The Pandemic Century

by The Pandemic Century- One Hundred Years of Panic, Hysteria

  If it is impossible to imagine AIDS being diagnosed without new Mabs technologies, it is also inconceivable that the virus would have been isolated without conceptual advances in oncology and knowledge of lentiviruses. The first lentivirus was described in 1954 by an Icelandic researcher investigating an outbreak of visna, a slow disease of sheep characterized by pneumonia and brain plaques similar to the demyelination of the central nervous system seen in multiple sclerosis. This was followed, three years later, by the description of kuru among members of the Fore tribe of Papua New Guinea highlands. A neurodegenerative disorder, kuru produces a steady deterioration of brain tissue similar to Bovine Spongiform Encephalopathy (BSE), also known as “mad cow disease.” Like BSE, kuru is thought to be due to the transmission of an infectious protein called a prion. The difference is that whereas BSE is caused by eating food contaminated with prions from the brains and spinal cords of infected cattle, kuru most likely resulted from funerary cannibalism practices in which the Fore consumed the brains of dead relatives.

  In parallel with discoveries of new lentiviruses, in the 1950s scientists were also describing new oncoviruses.* These viruses included mouse leukemia and Burkitt’s lymphoma, a rare jaw tumor especially prevalent in children in Uganda and other parts of East Africa with high rates of malaria, which was later found to be due to the Epstein-Barr virus, a close cousin of herpes. Until the 1960s, it was thought that all viruses, including oncoviruses, replicated by inserting their DNA into animal cells and co-opting the cell’s machinery to make multiple copies. The only difference in the case of oncoviruses was that, instead of being lytic and killing infected cells, they entered into a state of symbiosis with cells and caused them to replicate. However, this theory hit a major roadblock with the finding that the oncovirus of feline leukemia contained the “messenger” molecule, ribonucleic acid (RNA), rather than DNA, thereby violating one of the central tenets of molecular biology: namely, that genetic information flows from DNA to RNA to protein, not in the opposite direction.

  The first breakthrough came with the demonstration in 1970 by David Baltimore of the Massachusetts Institute of Technology and Howard Temin of the University of Wisconsin that certain RNA viruses could achieve integration into cellular genomes with the help of an enzyme, reverse transcriptase. This was an enzyme that they alone, among all RNA viruses, carried, and which enabled them to form DNA from the genes of viral RNA. At first, Baltimore and Temin’s discovery of reverse transcriptase was regarded as “heresy,” but it was eventually accepted and led to them being awarded the Nobel Prize in 1975. It also led to the coining of the term retroviruses for viruses that possessed this special ability, removing an epistemological obstacle to the understanding of how viral genes could cause cancerous transformations of cells. When a retrovirus infects a cell, the reverse transcriptase takes the clockwise RNA helix and retranscribes it in the reverse direction, rendering it into double-stranded DNA. This DNA “provirus” is then inserted into the host chromosomal DNA with the help of another viral enzyme, integrase. Because the integration site of the provirus is random, it frequently triggers disruptions of adjacent genes, causing cancer. At the same time, integrated into the cell, the virus is protected from attack by the immune system and is effectively invisible to detection with scientific instruments. The virus remains there for the life of the cell, being replicated along with cellular DNA and passed on to daughter cells.

  In 1975 only retroviruses causing cancer in animals were known (the classic examples being chicken sarcoma and feline leukemia) and many cancer researchers, discouraged by the contamination of cell lines with infectious viruses of other species, had given up hope of ever finding a human oncogenic retrovirus. Robert Gallo, an ambitious young researcher at the National Cancer Institute, a branch of the NIH, in Bethesda, Maryland, thought otherwise. The son of a metallurgist from Waterbury, Connecticut, with unkempt crinkly hair that betrayed his Italian heritage, Gallo understood right away that reverse transcriptase could add an important dimension to cancer research. He began searching for the enzyme in white blood cells from human leukemia patients. Gallo had two things going for him: a fierce competitive streak—he made no secret of the fact that he hankered after the Nobel Prize—and a novel technology that enabled him to continuously grow T cells in culture—the T cell growth factor, interleukin-2. Prior to the late 1970s, oncologists investigating leukemia had to laboriously culture malignant white blood cells on agar media in order to produce sufficient numbers for the detection of reverse transcriptase. However, the leukemia cells frequently refused to cooperate, resulting in frustration and wasted effort. But in 1976 all that changed when two of Gallo’s colleagues at his Laboratory of Tumor and Cell Biology discovered that a plant derivative stimulated certain T-lymphocytes and caused them to release a growth factor. This was interleukin-2, and soon Gallo’s lab had demonstrated that it could be used to prompt leukemia cells to grow and multiply, thereby perpetuating cell lines indefinitely. Nevertheless, even with this method it took nearly three years of trial and error before Gallo’s group hit paydirt, detecting reverse transcriptase in 1979 in the lymphocytes of a 28-year-old African American man from Alabama who had been diagnosed with mycosis fungoides, a type of T-cell lymphoma. Soon after, both Gallo’s laboratory and a group of Japanese researchers found the same virus in other patients with leukemia and in 1980 named it HTLV, short for Human T-cell Leukemia Virus. This discovery made headlines around the world, earning Gallo the prestigious Lasker Prize, and was followed, in 1982, by the isolation of a second human retrovirus in the same family, designated HTLV-II by Gallo.

  In his book on the discovery of AIDS, Virus Hunting: AIDS, Cancer & The Human Retrovirus, Gallo acknowledges that his interest in HTLV was partly inspired by the finding, a decade earlier, that the feline leukemia virus more often caused an AIDS-like immune deficiency in cats than it did leukemia. He was also inspired by research by his Harvard colleague, Myron “Max” Essex, that Japanese infectious disease wards were full of people who had tested positive for HTLV-I. Nevertheless, there is no doubt that the discovery of HTLV-I paved the way for the isolation in 1983 at the Pasteur Institute in Paris of the lymphadenopathy associated virus (LAV), the virus now known as HIV, by the French researchers Françoise Barré-Sinoussi and Luc Montagnier.

  HTLV infects CD4 cells and spreads by blood and sexual contact, often producing leukemias several decades after the originating infection. The difference is that HTLV is oncogenic; for reasons which are not fully understood but which involve a protein called Tax, it causes cells to replicate rather than killing them. However, similar techniques are required to grow the virus continuously in cell cultures, and had Gallo not demonstrated that HTLV depended on reverse transcriptase and was associated with a depletion of CD4 cells, it is unlikely that Barré-Sinoussi and Montagnier would have thought that the retrovirus they were studying might possess similar properties. However, it is also clear that Gallo’s conviction that the virus of AIDS was an oncogenic virus, similar to the feline leukemia virus, blinded him to other research avenues that might have seen him isolate HIV before the French. Instead, in May 1983, in a note published in the Morbidity and Mortality Weekly Report and followed by a series of articles in Science, Gallo announced that a variant of HTLV-I, or its near relative HTLV-II, was most likely the pathogen of AIDS. Unfortunately for Gallo, in the same issue of Science, Barré-Sinoussi and Montagnier announced their discovery of LAV. As the virus showed little or weak cross-reactivity with HTLV-I, it was clear that theirs was a different virus. Despite this, at the request of the editors, Montagnier agreed to an abstract, written by Gallo, stating that the French had discovered “a retrovirus belonging to the same family of recently discovered human T-cell leukemia viruses (HTLV), but clearly distinct from each previous isolate.” That sentence would leave the Pasteur Institute researchers with a nasty aftertaste, one that would provoke a bitter international dispute over the correct nomenclature of the virus and who had discovered it—a
dispute that in turn would engender misunderstandings about HIV’s identity and its precise relationship to AIDS, fueling conspiracy theories that persist to this day.

  The dispute between Gallo and Montagnier, and the scientific and commercial stakes that lay behind it (one of the fiercest issues was who should collect royalties for the development of an HIV diagnostic test), has been the subject of books by both of the principals and has also been analyzed extensively by other writers. The bad feeling between the French and American scientists was exacerbated by an ill-considered press conference in April 1984 at the US Department of Health and Human Services at which Gallo announced that he had isolated the virus of AIDS and followed up that announcement with four further papers in Science in which he named the virus HTLV-III.† In 1986, the dispute appeared to have been settled when the International Committee on the Taxonomy of Viruses renamed the virus HIV and, soon afterwards, Ronald Reagan and Frédéric Mitterrand, who was then the president of France, announced that both groups of scientists deserved equal credit for the discovery, only for the dispute to be reopened in 1990 by new genetic tests suggesting, wrongly as it turned out, that Gallo had misappropriated samples forwarded to his laboratory from the Pasteur Institute in 1983. This is not the time or place to revisit that fraught history or whether in naming the virus HTLV-III Gallo intended to suggest it was related to other viruses in the HTLV family or even that it was the cause of AIDS (he would subsequently say he had never made this claim). However, it is worth dwelling on one aspect of the dispute because it goes to the heart of the question as to what both groups of scientists knew, or thought they knew, about the virus at the time they first posited its etiological role in AIDS, and the extent to which Gallo was blinded by his belief that the AIDS virus belonged to the cancer family of retroviruses.

  In the second set of papers published in Science, Gallo described how he had isolated HTLV-III from forty-eight patients and spelled out how to grow the virus continually in laboratory cultures. This was a critical feat. HIV routinely kills the cells it infects, making it difficult to grow the virus in the quantities needed to study its properties and develop a blood test, let alone a vaccine. Indeed, using the new cell line, Gallo’s group was already well on the way to developing a prototype screening test (or ELISA), as well as a confirmatory test (known as the “Western blot”). However, in his earlier 1983 paper Gallo had made no mention of the virus’s cell-destroying properties, merely observing that it could be immunosuppressive in vitro: that is, it could harm the function of T cells in laboratory cultures. This left open the question of how precisely HTLV, a virus that was known to cause lymphocytes to divide, also resulted in them becoming depleted.

  By contrast, the French started from the premise that because the virus reduced and destroyed the numbers of circulating T cells, it would be difficult to isolate in peripheral blood. At this stage, Montagnier’s group accepted that it was most likely a retrovirus closely related to, or identical to, HTLV. However, rather than look for it in blood they decided to look for it in fluid taken from the lymph nodes of a presumed AIDS patient, reasoning that there might be higher levels of the virus present in people who were at an earlier stage of illness before most of their T cells had been killed off. Thus it was that on January 3, 1983, a researcher at the Pitié-Salpétrière Hospital in Paris removed a lymph node from the neck of a 33-year-old man with “lymphadenopathy syndrome”—a condition of chronically swollen lymph glands increasingly prevalent in gay men—and added interleukin-2 to encourage cell-line growth.‡ If the virus had been a species of HTLV, the addition of interleukin-2 should have maintained the culture and its population of T cells, but that is not what happened. Instead, no sooner had Barré-Sinoussi observed the production of reverse transcriptase by the cultured lymphocytes on January 25, than production of the enzyme reached a peak, before falling back. The virus seemed to be killing the T cells rather than causing them to replicate. Fearing that without a new supply of lymphocytes she would lose the virus, she asked a member of the team to obtain fresh blood from a nearby blood bank. Adding the new source of lymphocytes to the culture, she saw that cell death correlated once again with the detection of reverse transcriptase activity. It was as if the addition of the plasma containing fresh lymphocytes caused the elusive virus to begin gobbling up T cells again, leaving an unmistakable trail of reverse transcriptase, much as a shark leaves a blood trail after attacking its prey. It was at that moment that Barré-Sinoussi realized the virus was killing the T cells, that it was a new retrovirus and that it was almost certainly not Gallo’s HTLV. As she later recalled: “It was very easy. We received the first sample at the beginning of 1983 and, fifteen days later, we had the first sign of the virus in the culture.”

  If Barré-Sinoussi thought the wider world would immediately grasp the significance of her experiment she was wrong, however. The publication of her paper on LAV in the May 1983 edition of Science was completely overshadowed by the papers by Gallo and Essex. Not only that, but when in the fall of 1983 Montagnier traveled to an international virology conference held each September in Cold Spring Harbor, New York, and reported finding LAV in about 60 percent of patients with lymphadenopathy syndrome and 20 percent of those with AIDS, and that none of these patients appeared to be infected with HTLV, his findings were fiercely disputed by Gallo. In his book, Gallo would later write of his “regret” about his aggressive questioning of Montagnier and acknowledge his failure to spot LAV’s cell-killing properties earlier—a failure that he attributed to the “distortion” of his laboratory’s measurement of reverse transcriptase activity due to the fact that tests usually began later in the course of infection, by which time most of the T cells were already damaged or dying, as well as by inconclusive immunofluorescent assays that were sometimes positive for HTLV-I and sometimes not (perhaps because some of the subjects were infected with both HIV and HTLV simultaneously, or one or other of the viruses separately). However, in his account of his own investigation Montagnier argues persuasively that, with the superior financial resources available to the Americans, had Gallo believed in the French virus from the very beginning, he “would have rapidly left us far behind.” That is a conclusion with which Gallo reluctantly concurred, acknowledging that his “overconfidence” that AIDS could not be a type of retrovirus different from HTLV probably cost him six months and that he should have solved the problem before Montagnier’s group embarked on their first experiment. “AIDS being identified right after the discovery of the first and second human retroviruses . . . misled me,” Gallo admitted. “As well as leading me right, it also led me wrong.” Or as the historian of Science Mirko Grmek put it rather more directly, “If Gallo had not discovered HTLV-I, he might well have been the discoverer of HIV.”

  IN HER BOOK Illness as Metaphor, the cultural critic Susan Sontag draws attention to the way in which any disease whose causality is murky and for which treatment is ineffectual tends to be awash with significance. “First, the subjects of deepest dread (corruption, decay, pollution, anomie, weakness) are identified with the disease. The disease itself becomes a metaphor. Then, in the name of the disease (that is, using it as a metaphor), that horror is imposed on other things.” Those words were written in 1978 and were originally inspired by Sontag’s experiences as a cancer patient, when she had been made to feel that the disease was shameful and somehow her fault, but as she recognized when she revisited her thesis in the wake of the AIDS epidemic, her comments applied even more to AIDS. Indeed, by 1989 she argued that the secrecy, shame, and feelings of culpability experienced by cancer patients in the 1970s had to a large extent been replaced by those of AIDS patients. This was particularly the case for homosexual men and other designated at-risk groups, such as intravenous drug users, whose dangerous behaviors were thought to have somehow invited the affliction. Such groups, she argued, had been made to feel like “a community of pariahs.” Worse, whereas in the case of cancer, culpability for illness had been linked to unhealthy habit
s such as cigarette smoking and excessive drinking, the unsafe behavior that produced AIDS was viewed as something more than weakness of will. “It is indulgence, delinquency—addictions to chemicals that are illegal and to sex regarded as deviant.” The result was that what should have been considered an individual “calamity” that invited sympathy for the afflicted, was judged harshly “as a disease not only of sexual excess but of perversity,” resulting in the widespread stigmatization of people with AIDS.

  At what point this stigmatization morphed into hysteria and panic about the threat that such patients posed to wider society is harder to say. Initially, the public responded with indifference to news of the outbreak, perhaps taking their cue from White House press spokesman Larry Speakes who, when asked by a reporter in October 1982 whether the Reagan administration had any reaction to the CDC’s announcement of over six hundred cases of the mysterious new disease, famously responded, “I don’t know anything about it.” This indifference was due partly to ignorance and partly to prejudice about a disease that was thought to affect only homosexuals. As long as AIDS was framed as a disease of gay lifestyles, and therefore not a problem for “straight” society, it could be safely ignored by mainstream politicians. Instead, Ronald Reagan’s administration, backed by the Republican-controlled Senate, starved AIDS researchers of funds, forcing scientists at the NIH and CDC to beg and steal money from other programs. Indeed, for the first three years of the epidemic, Reagan refused to mention the “A”-word, only referring to AIDS in public for the first time in the fall of 1985. By then, of course, the actor Rock Hudson had been forced to admit that he had the dreaded disease, issuing a press release from his sickbed at the American Hospital in Paris, and the CDC was reporting that more than 10,000 people had been diagnosed with AIDS, many of them children and hemophiliacs. According to David France, a contributor to the New York Native who would go on to make an Oscar-nominated film telling the story of how AIDS activists took on the scientific establishment in the quest for medications that would prolong their lives, Hudson’s announcement was a game changer. “We prayed for a day when the disease struck someone who mattered,” he wrote. In particular, it prompted reporters to ask embarrassing questions about why the Hollywood icon had been forced to seek treatment in Paris, unleashing a wave of publicity that finally broke the administration’s murderous silence around AIDS and persuaded the White House to release much needed funds for research into experimental treatments, such as AZT. What France and other activists did not foresee is that it would also unleash a wave of fear and hysteria.