High Hopes for Primate Research : Monkey Doctors on Front Line in War Against AIDS

Night has fallen here, and the monkey doctors are having a party.

The scene is a dinner-dance at a Symposium on Nonhuman Primate Models for AIDS where 250 veterinarians and researchers are letting off steam after two days of intense scientific discussions.

With cowboy hats clamped to their heads, some down margaritas. Others venture onto the dance floor where a Texas trio warbles such tunes as “Your Cheatin’ Heart” and “Redneck Mother.” Mostly, though, they talk business, chattering excitedly about chimpanzees and macaques and mangabeys.

These are heady times for primatologists. AIDS has thrust them into the forefront of scientists seeking clues to one of the most confounding riddles in the history of biology. With their new role has come enhanced stature, more research grants and increased public attention--none of which means very much, to hear the monkey doctors, as they call themselves, tell it. “The driving force is to score a point or two against nature,” said Murray Gardner of UC Davis.

Moreover, any exhilaration the monkey doctors may feel is tempered by the potential dangers in their work, the terrible toll of AIDS, and by the long odds against quick success.

“I feel this great weight on my shoulders,” said Michael Murphey-Korb, who is working to create an AIDS vaccine at the Delta Regional Primate Center in Covington, La.

“It is hard to remain emotionally detached from our work,” added Max Essex, director of the new AIDS Institute at Harvard. “The human suffering is so obvious.”

Essex was just one of the prominent scientists who came to the conference held by the Southwest Foundation for Biomedical Research, one of the biggest primate research centers in the country. Others included the two brightest stars in the firmament of AIDS research: Luc Montagnier and Robert Gallo, discoverers of the human immunodeficiency virus, which causes AIDS; vaccine specialist Daniel Zagury, and Jay Levy of UC San Francisco.

“This year, we’ve got a Gallo and a Montagnier at a monkey meeting,” marveled Jon Allan, a scientist at the Southwest Foundation. “Why? Because (primate research) is where the exciting breakthroughs are going to come in AIDS.”

Non-human primates are markedly similar to humans in almost all aspects of their anatomy and physiology. These similarities underlie their value as models to scientists seeking vaccines and cures to a wide range of human diseases. While mice, guinea pigs and rabbits are useful in preliminary research, monkeys and chimpanzees are usually needed for final testing of the safety and efficacy of drugs and vaccines.

Polio would never have been eradicated in this country without the use of monkeys, scientists say. Indeed, “if you look back in history at the diseases for which we have solutions, virtually all of them had animal models,” said William I. Gay, director of the animal research program of the National Institutes of Health in Bethesda, Md.

Animal models, he said, give scientists the opportunity to watch a disease unfold step by step and to conduct experiments with possible vaccines and treatments. “You do with the monkey what you cannot do with man,” said Ronald Hunt, director of the New England Primate Center in Southborough, Mass.

As a result, scientists have been searching for a primate model since shortly after the first case of AIDS was discovered in the United States in 1981. Although they have found several, none is perfect.

In AIDS, there are two requirements for the ideal animal model. First, the animal must be susceptible to infection with the human immunodeficiency virus. Second, the animal’s immune system must collapse, and the animal must develop some of the cancers and opportunistic infections that characterize AIDS. So far, scientists have found non-human primates that meet one requirement or the other, but not both.

The chimp, for example, can be readily infected with HIV. But the human’s closest relative has confounded scientists. Though a chimp can be infected with HIV, it does not get sick.

Then there is the Asian macaque, or rhesus monkey. When infected with a viral cousin of HIV called simian immunodeficiency virus (SIV), macaques develop swollen lymph nodes, enlarged spleens, diarrhea, skin rashes, tumors, brain lesions and pneumonia--in short, all the hallmarks of human AIDS. In fact, scientists call the condition SAIDS, or simian acquired immune deficiency syndrome.

“SIV-macaque is the most promising animal system we have,” said Montagnier of the Pasteur Institute of Paris.

Added Gallo: “The SIV-macaque model is reaching its maturity, and this meeting is pointing that out. In paper after paper, many groups are working on it, and data is coming in. . . . It is wonderful to have another animal system to study biology, to study mechanisms.”

Different Virus

But will the SIV-macaque model speed the search for a vaccine or therapy for AIDS? “No one can predict that because it is not the same virus” as HIV, Gallo said.

Other leading scientists say the macaque has already proved its worth. “Realistically, I don’t think we can ask for a better model,” said Patricia Fultz of the Yerkes Primate Center in Atlanta.

“It is very frustrating to read in the media, ‘There is no model for AIDS,’ when we’ve known for a year and a half what a good model we have.”

The simian AIDS virus, she said, is the same size and shape as the human AIDS virus. And while SIV has only 50% of its genes in common with HIV, Fultz said SIV shares 75% of its genes with a second human AIDS virus, known as HIV-2, which is primarily found in West Africa and causes an AIDS-like illness in some patients.

Already, researchers are testing vaccine preparations and drugs on SIV-infected macaques. But Fultz acknowledged that progress has been slowed by the biological complexity of the viruses.

“Every isolate of SIV is different,” she said. Some strains are so virulent they can kill a macaque in two weeks; others take six months to a year, or even longer.

“That kind of variation is bad. It means many of our experiments have to be repeated,” Fultz said.

Even then, experiments that work simply point up new areas for investigation. “Every answer brings five new questions,” Fultz said.

Consider the chimpanzee. Learning that chimps could be infected with HIV was easy. Now scientists want to know why infected chimps do not fall ill--or even lose their Helper-T cells, key sentinels of the immune system whose destruction by HIV is thought to lead to AIDS in humans.

“Why don’t chimps get sick?” asked Peter Nara of the National Cancer Institute. “What is the natural mechanism that keeps them healthy? More importantly, is there some way we can transfer their resistance to infected humans?”

No Protection

Chimps have also been used in the search for an AIDS vaccine. But none of the 10 preparations tried so far has protected the animals from infection with HIV, and some of them even enhanced the virus’s ability to infect.

Two African monkey species, the mangabey and green monkey, provide scientists with similar lines of inquiry as the chimp. In both species, SIV--the same virus that wreaks havoc in Asian macaques--is harmless. Indeed, more than 50% of wild African green monkeys in one recent study were infected with SIV; all were healthy.

This finding intrigues scientists. The African species “must have evolved mechanisms that kept a potentially lethal pathogen from causing disease,” Harvard’s Essex theorized.

In short, what scientists are finding is that, given enough time, species appear to develop mechanisms that allow them to coexist with AIDS-like viruses. This would explain why SIV is harmless in monkeys from Africa--where the virus presumably has been present for centuries--but devastating in newly infected species from Asia like the macaque.

Macaques are believed to have had their first experience with SIV in the 1970s when they contracted the virus from infected African green monkeys in primate research centers.

“There is a rough parallel between the differential susceptibility of green monkeys and macaques and the very different susceptibility to AIDS of chimpanzees and human beings,” Essex said.

Essex’s explanation of why some species get sick and others do not is pure Charles Darwin: Through the process Darwin called “natural selection,” the fittest African green monkeys and chimpanzees--those that could resist the immunodeficiency viruses--survived and reproduced.

“Obviously, we do not have the luxury to wait for natural selection to give humans an immune system that can resist HIV,” Essex said. So he and his colleagues in animal research centers and laboratories around the country eagerly search out every opening in the virus’s armor and every element of the immune system that might be bolstered.

At times, the work is frustrating; at others, exhilarating. Always, it is fraught with danger. “A non-human primate is a biohazardous agent, period,” said Elizabeth Muchmore of the New York University Medical Center. Scientists say the risk of being infected by lethal pathogens carried by the animals is never far from their minds.

Surprisingly, AIDS is not at the top of the list of the scientists’ worries about being infected. That honor is reserved for Herpes B--not to be confused with the well-known herpes virus that causes painful blisters on the skin and mucous membranes of humans. Herpes B is a monkey virus that coexists peacefully with macaques but is usually fatal on the rare occasions it finds its way to man, generally through monkey bites or scratches.

“It is the scariest one that we know of,” Muchmore said.

Twenty percent to 60% of the macaques in U.S. primate research centers carry the Herpes B virus. Researchers say they have become a lot more careful in the wake of an incident last year in which two handlers died after being bitten by an infected animal and now wear face shields, goggles, gowns, gloves and boots when working with macaques.

Of course, disease-causing agents are not the researchers’ only worry. They also fret that shortages of laboratory animals will delay their work.

Chimpanzees, whose susceptibility to HIV infection make them ideal for testing vaccines, are in particularly short supply. Imports of chimps were banned by the Convention on International Trade in Endangered Species, which went into effect in 1976.

With AIDS as the impetus, the government launched a $4.5-million chimp breeding program in 1986 and has managed to increase by 200 the number of research chimps in the country, to 1,400 animals. A national chimpanzee management plan allocates the scarce animals to various areas of research; already, 100 chimps have been infected with HIV.

Scientists also worry that space to house their laboratory animals is at a premium. “I just doubled my isolation facility to hold 60 monkeys,” said Hunt, director of the New England Primate Research Center. “Now, I’m expanding it again, this time to 100. I also need to hire more people, but there is no place to put them.”

Animal Rights Lobbyists

Still, many of the scientists interviewed here said worries about space and the availability of animals pale compared to the threat to research they see from the vocal and highly organized “animal rights” lobby. Gay, for example, said he had received 36,000 post cards between February and August demanding a halt to the chimp-breeding program.

“I think those animal rights people should be forced to walk through a pediatric AIDS ward to see those children dying,” one researcher said.

It is not that they are being callous about the monkeys, the scientists say.

“These are intelligent animals. They are not numbers,” acknowledged Theresa J. Smith of the Army Research Center at Camp Detrick, Md. Monkey doctors, she said, “have to have the strong belief that (what) we are doing is going to make a difference.”

That belief was reinforced at the dinner-dance here, where Maurice Hilleman, scientific director of pharmaceutical giant Merck & Co.’s research institute, told the gathered scientists that they “stand at the very center of future developments in research on the control of AIDS.”

“Not bad for a bunch of monkey doctors,” commented Lisa Krugner-Higby of the Bowman Gray School of Medicine in Winston-Salem, N.C., using the self-deprecating label often voiced by primate researchers.

And so, they persevere, urged on by the hope that they may be helping the estimated 1.5 million Americans--and countless other people around the world--infected with HIV. “That huge iceberg is going to surface” as more and more infected people develop AIDS symptoms and die, said Gardner of UC Davis.

“No one person, no one group, is going to solve it,” he added, calling for concerted national effort to conquer AIDS, akin to the Manhattan Project that developed the atom bomb during World War II.

“Sometimes in my lab, I get this great sense of history. The physicists did it 40 years ago. Now it is the biologists’ turn. The people are waiting.”