The Coming Plague

by Laurie Garrett

  The discovery of monkey AIDS viruses dated back to the earliest days of the recognized human epidemic, when scientists with the California Primate Research Center in Davis noted similarities between disease symptoms experienced by gay men and those seen in four strange disease outbreaks among monkeys in their research facilities. The first outbreak occurred in 1969 and lasted six years. During that time, forty-two macaques suffered lymphomas and a host of opportunistic infections related to severe T-cell immune system depression. Two other outbreaks of macaques suffering immune deficiency and disease occurred in the California facility between 1976 and 1978.172

  The disease, dubbed SAIDS, or simian AIDS, was produced experimentally by injecting the blood of two dying monkeys into four healthy rhesus that had been separately housed. All the injected animals became sick, some developing Kaposi’s-like skin patches.173 The California work indicated two things: the disease was transmissible, it could be experimentally created in susceptible animals, and it had existed—at least among captive macaques—since 1969.174

  As described earlier in this chapter, in 1985 researchers at Harvard University and the New England Regional Primate Center discovered two simian AIDS viruses infecting their captive animals. The viruses were dubbed SIVmac (previously, STLV-IIImac) and SIVagm (STLV-IIIagm). While SIVmac seemed to be dangerous to macaques, Max Essex’s group found that most African green monkeys carried SIVagm without any apparent ill effects.175

  In March 1986 the Franco-American dispute over discovery of HIV was replayed, as Essex’s Harvard group clashed with Montagnier’s Pasteur lab over discovery of a second species of human AIDS virus. Dubbed HTLV-IV by Essex and LAV-II by Montagnier, the viruses were found exclusively in West Africa.176

  For nearly six years the two laboratories would argue over who first discovered the second AIDS virus (eventually named HIV-2), how dangerous the virus was to human beings, and what its relationship was to the monkey viruses.

  The Harvard group’s virus was found in the blood of healthy Senegalese female prostitutes, and the individuals’ immune responses to SIVagm and HTLV-IV were equally strong.177 Describing his new virus as “the missing link,” Essex asserted that it was very close to the monkey virus, and harmless to human beings. Between February 1985 and January 1987, Essex’s group analyzed sera obtained from 4,248 West Africans, discovering HIV-2 infection rates that ranged from zero to a high of 19.8 percent among female prostitutes. Few, if any, of the infected individuals were sick, and Essex suggested that HIV-2 might be a “harmless progenitor of HIV-1” that conferred immunity against AIDS upon those carrying the West African virus.178

  A battle ensued, with Montagnier’s group warning that a new lethal virus was rapidly spreading across West Africa, and Essex’s laboratory insisting that the microbe was basically harmless.

  “We’re saying that we’re at the dawn of a new epidemic due to a virus that looks like HIV-1, the AIDS virus, but is different, and can induce AIDS,” said the Pasteur’s François Clavel. “There is an epidemic that is rapidly spreading over West Africa of, if you like, HTLV-IV or HIV-2. And it is accompanied by AIDS.”

  And Montagnier announced in 1987 that his group had treated thirty individuals who were infected with HIV-2, seventeen of whom had died of AIDS. “This virus is cytopathic for T4 cells,” Montagnier said.

  It would eventually turn out that both groups were right and wrong. Essex’s closest colleagues at Harvard and in Gallo’s lab would do a detailed genetic analysis of HTLV-IV and SIVmac, eventually concluding that the viruses were not just close cousins, but were identical viruses. Presumably, they argued, contamination occurred in Essex’s laboratory, resulting in the mixing of monkey and human samples. 179 Essex and Kanki would eventually publish a concession on the point, acknowledging that their HTLV-IV was essentially identical to a particular macaque strain of SIV found in an animal in the New England Regional Primate Center, samples of which had been in the Harvard lab. But years later Essex would remain personally unconvinced that a contamination error had actually occurred.

  “There’s no reason whatsoever to consider SIV and HIV-2 different viruses. You don’t consider rabies a different virus if it’s in bats or dogs or people. You don’t consider eastern equine encephalitis a different virus if it’s in mosquitoes or birds or horses. But for some reason this one people will forever think of as a totally different virus if it’s called SIV in monkeys or HIV-2 in humans,” Essex would say.

  Montagnier’s laboratory would be credited with discovery of HIV-2, but would prove wrong about the lethality of the virus. With time it would become clear that HIV-2 was, as Essex and Kanki claimed, far less virulent and perhaps less infectious than HIV-1.180 In Senegal, M’Boup would track HIV-2 for nine years, concluding that it was an older, less dangerous virus, found primarily in middle-aged female prostitutes.

  As the technology for analyzing genetic material improved during the 1980s,181 it became possible to compare all the various monkey and human AIDS viruses nucleotide by nucleotide, noting where similarities and differences existed. Using such techniques, scientists would begin to construct family trees for the viruses: lineages of evolution. At the heart of the technique, which was called molecular epidemiology or archeoepidemiology, were a few key assumptions: the more alike two viral genetic sequences were—the higher their degree of homology, as scientists phrased it—the greater was the likelihood that they shared a recent common ancestor, or that one virus was descendant from the other; because genetic divergence required time, degrees of viral variation could be correlated with a timetable of years or centuries; there were certain genetic features that were so essential to the survival of HIVs and SIVs that they would be conserved over generations of viruses; and it was unlikely that evolution progressed from humanly infectious virus to monkey virus, therefore the family tree began with SIV.

  Each of these assumptions would be challenged with time, but the basic approach would survive criticism, remaining in use well into the 1990s.

  Gallo’s lab used such techniques to determine the genetic DNA sequences of SIVagm, HIV-1, and the Pasteur group’s strain of HIV-2, discovering that the two human viruses (HIV-1 and HIV-2) shared about 43 percent genetic homology. In other words, they were more different than they were alike. The SIVagm and HIV-1 were also about 43 percent homologous. But SIVagm and HIV-2 shared 72 percent of their genetic sequences. 182

  Vanessa Hirsch’s group at Georgetown University in Washington, D.C., found 91.4 percent homology for the envelope genes of SIVagm and SIVmac.

  A joint Pasteur Institute/New England Regional Primate Center study of HIV-2, SIVagm, SIVmac, and HIV-1 confirmed the Georgetown findings, showing that SIV and HIV-2 were close, sharing over 75 percent homology. In contrast, HIV-1 had only 40 percent homology with either virus.

  As for HTLV-IV, Essex’s virus, the Paris/Boston team concluded that it was “a laboratory acquired contaminant”: SIVmac.183 And Beatrice Hahn, then working with Robert Gallo, announced that STLV-III and HTLV-IV were “99% identical and we conclude they are the same virus.”184

  The scientific community recognized that they had a problem on their hands as long as emphasis remained on analysis of monkeys raised or studied in captivity, because the animals were in unnaturally close contact with species of simians they would never see in the wild. Under such conditions disease and contamination were commonplace.

  The key lay with the very difficult task of capturing and testing reasonable samplings of wild primates. A Japanese team of scientists did just that, testing enough wild African green monkeys to be able to say definitively that SIVagm was a bona fide wild virus found in about half of all wild African greens on the African continent, but not found in Asian monkeys. 185 The same team sequenced their wild monkey virus, and showed that it
was equally similar/dissimilar to both HIV-1 and HIV-2. That meant that neither human virus came recently from SIVagm: rather, they both evolved at some equally distant time from the monkey virus, probably through some intermediaries.

  The discovery of other simian AIDS viruses helped clarify the picture. The Japanese team found that wild mandrills carried another virus, SIVmnd. And that virus shared the same percentages of genetic homology with SIVagm, HIV-1, and HIV-2. That put another distant point somewhere on the AIDS family tree.186

  Eventually, viruses were found in sooty mangabeys (SIVsm1 and SIVsm2), stump-tailed macaques (SIVstm), cynomolgus monkeys (SIVcyn), and chimpanzees (SIVcpz). And careful examination of the genetic sequences of these and various HIV viruses would reveal that some particular strains of HIV-2 and SIVs were so similar that scientists concluded cross-species transmission had occurred within the post-World War II period; some were convinced that monkey/human transmission was still occurring, albeit rarely, in the 1990s.187

  Tragic proof that SIV infection of humans could occur would be found in a July 2, 1992, memo from the office of NIH director Bernardine Healy. Two U.S. lab workers had become infected as a result of bites, needle sticks, and scratches while handling macaques or their tissue. One technician had early symptoms of HIV-2 disease. Genetic analysis of the SIV-2 strain found in one of the workers would show a near-perfect match with a strain found in a sooty mangabey. The scientists who did the genetic analysis would conclude: “Our findings support both the idea that this lentivirus can cause zoonotic infections and the hypothesis that HIV-2 originated from SIV.”188

  Eventually some consensus was reached. The macaque virus (SIVmac) and HIV-2 were so similar that some scientists took to using a new notation system for the two: HIV-2/SIVmac.

  In Liberia in 1989, a team of researchers led by Beatrice Hahn of the University of Alabama in Birmingham tested 372 villagers living in the country’s remote northern region and 944 employees of the huge Firestone rubber plantation. Three individuals were HIV-1 positive, five carried HIV-2. Detailed genetic analysis of two of the HIV-2 strains found in the Liberian men revealed remarkable homogeneity between the local human virus and two monkey viruses: SIVsm and SIVmac. Capture and testing of wild sooty mangabeys found in Côte d’Ivoire and Liberia revealed that 10 percent of the animals carried SIVsm. And the SIVsm virus had pieces of genetic information otherwise found exclusively in HIV-2.

  The researchers concluded that SIVsm, found in wild mangabeys, SIVmac—only seen in captive macaques—and HIV-2 were all members of “a single, albeit genetically diverse, group of viruses. Although the evolutionary origins and transmission patterns of this virus group remain to be defined, there is mounting evidence that the sooty mangabey is a natural reservoir and that the human infection probably represents a zoonosis (a disease communicable from animals to man under natural conditions).” 189

  Hahn concluded that SIVsm was probably a sooty mangabey virus that first infected rhesus macaques when the species were co-housed in captivity in a primate research facility or zoo, probably within the previous twenty years. And HIV-2, she averred, was derived from the mangabey virus. She suggested that mangabey-to-man transmission of the SIVsm was an event that had occurred periodically for decades, and still took place in the 1990s, as a result of scratches, bites, or blood exposures people experienced in West Africa while hunting the animals, transporting captured mangabeys, or butchering the monkeys and preparing their meat for human consumption. 190

  If the monkeys had carried SIVsm in days prior to colonialism, human exposure and HIV-2 cases might have occasionally occurred across a vast expanse, from Senegal to Ethiopia. But since the advent of colonialism the rain forest niches of sooty mangabeys had steadily undergone destruction, shrinking the animals’ terrain down to a tropical jungle region of Central and West Africa, particularly Congo, Cameroon, Gabon, Liberia, Côte d’Ivoire, Sierra Leone, Guinea, Ghana, Burkina Faso, and Senegal. The postcolonial terrain of sooty mangabeys exactly matched the human HIV-2 region.

  In 1993 the Smithsonian Institution’s Natural History Museum in Washington, D.C., extracted pieces of DNA from preserved monkey tissue in the museum’s archives. They discovered that 57 percent of the wild-caught sooty mangabey samples, dating back to 1896, carried an SIVsm strain that was virtually identical to that found in 1971 and 1981 wild animal samples. That study proved that the monkey virus, which was essentially the same as HIV-2, had been prevalent in Africa for at least a century.

  And it begged a critical question: Why wasn’t the human disease—HIV-2-caused AIDS—also prevalent prior to 1980?

  There was one notable epidemiological exception in the pattern of HIV-2 distribution in human beings: Pygmies. For millennia the Pygmy people had lived in the dense rain forests of Cameroon, Congo, and the Central African Republic, surviving as the continent’s most expert jungle hunters. Monkey meat had always been part of the Pygmy diet, and the people—particularly the male hunters—had frequent, often combative, contact with simians.

  Yet blood test surveys of Pygmy volunteers revealed no cases of HIV-2 or HIV-1 infection. Both the CDC (David Heymann and Pat Webb) and the Pasteur group (Françoise Brun-Vézinet) screened blood samples extracted from Pygmies during the late 1970s and again in the 1980s, finding no HIV carriers. That seemed to argue that HIV-2/SIVsm zoonotic flux was a relatively recent one, related in some fashion to urban lifestyles.191 Perhaps, scientists theorized, HIV-2 was a virus that had for decades gone back and forth between humans and monkeys, never evolving particularly well to meet the challenges of infecting either species. In a sense, they argued, HIV-2, SIVsm, SIVmac, and perhaps other simian viruses represented a large fluid genetic pool that shuffled about among a range of primates—including Homo sapiens—in West Africa. In contrast, HIV-1 had become such a genetically specialized human killer that scientists were at pains to find ways to infect research monkeys and apes with it, and could not produce clear-cut AIDS in any nonhuman primate.192

  As evidence mounted supporting Essex and Kanki’s original assertions that HIV-2 was less virulent than HIV-1 (though they were wrong to conclude that HIV-2 was harmless), researchers began looking aggressively for evolutionary clues. Natural carriers of the various SIVs were unharmed by the viruses within them, and SIVagm, for example, was dangerous only when it spread from an African green monkey to another simian species.

  If HIV-2 were the older, more highly evolved of the two AIDS viruses, then there ought to be many human beings who carried it harmlessly. Essex, Kanki, and MBoup believed that was the case, and their Senegal surveys certainly revealed that well over three-quarters of all HIV-2-positive people in that country were healthy.

  In 1989 a German research group discovered a completely healthy woman from Ghana who carried a previously unidentified strain of HIV-2 that bore only 76 percent genetic homology with the classic HIV-2 strains found elsewhere in West Africa, and only 76 percent homology to SIVsm. The group asserted that the Ghanaian HIV-2 strain represented something further back in the evolutionary chain—something close to a common ancestor of other HIV-2s, SIVmac, and SIVsm.

  “In our evolutionary tree, HIV-2alt [the Ghanaian strain] is closely related to this common ancestor and branches earlier than SIVsm/SIVmac and the HIV-2 prototypes,” said researcher Ursula Dietrich of the Chemotherapeutisches Forschunginstitut in Frankfurt. “It is still unclear whether the host of a common ancestor of the HIV-2/SIVsm/SIVmac group was human or simian … . Because captive monkeys were injected with human material [in vaccine studies] back in the 1960s, artificial transmission from a human to a simian host could have occurred. It is possible, therefore, that SIVagm and SIVmac are fundamentally human viruses. In addition, the finding of HIV-2alt, a virus in a human which is evolutionarily older than SIVsm, could indicate that all subtypes of the HIV-2/SIVsm/SIVmac group are of human origin.”193
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  In light of such discoveries, several means for human-to-monkey transmission of HIV-2 were suggested, including: tissue culture research in Europe and North America during the 1960s in which monkey and human cells were deliberately mixed, or human cells were injected into captive monkeys; and general export of simians worldwide, and those animals’ exposure to human handlers on two or more continents.194

  Most arguments, accusations, and scientific attention focused, however, on the more lethal HIV-1. And there, the waters were considerably muddier.

  It wouldn’t be until 1990 that a simian virus bearing significant homology with HIV-1 would be found—in chimpanzees. A Pasteur Institute team, led by Simon Wain-Hobson, discovered SIVcpz in two out of eighty-three wild chimpanzees tested in Gabon. When the Paris group did molecular analysis of the SIVcpz virus they found that it was remarkably similar to several HIV-1 strains, and only distantly related to HIV-2 and all other known SIVs.195

  In the case of two of the viruses’ most important regulatory genes, crucial to the microbes’ abilities to get into cells and reproduce (designated gag and nef), the chimp virus and HIV-1 had about 75 percent homology. Since within the world of all known HIV-1 strains major genetic groups often varied from one another by about 30 percent, the Gabon chimp virus was as similar generally to HIV-1 as the various subtypes of HIV-1 were to one another.

  Another SIV chimpanzee strain was found in Cameroon, and it was only 50 percent homologous to the Pasteur group’s Gabon strain. That seemed terribly puzzling, until researchers discovered a bizarre HIV-1 strain among Cameroonian people, dubbed ANT70,196 or Type O. It was highly different from all other HIV-1s, but nearly identical to the new chimp virus.197

  In 1987, in an attempt to sort out confusion and keep track of the burgeoning genetic information on different AIDS viruses, the U.S. government’s Los Alamos National Laboratory decided to dedicate some of its considerable supercomputer space to a special GenBank AIDS project. At its helm, Dr. Gerald Myers kept track of the decoded sequences of every human and monkey AIDS virus in the world. In addition, GenBank became the repository for the genetic sequences of thousands of other species of organisms, as well as the discoveries of the Human Genome Project, an international effort to decipher the entire contents of Homo sapiens’ twenty-three chromosome pairs.