Spillover: Animal Infections and the Next Human Pandemic

by David Quammen

At the center of the network, connected directly to eight disks and indirectly to all the rest, was a disk labeled “0.” Although the researchers didn’t name him, that patient was Gaëtan Dugas.

were among the earliest recognized cases of what has retrospectively been identified as AIDS. But they weren’t among the first victims. Not even close.

Naming the syndrome was the least of the early challenges. More urgent was to identify its cause.

There was still no solid proof that AIDS was caused by a virus at all. But three kinds of evidence pointed that way,

First, the incidence of AIDS among homosexuals linked by sexual interactions suggested that it was an infectious disease. Second, the incidence among intravenous drug users suggested a blood-borne infectious agent. Third, the cases among hemophiliacs implied a blood-borne agent that escaped detection in processed blood products such as clotting factor.

It wasn’t a petty squabble. It was a big squabble, in which pettiness played no small part. What was ultimately at stake, besides money and ego and national pride, was not just advancing or retarding research toward an AIDS cure or vaccine but also the Nobel Prize in medicine, which eventually went to Luc Montagnier and his chief collaborator, Françoise Barré-Sinoussi.

Our data cannot reflect a contamination of our cultures with LAV,” he wrote, “since the original French isolate was never received in our laboratory.” Harmless as that may sound, it was an implicit jab at Robert Gallo.

For our purposes here, the essential point is that a virus discovered in the early 1980s, in three different places under three different names, became persuasively implicated as the causal agent of AIDS.

Depending on the population, between 30 and 70 percent of those animals tested SIV-positive. But the monkeys weren’t sick. They didn’t seem to be suffering from immune deficiency. Unlike the Asian macaques, the African green monkeys “must have evolved mechanisms that kept a potentially lethal pathogen from causing disease,” Essex and Kanki wrote.

The difference between HIV-2 and HIV-1 is the difference between a nasty little West African disease and a global pandemic.

Yet the sooty mangabeys (native to Africa), unlike the rhesus macaques (native to Asia), showed no symptoms of simian AIDS. They were infected but healthy, which suggested that the virus had a long history in their kind. The same virus made the macaques sick, presumably because it was new to them.

HIV-2 is both less transmissible and less virulent than HIV-1.

Chimpanzees, not monkeys, might be the source of the pandemic bug.

These two factors—the absence of evidence from wild populations and the extreme rarity of SIV in captive chimps—left open the possibility that both HIV-1 and SIVcpz derived directly from a common ancestral virus in some other primate.

Each group was a cluster of strains that was genetically discrete from the other clusters; there was variation within each group, since HIV is always evolving, but the differences between groups were far larger.

Scientists think that each of those twelve groups (eight of HIV-2, four of HIV-1) reflects an independent instance of cross-species transmission. Twelve spillovers. In other words, HIV hasn’t happened to humanity just once. It has happened at least a dozen times—a dozen that we know of, and probably many more times in earlier history.

The arrival of HIV in human bloodstreams was, on the contrary, part of a small trend. Due to the nature of our interactions with African primates, it seems to occur pretty often.

Comparing his sequence with ZR59, the other earliest known strain, he reached a dramatic conclusion: that the AIDS virus has been present in humans for decades longer than anyone thought. The pandemic may have gotten its start with a spillover as early as 1908.

HIV-1 also came from an African primate, and that it had probably gotten into humans by way of two separate instances (for groups M and O, the ones then recognized) of butchering bushmeat. This became known as the cut-hunter hypothesis.

All that mattered was blood-to-blood contact.

that HIV-1 first got into humans by way of a contaminated polio vaccine tested on a million unsuspecting Africans. The vaccine itself, by this theory, had been an unintended delivery system for AIDS. Someone, according to the theory, had monumentally goofed.

The heterodox theory argued two additional points about this enterprise: First, that Koprowski’s vaccine was produced by growing the virus in chimpanzee kidney cells (rather than in monkey kidney cells, the standard technique); second, that at least some batches of that vaccine were produced from chimpanzee kidneys drawn from animals infected with SIVcpz

The origin of the AIDS virus is of no importance to science today.” He quoted another expert, William Haseltine of Harvard, as saying: “It’s distracting, it’s nonproductive, it’s confusing to the public, and I think it’s grossly misleading in terms of getting to the solution of the problem.”

Hooper’s river was a metaphorical one: the flow of history, the stream of cause-and-effect, from a very small beginning to an ocean of consequences.

“If you take too many risks, you don’t get home,” he said. “If you take too few, you don’t get the data.”

That rate of mutation is considered the “molecular clock” for the virus.

Well, one section of genome differed by 12 percent between the two versions. And how different was that, measured in time? About fifty years’ worth, Worobey figured. More precisely, he placed the most recent common ancestor of DRC60 and ZR59 in the year 1908, give or take a margin of error.

Worobey’s work directly refuted the OPV hypothesis. If HIV-1 existed in humans as early as 1908, then obviously it hadn’t been introduced via vaccine trials beginning in 1958.

A molecular phylogeneticist scrutinizes the nucleotide sequences in the DNA or RNA of different organisms, comparing and contrasting, for the same reason a paleontologist scrutinizes fragments of petrified bone from extinct giant saurians—to learn the shape of lineages and the story of evolutionary descent.

That chimpanzee lives only in western Central Africa, north of the Congo River and west of the Oubangui. So the Gao study effectively identified both the reservoir and also the geographical area from which AIDS must have arisen.

These are the constraints within which a molecular biologist studying wild animals labors: the relative availability and other parameters of blood, shit, and piss.

The first surprise to emerge from the fecal samples was the high prevalence of SIVcpz in some communities of Cameroonian chimps.

“We can sample hundreds of chimps at a site and find nothing.” But go just a little farther east, cross a certain river, sample again, and the prevalence spikes upward.

This wedge of Cameroon appears to jab down into the Republic of the Congo, its neighbor to the southeast. The wedge was a hotspot for SIVcpz.

The second surprise came once he extracted viral fragments from the samples, amplified those fragments, sequenced them, and fed the genetic sequences into a program that would compare these new strains with many other known strains of SIV and HIV. The program expressed its comparisons in the form of a most-probable phylogeny—a family tree.

Your celebration is always provisional, Keele told me, until you’ve written the paper and gotten that congratulatory note of acceptance from the editors of Science.

Again they found the new SIVcpz shockingly similar to HIV-1 group M. The similarity was so close as to leave almost no chance that any other variant, yet undiscovered, could be much closer. Hahn’s lab had located the geographical origin of the pandemic.

AIDS began with a spillover from one chimp to one human, in southeastern Cameroon, no later than 1908 (give or take a margin of error), and grew slowly but inexorably from there. That leaves our third question: how?

When I read Keele’s presentation of the chimp data and the analysis, in early 2007, my jaw dropped like a pound of ham. These folks had located Ground Zero, if not Patient Zero.

“What brings the money are the protected species,” he said. “Things that are rare.” It sounded like the Era of Wild Flavor back in southern China.

“If you’re thinking about infection,” he said, knowing that I was, “don’t just think of villages.” Any chimpanzee killed in the southeastern corner of the country, including an SIV-positive individual, might easily end up here in Yaoundé, being sold for meat in a back alley or served through a very discreet restaurant.

“We cannot do without these animals,” the Bakwele chief complained, “if we must perform this important traditional rite.”

It’s no condescension against Bakwele culture to note that butchering chimpanzees to eat their arms, as part of an ancient and bloody ritual, could be a very good way to acquire SIVcpz

Throughout the rest of the world you see AIDS-education materials crying out: Practice safe sex! Wear a condom! Don’t reuse needles! Here the message was: Don’t eat apes!

It did what a retrovirus does: penetrated cells, converted its RNA genome into double-stranded DNA, then penetrated further, into the cells’ nuclei, and inserted itself as DNA in the DNA genome of those host cells.

The Cut Hunter was now infected, though apart from a slash on the hand he felt fine. Forget about Gaëtan Dugas. This man was Patient Zero.

Then there were plenty of ready bugs, in the forest, in the village, to kill him or her. That wouldn’t have seemed remarkable either. People died of malaria. People died of tuberculosis. People died of pneumonia. People died of nameless fever. It was routine. Some of those people might have recovered, had their immune systems been capable, but no one noticed a new disease. Or if someone did notice, the report hasn’t survived. This thing remained invisible.

it continued to mutate. The wide divergence between ZR59 and DRC60 tells us that. It continued to evolve.

Studying the evolutionary history of HIV-1 is more than an idle exercise. The point is to understand how one strain of the virus (group M) made itself so deadly and widespread among humans. Such understanding, in turn, may lead toward better measures to control the devastation of AIDS, possibly by way of a vaccine, more likely by way of improved treatments.

In plain words: The chimp virus contains genetic material from the virus of red-capped mangabeys and also genetic material from the virus of greater spot-nosed monkeys. How did it happen? By recombination—that is, genetic mixing.