic to patients.

Protease inhibitors. After HIV comes off the cellular assembly line, enzymes called protease control the next step in the growth process . Scientists had hoped protease inhibitors would block that step, but so far the drugs have proven so insoluble in liquids that they can't even be tested.

Castanospermine, a promising antiviral that inhibits the virus. In the past year, it has proven overly toxic. As previously had Compound Q, HPA23, suramin and other passing fads among AIDS patients.

Other treatments. No refereed clinical studies have found ribavirin, Peptide T, Kemron or ampligen beneficial in patients, despite their strong support among some AIDS patients and activists.

"So," says Haseltine, "I believe we've just completed five years of a 25-to-30-year development program."

Science has eliminated the easy options and can now focus on those which require greater intellectual leaps, Haseltine says. We've "also examined extracts of hundreds of thousands of plants, including the ingredients of the traditional medicines of China, India and South America. Despite this massive effort of traditional drug discovery, we still don't have drugs that do anything but slow the progression of the virus."

* * *

Gazing from his office window at a crisp autumn Boston sunset, Haseltine recalls how Harvard University's Dana-Farber Cancer Institute waged war to conquer childhood leukemia. It took 40 years, but the battle was won, eventually, through careful, repetitive, basic science. Now the dapper scientist heads the world's only academic division of retroviral research, staffed by nine senior scientists and 51 other researchers.

Nearly all are working on what they call "the AIDS problem."

Their weekdays begin at 7 a.m. and rarely end before 11 p.m.; most of the staff also works Saturdays and Sundays, Haseltine boasts. Even as his group works, Haseltine is training the next generation of potential AIDS researchers. Harvard graduate students munch tortilla chips and gulp Diet Cokes as they listen to Haseltine describe his latest findings.

"These are dendritic cells," he tells them, pointing at the large billowy white blobs on the projection screen. He goes on to explain that the cells are found in mucosal areas, such as the linings of the rectum, male and female genitals, stomach and mouth. It is these cells - even more than the cells of the immune system - that are the real HIV targets. When HIV gets into dendritic cells, it can multiply many times over but remain hidden from the immune system. When the virus is ready to pounce, it can flood the body suddenly with whole armies of viruses, secretly manufactured inside the dendritic cells.

Recent studies in California and Britain have caused a sensation in the AIDS world because they show that monkeys vaccinated against HIV may be immune if the virus tries to infect through the blood stream. But the monkeys can still get HIV if the virus attacks through their rectums or genitals. Haseltine thinks that means the virus easily enters dendritic cells, evading even a supposedly vaccinated immune system. If the monkey studies hold up, implications for vaccine development, prevention of transmission and treatment are enormous because they more accurately explain how the virus may be passed.

Haseltine, like most virologists, relies on other scientists to do such animal work.

Twenty-seven miles west at Harvard's New England Primate Research Center, in the woody countryside outside Framingham, Mass., a dozen young rhesus macaques frolic at a maddening pace, displacing one another from atop a large jungle gym in an endless game of king of the mountain. They, and dozens of others in the facility, will play a key role in the search for an HIV treatment or vaccine. The animals are housed in a clean neat facility built with deliberate obscurity far from any major city. No signs along the roads say "Primate Center" because animal-rights activists oppose the use of research monkeys - even to fight diseases such as AIDS.

"I wish we could make a vaccine without using animals, but it simply is not possible. It would be great if you could develop vaccines without animals, but I know of no way," says Dr. Ronald Derosier, head of the center's molecular biology program. In 1984, Derosier discovered the simian immunodeficiency virus, or SIV, the monkey equivalent of HIV. He and colleagues at perhaps a dozen leading primate centers around the world use the SIV/macaque model as a way of learning what might slow the seemingly inevitable march towards death.

"What's remarkable about the SIV model is how closely it correlates with the HIV human model, point for point, down the line," Derosier says.

His labs have found that by deleting a gene, called nef, from the SIV , all viral replication stops. Animals loaded with nef-deletedviruses stay completely well. Derosier isn't sure what implications - if any - the finding might have for human treatment.

He's also uncertain about the possibility of developing a vaccine for AIDS, although he considers it the most urgent priority in the epidemic. Saying researchers are still at "square one" in their vaccine effort, Derosier wonders aloud how the immune system could ever tackle viruses, such as SIV and HIV, which cloak themselves in layers of sugar and carbohydrates, a process called glycosylation.

"It is interesting that these SIV and HIV envelopes are among the most heavily glycosylated proteins known to man," Derosier says. "We don't know what that glycosylation is doing."

On one end of his office sofa sits a neat pile of manuscripts Derosier must review for possible publication in a scientific journal. As he discusses the curious sugar-coating of HIV, Derosier taps a manuscript by Dr. Gerald Myers. It's awfully curious, Derosier notes, that in both SIV and HIV the sugar coating covers nearly the entire virus, leaving no protein targets easily vulnerable to the immune system.

It's what Myers calls, "the sugar-coated monstrosity." He wishes there were more glycosylation biochemists around who could try to decipher the significance of the patterns of glycosylation seen with various strains of HIV. One set of patterns is seen in HIVs found in brains, another set in the babies of infected mothers, and so on.

Myers and a small staff of fellow computer experts at Los Alamos run GenBank, a data bank of DNA blueprints, or sequences of genes, that are the code that produce viral proteins. Myers spends much of his time analyzing approximately a thousand different sequences of an HIV component called V3, which is one of the only proteins that protrudes from the sugar coating. Because infected people do make anti-V3 antibodies, it's a likely vaccine target. But the virus constantly mutates its V3 to elude such an attack. Myers hopes continued computer analysis will reveal some V3 vulnerability common among the hundreds of known HIV strains.

He has about 50 whole-virus HIV sequences in GenBank's supercomputer and hundreds of pieces from HIV strains found all over the world. Long ago scientists hoped computer analysis would uncover some common gene - something every HIV strain has and needs, which would serve as a target at which to aim a drug.

Speaking in a deliberate monotone, Myers says he has identified at least five distinct subtypes of HIV, and there may well be seven or eight subtypes in the world. Within each subtype category are hundreds of different strains. Haseltine says even within each infected person there are dozens of different strains which mutate constantly, so that on any given day the genetic strains of HIV may vary.

"For six years we've been staring at the horror of it," says Myers. "The virus, of course, is extraordinary. We've never really dealt with anything quite like this before in medicine.

"It's just a formidable problem. There's loads and loads of data, but it's noisy data, and we don't know what it means." Myers crunches data sent to him by gene sequencers such as Steve Wolinsky. "Ask Steve Wolinsky about his maternal-fetal glycosylation patterns."

At Northwestern University in Evanston, Ill., Wolinsky has been studying the sugar coatings of HIVs taken from four mothers and their babies; pairs from Haiti, the United States and Rwanda, Africa. He has found that the HIV glycosylations in the mothers are not the same as those in their babies.

But the surprise, Wolinsky says, was that all four babies, from different parts of the world, had the same sugar patterns. He doesn't know what to make of it except to note, "The virus is a lot smarter than we are."

Scientists, such as those in Wong-Staal's modern facilities in La Jolla, Calif., are trying to outsmart the virus by figuring out which genes are most crucial to all HIVs and to find a way to shut them off. There are several possible targets, she says, and theoretically a long list of ways to get at them. But the key word is theoretically.

Wong-Staal is working on one approach that involves making a strip of DNA that binds onto the viral RNA. Once bound, the AIDS virus, for example, would be physically unable to insert itself into the cell's DNA. The technique is called antisense.

At Memorial Sloan-Kettering Cancer Center in Manhattan, Drs. Eli Gilboa and Clay Smith are using pieces of RNA as viral decoys. They make decoy copies of key viral genes, attach them to mouse viruses that then infect bone marrow cells, Smith says. The infected cells manufacture the decoys, which block HIV genes from spreading.

"We think it holds promise," Smith says. "We feel very strongly this is the future, but there is a lot of rigorous work that will have to be done before we could say we have a curative treatment."

Such approaches that target HIV genes are called gene therapy. Fauci says, "Gene therapy is obviously exciting to everyone because of the potential," of completely reversing viral infection, "but there is a large leap between theoretical possibility and the reality of making genes inside cells in the human body."

Haseltine puts it more bluntly: "Although we have gene dreams, or Star Wars, there are fundamental problems we don't understand and can't circumvent." Uppermost, he says, is the confounding ability of HIV to mutate around virtually anything thrown its way. And nobody knows how to effectively get such genetic weapons inside the cells of living human beings.

If there is any bright spot in the epidemic, it is the increasing international cooperation. "I'd say there's really an international effort right now, well orchestrated," says WHO's Heymann. It can be felt at all tiers of the epidemic; in the clinics, in the development of drugs to treat the secondary infections of people with AIDS, in the hunt for anti-HIVs and in vaccine research. Most dramatically, within two years scientists from private, government and corporate centers throughout the world are hoping to conduct field trials of HIV vaccines in four developing countries. While none of the candidate vaccines are considered effective at this point, the hope is that such trials will provide researchers with the crucial information needed to lead to a second generation of useful vaccines, though that could take decades.

"Our Holy Grail is vaccines because an effective vaccine would truly save the world," Haseltine says. "Every day we don't vaccinate, we're signing the death certificates of 5,000 more people.

"Nobody can say with certainty when, or ever, there will be an effective vaccine," he continues. "We don't yet have a fundamental knowledge base to make that prediction."

Some scientists are more optimistic and predict that with continued close cooperation a vaccine might be available within 15 years.

Such global cooperation was not always so. As little as two years ago the worldwide research effort seemed hopelessly bogged down by nationalism and individual competitions for patents and scientific prizes. In most sciences the competitive spirit keeps researchers from sharing their data before it is published. The reverse is true in AIDS, where such behavior is now condemned as unethical, Derosier says.

"The underlying force is the seriousness of the epidemic," he says. "People are concerned with advancing their own careers, but that is superseded by the severity of the problem. Today, for example, we had an experiment we did three days ago, and I'm sending it off before it's published to two people in London and North Carolina because I know they're going to want to know about it."

The questions now most debated are whether the global basic research effort needs more money and whether it should be more strictly coordinated, along the lines of World War II's Manhattan Project that resulted in the atom bomb.

"It's not like saying go out and make a bomb. To completely Manhattanize it would take away from the creativity," Fauci says.

But AIDS activists, particularly those infected with the virus, feel that in the absence of a game plan, precious time is being lost.

"I've said this all along. A general has to be put in charge of the army, and he or she has got to be given emergency powers to cut through all the red tape that prevents research from being entered into in this country," Kramer says. "I'm talking about a Manhattan Project. It's as simple as that."

The National Institute of Allergy and Infectious Diseases does have a plan of action, says Fauci, who is also its director, but it is not written in stone. And it changes each year to reflect new discoveries and ebbs in congressional and White House funding.

And it all comes down to funding, says Jeffrey Levi of the AIDS Action Council in Washington.

"One reason we don't have a plan is we don't have the resources we need," he asserts. And on that point - lack of funding - scientists and activists seem to be in wholehearted agreement.

"As an adviser to many government programs, I can say with authority that the federal budget for fundamental research on AIDS is inadequate," Haseltine says. "There are many promising research initiatives which go unfunded and under-explored as a result of the failure of the government to provide enough money for research. The federal research budget for AIDS has been frozen for two years, in real dollars. From that same budget, the Congress and the Public Health Service have demanded it cover more and more research initiatives."

As Congress has heard the cries from AIDS-ravaged communities for more local research, it has earmarked dollars for specific programs.. That has decreased the amount of real dollars available for general research on the virus. In addition, White House suggested allocations have decreased.

"Can we use more money? Certainly," Fauci says. "If you take money away from other areas, would that be right? No. Absolutely not. So where will the money come from? I would hope the American public would realize it's important to give more money for biomedical research so that if you need more money for AIDS, you can get it without taking away from cancer or hematology or whatever."

It's hard to see where dollars could come from during a recession, particularly given the national debt crisis, Fauci says. Increased funds will require increased demand from the public. And at the moment, the public not only seems unwilling to see more tax money spent on AIDS research, but it's unwilling to make private donations. Private AIDS research funds are 1/100th of those given for cancer research, Haseltine says. At the moment, AIDS research garners a lower percentage of its funds from charitable donations then does basic scientific work on any other disease in the United States.

"If we don't do everything we can now," says Wong-Staal, "pretty soon everybody will have a friend who is dying of AIDS."

***

The Virus

The History

June, 1981. The Center for Disease Control publishes a report describing a disease that attacks the immune system. The center refers to the disease as Gay-Related Immune Disorder, or GRID.

July, 1981. The same disease is found in intravenous drug users in New York.

June, 1982. A hemophiliac is diagnosed with the disease.

July, 1982. The CDC changes the disease's name to AIDS.

January, 1983. In France, a researcher discovers a new virus he believes is causing the disease.

April, 1984. A researcher at the National Cancer Institure identifies the same virus discovered in France as the cause of AIDS.

March, 1985: Food and Drug Administration approves test to detect the AIDS virus, which became known as HIV, in blood.

September, 1986. The National Cancer Institute announces that an anti-viral drug called AZT is able to block HIV.

March, 1987. FDA licenses AZT.

August, 1987. Human vaccine trials begin all over the country.

August, 1989. Studies find that AZT postpones the onset of AIDS in people with HIV.

September, 1989. FDA allows distribution of experimental AIDS drug DDI while it is being tested for safety and efficacy.

January, 1991. FDA proposes to expedite approval of drugs for AIDS and other life-threatening diseases.

Invading a Cell

1. Virus enters the cell and fuses with the cell's DNA

2. After a latent period, AIDS DNA then commands cell to crank out new viruses.

3. New viruses then bud off from the original cell, leaving it intact

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