Dying monkeys: A clue to AIDS

First published on March 06, 1983.

Pathologists here at the New England Regional Primate Research Center are bewildered by all the deaths. Something is killing their monkeys, and they have no idea what it is or how to stop it.

The animals seem to be wasting away. They refuse food, lose weight, become profoundly weak, and then die. More than 60 have died in the last three years, most of them members of a rare and endangered species.

A similar epidemic has stricken the California Primate Research Center in Davis, Calif., where 152 monkeys have died mysterious deaths.

Small outbreaks of one disease or another are not unusual at animal centers. What is so mysterious here is that the animals are being killed not by any one disease, but by a variety of diseases. It is almost as though something is wiping out the animals' immunologic defenses, leaving them hopelessly vulnerable to any infection that happens along.

The mystery killer is shockingly similar to AIDS (acquired immune deficiency syndrome), the expanding epidemic that already has stricken more than 1,100 people nationwide, killing more than 400.

It is a frightening epidemic for which doctors have no prevention, no cure, no very good clues to a cause, and no knowledge of how it is spread, except for suspicions that the disease may be transmitted through certain sexual practices and/or through certain blood transfusions.

Scientists do not know whether the monkeys and the humans are being killed by a similar "agent" (that is, a bacterium, virus or other microorganism), but the similarity between the two outbreaks is striking.

Furthermore, the discovery of an AIDS -like disease in nonhuman primates could be immensely important in solving the AIDS mystery.

Through experiments with the animals, the physicians might learn how to screen for the human disease, isolate the microorganisms or even, perhaps, develop a vaccine or find a cure.

"The whole thing will break open as soon as we get a system to reproduce the agent," said Gary Noble, acting director of viral diseases at the Centers for Disease Control, the federal agency leading the AIDS investigation. "It would provide a tremendous opportunity. "

The big question is whether the human and monkey outbreaks really are being caused by the same or similar agents.

To try to answer that question, more than 250 researchers - most of whom are investigating the human disease - gathered Wednesday in Bethesda, Md., at a meeting called by the National Institutes of Health (NIH). They spent the day discussing the monkey outbreaks and what they might mean.

There were no firm conclusions, but one thing was clear: Monkeys were now dying of a disease every bit as sinister and mysterious as the one that has been killing human beings.

The human AIDS epidemic, first reported 22 months ago in California and New York homosexual communities, continues to grow, and victims now are being found in virtually every major American city.

As of Friday, the number of cases in this country reached 1,128, with 423 deaths. Sixty-nine cases have been reported in 15 nations abroad.

Once considered exclusively a disease of sexually active homosexuals, AIDS now is claiming heterosexuals as 28 percent of its victims. Most of the heterosexual victims are Haitian immigrants, intravenous drug users and hemophiliacs. The number of hemophiliac victims has climbed to 12, including one bisexual hemophiliac, strengthening the theory that AIDS can be passed through the blood via transfusions.

Because of this urgent concern, Dr. Edward N. Brandt Jr., assistant secretary of health in the U.S. Department of Health and Human Services, issued an official recommendation Friday asking all people who might be at risk of developing AIDS to temporarily refrain from donating plasma or blood.

The recommendation applies to AIDS victims, their sexual partners, Haitians, IV drug users and "sexually active homosexual or bisexual men with multiple sexual partners. "

The Southeastern Pennsylvania chapter of the American Red Cross said Friday that it was going a step further and "deferring" all male homosexual donors, regardless of the extent of their sexual activity.

The policy was immediately attacked by the AIDS Task Force, a Philadelphia area group composed mostly of gay health workers. Dr. Nicholas Ifft, the group's coordinator, said the policy discriminated against gay men who had had few sexual contacts and hence were not so much at risk.

The Red Cross argued that it was difficult for it to screen out potential donors on the basis of how many sexual partners they had had.

Ifft's group is advising homosexual men to rely on their own consciences in deciding whether to give blood, but to bear in mind that the risk of being a transmitter of AIDS increases as the number of sexual partners increases.

While blood-collection agencies try to protect the nation's blood supply, scientists continue to seek the cause of AIDS.

As the epidemic grows, epidemiologists are continuing to interview new victims and, especially, people who have donated blood to people who subsequently developed AIDS . So far, no clues have turned up.

People in the lab continue to look for the AIDS bug. They are examining microorganisms grown from infected tissue samples, and peering at other samples through electron microscopes. Nothing appears unusual.

And scientists are continuing to monitor a variety of animals, including monkeys and chimps, that have been inoculated with specimens from AIDS victims. None of the animals has come down with AIDS.

Everywhere, the investigation seems to be drawing blanks.

As of last week, scientists had one new lead: the reports that the monkeys in California and Massachusetts had developed a disease surprisingly similar to AIDS .

The pathologists at the New England Regional Primate Research Center in Southborough, 25 miles west of Boston, first began to suspect AIDS at the beginning of last year, when they noticed a sharp increase in the death rate of a particular species of monkey - the Macaca cyclopis, or Taiwanese rock monkey.

Reviewing death records, Ronald D. Hunt, director of the center, and Norval W. King Jr. discovered that in 1980 the death rate of their animals had shot up from 12 percent a year to more than 30 percent. About 25 monkeys in a colony of 80 died, most of them from diseases that are rare in monkeys.

The first logical suspicion would be that they had died of complications

from medical experiments. The Southborough facility, which is funded by the National Institutes of Health and operated by Harvard University, is one of seven national centers that provide primates for medical research. Scientists

from as many as 20 institutions have done research at Southborough.

But Hunt and King quickly determined that none of the animals that died of suspicious causes had been used in studies. Most had been young, healthy monkeys who had received no drugs except for vitamins and protective vaccinations.

Perhaps the disease was something the animals caught in the wild, before they were trapped and sold to the center, they thought. But this did not check out, either. The records showed that imported animals were no more likely to get the mystery disease than those born on the grounds.

There was, however, one common link. The disease seemed to concentrate in one of three buildings that housed animals, the Butler Building. Monkeys housed in this building were seven times more likely to die than monkeys of the same species housed elsewhere.

And in the Butler Building, the most vulnerable animals were those living in Cage 43. The next most vulnerable were the animals living in cages adjacent to Cage 43.

No toxins could be found in the food, or the water, or the buildings, so the pathologists suspected that an infectious agent was being spread from one animal to the next. But it would have to be an unusual infectious agent - one that did its damage by destroying the animals' natural immunity - because the monkeys were dying from many different diseases.

Except for congenital disorders, this was the first disease the scientists had ever seen that specifically attacked the immune system in primates.

About the time Hunt and King were making this discovery, they also were reading about AIDS . Except for congenital disorders, AIDS was the first disease doctors had ever known that specifically attacked the immune system in humans. The parallel was very intriguing.

Hunt and King could no longer keep their suspicions to themselves. They made the 25-mile drive into Boston and huddled with the head of their department at Harvard, Dr. Baruj Benacerraf.

Benacerraf won the Nobel prize in 1980 for work that led to a better understanding of rejection of transplanted organs. If anyone could offer insight on a disease of the immune system, it would be this noted immunologist.

Unbeknown to the Harvard people, their counterparts at the University of California's center were having similar problems with their monkeys.

Dozens of animals - rhesus and stump-tailed macaques - were dying in outdoor cages of the same type of diseases that were killing human AIDS patients. They were dying of malignant lymphoma, the lung infection Pneumocystis carinii, cytomegalovirus and herpes virus infections, and the neurologic disease progressive multifocal leucoencephalopathy. Some of the animals were being stricken by one disease after another, or by several at once.

This was all very similar to what happens with the human AIDS victims. And, just like humans, the monkeys suffered lymphadenopathy (swollen lymph glands), fever, diarrhea and severe weight loss. Most striking of all, tests indicated that the monkeys' immune systems were impaired.

The California outbreak also was associated with a particular cage, again suggesting that whatever caused the deaths had started from one point and spread in a contagious process. This was not surprising; the living habits of monkeys in captivity include frequent sexual intercourse, oral-genital contact and contamination with each other's urine and feces.

Unlike the New England facility, the California center seemed to have been stricken by four separate outbreaks, the first one starting in 1969.

Benacerraf listened intently to what Hunt and King had to say. They told the famous immunologist that they suspected an immune deficiency disease and that they wanted to hire an immunologist. Did he have some suggestions?

Benacerraf agreed with their interpretation of the data and called Dr. Stuart Schlossman, a Harvard immunologist who had played a vital role in developing monoclonal antibodies, a revolutionary new type of biochemical that is extremely sensitive in identifying different types of cells in the body.

Because of this remarkable sensitivity, monoclonals can detect abnormal cells in the body, and hence diseases that are missed by conventional diagnostic methods. Physicians also are using them to detect defects in the composition of the blood's white cells - defects associated with AIDS .

Schlossman also was intrigued by what Hunt and King had found, and asked them to send him blood from infected animals. It would be exciting, and possibly very important, if he could find the same type of defect in the composition of the animals' white cells that is found in AIDS patients.

Benacerraf was so intrigued by the discovery of an AIDS -like disease among monkeys that he advised one of his most promising proteges, Dr. Norman L. Letvin, to take the immunology job at the primate center.

After reviewing the data Hunt and King had assembled, Letvin took the job eagerly.

The team, now three members, started poring over slides of tissue from stricken animals. Letvin carefully reviewed the medical reports of every animal that had died during the last three years.

He also looked at the medical records of the 60 or so center employees who have regular contact with animals. It would be extremely important, not to say frightening, to discover AIDS or even vague symptoms of the disease among staff members. So far, Letvin has found nothing.

Every month, blood was drawn from the center's 60 surviving Taiwanese rock monkeys, in hopes of finding some clue during the earliest stages of the disease, even before symptoms appeared.

They discovered swollen lymph glands and enlarged livers in some of the animals, and immediately did biopsies, again with the hope of finding viruses or bacteria that might exist in the animals only during the early stage of the disease. They found nothing here, either.

But Letvin did find something intriguing.

He found strange, large white cells in some of the stricken animals, but not in animals that were still healthy. Maybe this means that scientists can recognize by the animal's white cells when it is about to develop AIDS . There is nothing comparable in human AIDS patients.

Using the monoclonal antibodies, Schlossman's lab at Harvard came up with an interesting finding, too. All the Taiwanese monkeys, whether or not they were sick, had the same white-cell composition that human AIDS patients have.

Does this explain why this species is more likely than other species at the center to get the AIDS -like disease? The researchers wondered.

Carefully examining their monkeys, the Harvard researchers discovered lymphoma in one of the animals. Since lymphoma - a cancer of the white blood cells - was found in some of the human AIDS patients, the researchers thought that the tumor might be linked to the AIDS -like animal disease. Perhaps the AIDS bug was even in the tumor, they reasoned.

A common way to find disease-causing agents is to infect healthy animals with tissue from diseased animals.

If the inoculation makes the healthy animal sick, it is then presumed that the tissue specimen contains the bug that is being sought.

So the researchers used this technique in an attempt to transfer the lymphoma to two healthy monkeys.

One of the recipient animals developed the cancer. The other did not. Taking tissue from both animals, they then injected another bunch of healthy monkeys. None of those animals got the cancer, but within two months they all died from AIDS -like diseases.

Taking specimens from the third series of animals, they stored some of the material in a freezer and used the rest to inoculate a fourth group of monkeys. This time the animals died within a month.

Hunt and King now think it is very likely that their freezer contains the mysterious agent that they and everyone else are looking for. The problem now is how to tease the microorganism out of the samples.

Hunt, King, Letvin and their counterparts from California went to the NIH meeting in Bethesda on Wednesday, and disclosed their findings to the people who had been working so long to understand the human disease.

About 250 people filled the seats in the Masur Auditorium, a large room glowing red from the light reflecting off the bright red seats and bright red walls.

Flashing aerial photographs of the California center and interior photographs of the Butler Building in Massachusetts, the primate researchers told the audience about the outbreaks among the monkeys, and their apparent similarities with the human disease.

The scientists studying the human disease, many of them from New York City, which has half of all AIDS cases in the country, asked questions, but were skeptical. Many of the diseases that have killed the animals are not the same as those that are killing the human AIDS victims.

The primate researchers saw this as less of a problem.

"Infect the same bug into six different species," one primate researcher said, "and you'll get six different diseases. "

At the end of the morning session, Dr. Sheldon Wolff of Tufts University in Medford, Mass., summarized the findings.

Wolff said there were many differences between the human disease and the animal disease, but also many similarities. He tended to doubt that the same agent was causing both diseases.

Still, Wolff said, "I believe these animals will be helpful in studying the human disease."