Medicine October 2000

The Hunt for the Origin of AIDS

The notion that AIDS arose from a polio vaccine made with contaminated chimpanzee cells—the thesis of the best-selling book The River—is far from the only theory about how the epidemic started, and it is hotly disputed. The quest for the source of the epidemic is intensifying, as researchers scour the jungle for clues and try to "walk back" the disease genetically with the help of the world's most powerful computers
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As Paul Telfer navigated his Land Cruiser through a field of elephant grass at a game reserve in Bakoumba, Gabon, I asked him how many people in the world do what he does. Telfer briefly took a hand off the steering wheel and lifted a single finger.

Telfer is a thirty-seven-year-old field biologist from California. He works with the only team of scientists anywhere engaged in a long-running, systematic effort to track down wild primates in order to clarify the origin of the AIDS epidemic. When I accompanied him to Bakoumba, during a visit to Gabon last March, he was making the ninety-minute trek from the International Center for Medical Research of Franceville, a research station where he works and lives, to an area frequented by mandrill monkeys.

Telfer parked his car on a hill where the savanna abuts the forest. "You have to be patient," he said, leading the way down a footpath into thick, dank jungle. A bridge of vines and planks took us across a river. Telfer stopped suddenly and picked up a leaf that had been rolled into a cone and nibbled at one end. "Gorilla feeding," he said.

At last we came to a clearing. Telfer had tied a hundred ears of corn to the trees ringing it, in hopes that mandrills would begin spending time there and that he would eventually be able to capture them in corn-baited traps. He would anesthetize the animals and draw their blood, and then set them free. If he and his colleagues were lucky, they might isolate from one of the samples a simian immunodeficiency virus—SIV—that could shed some light on the origin of the virus's human cousin, HIV.

But the mandrills hadn't touched the corn, which in the fecund forest had sprouted orchidlike tendrils. We watched the clearing for the rest of the afternoon, leaving only when the jungle began to darken. We heard a few monkey shrieks, but saw no mandrills or any other primates. "Ninety percent of this game is waiting and not seeing much," Telfer said. "But when you do see something, it's pretty spectacular."

Those of us who observe the researchers struggling to understand the origin of the AIDS epidemic have likewise done a lot of waiting—and also a lot of listening to arguments. Although scientists generally agree that HIV arose from an SIV in chimpanzees, dubbed SIVcpz (for "simian immunodeficiency virus-chimpanzee"), spirited and sometimes high-pitched battles are waged by proponents of the different theories about how the virus crossed over into human beings and then spread. Most researchers believe that a precursor to HIV first entered people living in African communities where chimpanzees are hunted for food. They posit that urbanization, the introduction of needles, and various other aspects of modernization can explain how and when SIVcpz became adapted to human beings and caused an epidemic that now afflicts some 34 million people.

But a small number of scientists, journalists, and AIDS activists are dissatisfied with this explanation. They argue that the epidemic began because an otherwise largely forgotten experimental polio vaccine that was widely tested in Africa during the late 1950s was contaminated with SIVcpz. This controversial theory has drawn attacks from mainstream researchers, some of whom have brought forth new data that, they say, convincingly refutes it. In turn, the attacks have only fueled the determination of the polio-vaccine adherents to prove their point, and their theory has won increasing attention from both the public and the scientific community.

The consequences of the debate extend far beyond university hallways and letters to the editors of scientific journals. Researchers have found SIVs in nearly two dozen primate species. If, as the mainstream theory suggests, these viruses have repeatedly jumped from nonhuman primates to human beings, in a process known as zoonotic transfer, there are probably new epidemics in waiting that science might be able to derail. On the other hand, if it turns out that the polio vaccine sparked the AIDS epidemic, the implications for even the best-intentioned medical interventions are considerable indeed.

Finding evidence to settle the debate is a formidable undertaking. Although the United States alone spends about $2 billion annually on AIDS research, the bulk of this amount rightly goes toward the search for better ways to prevent and treat HIV infections; perhaps $1 million is spent on investigations into the epidemic's origin. The few people who have committed themselves to the inquiry have done so at great risk, professionally and sometimes physically. Results are hard-won: tests of thousands of old blood samples have revealed fewer than a hundred that contain evidence of HIV infection, and researchers have found SIVcpz in only half a dozen chimps. Critical records from the manufacture and testing of the polio vaccine in question have yet to surface (if indeed they still exist), and libel suits have greeted some journalists who have advanced the vaccine theory. Those who conduct research in Africa must deal with crumbling infrastructure that forces them to move at a maddeningly slow pace, must contend with the ever-present disruption and danger of civil war, and must hope to avoid a long list of infectious diseases, one of which recently took the life of a prominent biologist.

As for the vaccine itself, only a small sample has been found, and portions were only recently released for testing. (The results, as of this writing, were expected to be announced shortly after this magazine went to press.) Although the results will lend weight to one theory or the other, they cannot resolve the debate. If scientists find SIVcpz in the vaccine, that will be the strongest evidence to date that the vaccine might have caused the epidemic, and will make many take the idea more seriously; however, several other conditions would have to be satisfied for the theory to be proved. A negative finding would prove only that a very small amount of the vaccine showed no signs of contamination.

Despite the obstacles, researchers are more determined now than ever before to discover the origin of AIDS. During the past year several groups have followed the lead of the Franceville group and begun searching in the wild for HIV-like viruses in chimps and other nonhuman primates. Sophisticated modeling programs, run on the world's fastest computers, have come up with intriguing estimates of the age of the epidemic. And Britain's Royal Society has joined the fray, sponsoring a landmark meeting in London last month that brought most of the principal researchers on the subject together for the first time.

An Extraordinary Claim

THEORIES about the origin of the AIDS epidemic have abounded ever since doctors first noticed the disease, in five gay men in Los Angeles in 1981. Some were entirely unscientific: most famously, God was punishing homosexuals. Others were grounded to various degrees in science: A contaminated hepatitis B vaccine tested in gay men was to blame. A campaign by the World Health Organization to eradicate smallpox had somehow awakened dormant HIVs that had long infected human beings harmlessly. The CIA had concocted the virus in a lab, or it came from space, or from a distantly related cow virus that had contaminated all sorts of vaccines.

Even the more plausible of these theories failed to attract serious scientific support. Indeed, on the whole the origin-of-AIDS question received relatively little public attention until last fall, when the British writer Edward Hooper published The River: A Journey to the Source of HIV and AIDS. A hefty book, containing 851 pages of text and another 174 of footnotes, The River makes the case for the polio-vaccine theory in great detail. It has riled many AIDS researchers, but it has also brought a new sense of urgency to solving the riddle; it was the catalyst for the Royal Society meeting last month.

The book's title refers to the Nile. Hooper chose it because of the long confusion concerning the Nile's source, which nineteenth-century explorers erroneously believed was in Uganda. To Hooper, that mistake has been "strangely echoed" by the mistakes AIDS researchers have made in their claims about the epidemic's origins. A former radio reporter who covered AIDS in Africa for the BBC, Hooper has devoted the past decade to researching his book; he portrays himself as an indefatigable investigator who will go to enormous lengths in his campaign to confront mainstream researchers with their inconsistencies, illogical conclusions, and outright errors. (The River takes me to task as well, for a 1992 Science article in which I critically examined a Rolling Stone story by Tom Curtis about the polio-vaccine theory.) Hooper's persona in the book is often professorial—"we shall see," "let us," and "one wonders" are among his pet phrases—and even condescending, and many researchers who have spoken with him find him obstinate, overzealous, belligerent, or worse. Still, he is without question an earnest man consumed by a mystery of undeniable import.

Soon after AIDS surfaced in Los Angeles, researchers found cases in other large cities in the United States and Europe, and also in Haiti. In 1984 Robert Gallo, a scientist at the National Cancer Institute, argued that a virus he identified as HTLV-III caused AIDS, and at about the same time, researchers described the first known African cases of the disease.

Gallo, who strongly influenced the thinking about AIDS in the early days of the epidemic, published a paper in Science in 1985 in which he traced the epidemic's origins to Africa, suggesting that it might have existed there for some time without being recognized as a distinct disease. His argument had two strands. First, his lab had found antibodies to the AIDS virus in fifty of seventy-five stored samples of blood that had been taken from Ugandan children in 1972 and 1973. Second, he believed that the AIDS virus had close ties to another virus that he and his co-workers had discovered, HTLV-I, which came from central Africa and had striking similarities to viruses found in monkeys there.

Gallo eventually dropped his contention that the AIDS virus belonged to the HTLV family, and the antibody test performed on the Ugandan blood samples was subsequently shown to be highly unreliable. Still, the notion that AIDS began in Africa and came from primates gained wide currency, and other, sturdier data soon backed it. Those data included reports in 1986 of HIV antibodies in a chimpanzee and of HIV itself in a blood sample taken in 1959 from a man living in what was then Léopoldville, the Belgian Congo (now Kinshasa, the Democratic Republic of the Congo).

Of all the immunodeficiency viruses that have been found in primates, SIVcpz is the one that most closely resembles HIV-1, the main type of the virus found in human beings. Indeed, the other SIVs differ dramatically from HIV-1 in their genetic makeup, and scientists concur that none of them could have evolved into the virus that caused the AIDS epidemic.

Hooper, too, thinks that HIV made a zoonotic hop from chimpanzees to people. But when it comes to explaining how and when it spread at an epidemic rate, he parts company with the "natural-transfer" theorists, who believe that the virus entered human beings decades if not centuries before the start of the epidemic, when someone with a cut—perhaps a hunter or someone preparing a meal—was handling an infected chimp. They offer various hypotheses to explain the time lag. Beatrice Hahn, an AIDS researcher at the University of Alabama at Birmingham, subscribes to what has become the most popular view. "These transmissions may have been going on forever and usually didn't do anything—they may have killed the person but they did not go anywhere," she says. "An infected person at some point got out of west central Africa into an urban area, Kinshasa or Brazzaville, and seeded an epidemic."

Hahn specializes in the phylogenetics, or evolutionary genetics, of SIVs and HIVs, studying the SIVcpzs isolated by the research station in Franceville and by primatologists elsewhere. Along with other mainstream theorists, she believes that once the virus reached an urban environment, it spread through sex, improperly sterilized needles, and "who knows what." Infected people may have eventually fanned out, she says, probably traveling up the Congo River and giving HIV a foothold in the eastern Congo, Uganda, Burundi, Rwanda, and Tanzania—among the first places in Africa to suffer AIDS epidemics.

The growing epidemic went undetected by the medical establishment, this theory holds, because AIDS is not a single disease with a single telltale symptom; infected people suffer from a variety of ailments. Thus an increase in cases of tuberculosis, wasting disease, and chronic diarrhea—three common AIDS-related diseases in Africa—might have worried doctors, but they would have had no reason to suspect that a new disease had struck, particularly if the increases were modest.

Theorists have some strong support for this hypothesis. In 1976 researchers studying an outbreak of Ebola in Yambuku, Zaire, collected blood samples from 659 people. Five of the samples, or 0.8 percent, later proved to contain HIV antibodies. The researchers returned to Yambuku in 1986. Two of the five people were still healthy, but three had died, having exhibited symptoms such as weight loss, fever, cough, diarrhea, pneumonia, and skin rash. Only one of the five had ever traveled outside the region of her village. A new survey at that time, of 388 people, revealed three HIV infections—exactly 0.8 percent. "These findings illustrate that HIV infection and AIDS could have existed and remained stable in a rural area of Africa for a long period," the researchers concluded in an article published in The New England Journal of Medicine in 1988.

Edward Hooper challenges virtually every part of the natural-transfer theory. "Proponents of natural transfer really don't have many facts to support their cause, but rely on speculation," he asserts. Hooper builds on a theory, first publicized in Tom Curtis's Rolling Stone article, that traces the AIDS epidemic to an experimental polio vaccine developed in the 1950s by Hilary Koprowski, who became the director of the Wistar Institute, in Philadelphia, in 1957. Although Koprowski developed the world's first oral polio vaccine, or OPV, his vaccine was never marketed in the United States; it was superseded by an OPV made by Albert Sabin (which those who grew up in the 1960s may remember taking on a sugar cube). However, as Hooper documents, from 1957 to 1960 more than 900,000 people in what are now the Congo, Rwanda, and Burundi received an experimental version of Koprowski's vaccine, known as CHAT (an abbreviation for Charlton, the surname of the girl from whom Koprowski took the poliovirus for his vaccine). He speculates that CHAT became contaminated with SIVcpz during the manufacturing process. Although Hooper goes to great lengths to challenge Koprowski's insistence that monkey, not chimpanzee, kidney cells were used to grow weakened poliovirus for his vaccine, The River contains no proof to back him up. In the end, as the Cornell University AIDS researcher John Moore wrote in a review of Hooper's book last year in the scientific journal Nature, "[as in] the grassy knoll theory, there is no smoking gun."

The undisputed facts outlined in The River include rich details about tests of the polio vaccine at Camp Lindi, a former colony of perhaps 400 chimpanzees near what is now Kisangani. Researchers abandoned the camp in 1960, when the Congo won independence from Belgium. Hooper convincingly shows that the researchers "sacrificed" many of the chimpanzees and offers some evidence that they harvested the animals' organs for use elsewhere. He suggests that labs in Philadelphia, Belgium, or the Congo used kidneys from the Lindi chimps to manufacture batches of Koprowski's vaccine.

The cornerstone of Hooper's argument in The River, though, consists of geographic links between early HIV/AIDS cases and CHAT vaccinations in human beings. Even his fiercest critics admire his resourcefulness in gathering data to support these links—a process that involved combing through old newspapers from several countries, reviewing obscure scientific articles and digging through archives, interviewing the aging principals from the OPV days, and mastering maps dotted with little-known towns and villages. Hooper wound up focusing on the thirty-eight earliest cases of "plausible" AIDS and on forty-six blood samples, ten of which came from the AIDS group, containing HIV antibodies or pieces of the virus itself. He identified what he called "likely place[s] of infection" for twenty-eight of the people with symptomatic AIDS and for all the people who had given the blood samples. He found that for eighteen of those twenty-eight people with AIDS (64 percent) and thirty-nine of the forty-six people with positive blood samples (85 percent) the likely place of infection was a town where a CHAT trial had been held. Six more of those with AIDS, and all the remaining people with positive blood samples, could be traced to towns within 175 miles of a confirmed or suspected CHAT testing site.

One of Hooper's strongest qualities is his ability to anticipate every argument that might be raised against his theory. "Skeptics would argue that you can propose anything on the basis of epidemiological data," he acknowledges in The River. "All those lists and maps and percentages may look as if they support the OPV/AIDS hypothesis certainly, but what of the other possible explanations?"

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Jon Cohen is a correspondent with Science and the author of Almost Chimpanzee (Times Books/Henry Holt & Company, 2010), from which his October 2010 Atlantic story was adapted.

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