COLD SPRING HARBOR, NEW YORK—When I walked into the dining hall of the Cold Spring Harbor Laboratory (CSHL) here at dusk on 13 October, I immediately noticed Françoise Barré-Sinoussi having dinner with Robert Gallo at a long table that otherwise was empty. They had plates of food on brown plastic cafeteria trays, and were smiling about this and that, two old friends reminiscing in what could have been the mess hall of a summer camp set on the picturesque Long Island Sound. A most unusual conference on the history and future of HIV/AIDS research would begin later that evening, and these two scientists would be the stars for the central roles their laboratories played in discovering this peculiar retrovirus and proving that it caused the devastating disease.
But for too many years, that grand achievement had them—or at least their employers, France’s Pasteur Institute in Paris for Barré-Sinoussi and the U.S. National Cancer Institute (NCI) in Bethesda, Maryland, for Gallo—on opposing sides of a historic who-did-what-when battle that began over the HIV blood test patent. That feud grew into an epic drama of Homeric proportions. Now, here they were, schmoozing.
We’re a bunch of people here who are starting to be quite old, including myself, and we have to make sure the next generation in particular will have the history in mind for HIV and other diseases. The next generation should not make the same mistakes.
CSHL meetings indeed are something like adult summer camp with participants bunking in cabins or dormlike rooms scattered around the 40-hectare campus (which once was a whaling company), sharing cafeteria-style meals, listening to talks that run off and on for 12 hours a day, and packing into the small bar at evening’s end. The meetings are famous for being Who’s Who gatherings. Barré-Sinoussi and Gallo were joined by 125 other luminaries in the HIV/AIDS field who traveled here for this 3-day get together to recount the bad old days and their grand accomplishments. (I’ve covered the twists and turns of the field for 30 years and was the only reporter at the meeting.) During the entire meeting, nary a public whisper was heard about the blood test patent feud that led to a peace treaty of sorts signed by no less than former French President Jacques Chirac and former U.S. President Ronald Reagan, as well as multilayered government probes, the enrichment of many lawyers, microscopic press coverage, books, an HBO movie, and vociferous outrage from Gallo’s many supporters who assailed the decision to cut him out of the Nobel Prize, which in 2008 went to Barré -Sinoussi and her associate, Luc Montagnier. Instead, the attendees heard talks from researchers and clinicians who treated the first AIDS patients in early 1981, discovered the causative virus, elucidated details of HIV’s genetics and the infection process, identified effective immune responses, developed the first anti-HIV drugs, traced the epidemic’s origins, and now are at the forefront of the search for a cure and a vaccine.
Of course the meeting was not meant to be the definitive history of the epidemic. How could it be? Nearly 37 million people are still living with the virus, and although 17 million are receiving life-saving antiretroviral drugs, another 20 million are not. Some 2.1 million people became infected last year alone. There’s no cure or vaccine. The epidemic, in short, isn’t history. But given the advanced age of many of the participants, there was no time like the present to hold the gathering. “We’re a bunch of people here who are starting to be quite old, including myself, and we have to make sure the next generation in particular will have the history in mind for HIV and other diseases,” Barré-Sinoussi told me. “The next generation should not make the same mistakes.”
James Watson, the 88-year-old former director of CSHL who won the Nobel himself for elucidating DNA’s double helix, kicked off the meeting. Like many presenters, the infamously rascally Watson couldn’t resist making a Donald Trump wisecrack. “There’s no greater success story than the one we’re going to hear about today,” said Watson, referring to the identification of HIV and its routes of transmission, and the subsequent development of a blood test and drugs that can stop it. “Imagine if it was not conquered. Then you would hear, ‘Can you get HIV from groping?’ The possibilities are great.”
The first speakers, including Nobel laureate Harold Varmus, who formerly headed the NCI and its parent, the U.S. National Institutes of Health (NIH), connected the dots between the century-old study of retroviruses and the early hunt for HIV. The signature retroviral enzyme, reverse transcriptase (RT), played an essential role, said John Coffin of Tufts University in Boston. RT was discovered in 1970 by Coffin’s mentor, the late Howard Temin, and separately, David Baltimore (another attendee). The enzyme converts RNA into DNA, a once heretical idea, thereby enabling retroviruses to integrate with human chromosomes. “This is the most dramatic scientific discovery that I’m quite sure I’ll ever be associated with,” Coffin said.
I remember their names. I remember what they looked like. I remember them in greater detail than patients I saw last week.
RT is relatively easy to detect in a cell culture, where it can signal the presence of a retrovirus. Both the French team that first isolated HIV in 1983 and the U.S. group that a year later convincingly proved the virus caused AIDS relied on detecting RT in samples from patients. Without that preexisting knowledge of RT and its role in the retroviral life cycle, “I’d postulate it would have been a much longer time before we were able to deal with HIV,” Coffin said.
As it was, for 3 years after the first report of AIDS appeared, buried on the second page of the 5 June 1981 Morbidity and Mortality Weekly Report, the disease remained a mystery, and speculation ran wild about what caused this frightening destruction of the immune system and how it spread. Michael Gottlieb, a clinician then at the University of California (UC) in Los Angeles who described the first five AIDS cases—all young gay men whose immune systems had mysteriously been destroyed, allowing Pneumocystis carinii pneumonia to thrive—said he remained haunted by those days. “These first patients certainly made an impression on all of us,” said Gottlieb, who now treats HIV and hepatitis C in private practice in Los Angeles. “I remember their names. I remember what they looked like. I remember them in greater detail than patients I saw last week.” All five died within the year.
Oncologist Paul Volberding similarly cannot forget his first AIDS patient, a 22-year-old gay man from the Deep South he met on 1 July 1981 at San Francisco General Hospital in California. Volberding, who had come to UC San Francisco (UCSF) to study retroviruses in the lab of Jay Levy, showed a photo of the shirtless man, who had been estranged from his family and had purple splotches of Kaposi sarcoma all over his torso. “He challenged us because my cancer patients at the general [hospital], even if they were poor recent immigrants, typically had a family or some usual sort of home to help with their care, but the early patients didn’t have that,” Volberding said. The man quickly died.
Volberding next showed a nightmarish photo of an early patient who had Kaposi on his eyelids, lips, and cheek. Staff knew their patients like family, but he said sometimes the Kaposi would so swell and disfigure faces that people weren’t recognizable from one clinic visit to the next. “The only social activity some of them would engage in was going to the movies at night so no one would notice them,” he said. “Horrible disease.” P. carinii pneumonia so reduced oxygen levels in the blood that patients turned blue the moment he took off their oxygen masks. Cytomegalovirus, another opportunistic infection, left people blind and demented. “Horrible disease,” he said again.
Volberding, whose wife also was a clinician who cared for the first AIDS patients, worried that he would become infected—a fear that ran so deep they never discussed it. He noted that he took “zero” precautions to protect himself. “My recurring nightmare was that I had given it to my kids.” He was one of the first to take the HIV test when it became available in 1985, and “obviously hugely relieved” to learn he was negative. He still works at UCSF, and says that to medical students today, AIDS is more remote than polio was when he started his training. “It’s important to remember how devastating and stigmatizing this disease was,” he said.
People who worked for the U.S. government also had difficult terrain to navigate when the epidemic surfaced. As James Curran, then with the Centers for Disease Control and Prevention (CDC) in Atlanta, explained, Reagan had just come into office buoyed by the conservative Christian Coalition of America, which saw homosexuality as a sin. (Baptist minister Jerry Falwell, co-founder of the Moral Majority, once said, “AIDS is not just God’s punishment for homosexuals. It is God’s punishment for the society that tolerates homosexuals.”) Money for research was scarce. CDC also didn’t have “the horsepower” to find the virus, which led Curran to speak at an NCI Advisory Council meeting, hoping to pique Gallo’s interest. Gallo’s lab had recently discovered the first human retrovirus, a leukemia and lymphoma virus known as HTLV-1. “We needed the basic scientists,” Curran said. “Somebody told me later I was the first to ever talk about anal sex and fisting at a National Cancer Advisory Board.”
Gallo, who described Curran as “the town crier,” said it was by chance that he heard his talk at NCI. “Everything was happenstance,” Gallo said. “He did make the comment somewhere along the line of, ‘Where are all the virologists?’”
Gallo reminded the audience that a plethora of theories were floated about the cause of AIDS, including the idea that rough sex led to an autoimmune reaction—“one objection would be that maybe rough sex existed for about 3 million years,” he quipped. Other proposed causes were a fungus, mycoplasma, cytomegalovirus, and Epstein-Barr virus. Then Gallo and his co-workers published four back-to-back papers about HIV (which he mistakenly thought was a human T-lymphotropic virus relative) in the 4 May 1984 issue of Science, making the case that this virus, found in blood samples from AIDS patients, was the cause. Barré-Sinoussi and colleagues, who a year earlier had identified the virus but did not have enough evidence to prove causation, quickly confirmed the Gallo lab’s reports with HIV they separately had isolated from patient samples.
Still, a plethora of “ridiculous” theories persisted, Gallo said, including the assertion that HIV was created by the U.S. government. “I got some assassination letters that I’d be dead in 3 weeks, and I used to have to go home with dogs and these police,” Gallo said. “This was not a happy time completely.” He took particular exception to Peter Duesberg, a retrovirologist at UC Berkeley who argued that HIV was a “pussycat,” a harmless passenger virus that didn’t cause the disease. One of Duesberg’s prominent supporters was Kary Mullis, who won the Nobel Prize for his role in discovering the polymerase chain reaction. Here’s how Gallo described a photo he showed of the two: “Our friends Kary Mullis and Peter Duesberg, I hope you know I say that with intent to be malicious.”
Anthony Fauci, an immunologist at NIH, also helped change the course of the epidemic. A clinician who struggled to keep his research afloat in the early years because caring for dying AIDS patients sapped so much of his time, Fauci explained that in 1984, he took an offer to head the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda in part out of frustration. “I was not particularly enamored of administration, but I felt that infectious disease and certainly HIV/AIDS was not going in the right direction and did not have the support I thought it should have,” Fauci said. “That opened my life to things I never would have been prepared for as a clinician, as a scientist.” Under Fauci’s leadership, NIAID became the single largest funder of HIV/AIDS research in the world. His own lab’s research also has helped clarify fundamental relationships between the virus and the immune system.
Fauci showed a photo of himself testifying before a congressional hearing, which he said he has done 245 times since taking the job—often about the HIV/AIDS budget and other issues related to the epidemic. “I may have the all-time indoor record of testifying before Congress,” Fauci said. “You either get praised or you get killed. You just got to know when to duck.”
His job also put him in the hot seat with AIDS activists, who believed the federal government for the first decade was dragging its feet in its response to the epidemic. Fauci quoted a headline of an article published in The San Francisco Examiner in 1988 by Larry Kramer, who founded the AIDS Coalition to Unleash Power, ACT UP. “I call you murderers, an open letter to an incompetent idiot, Dr. Anthony Fauci,” it read. “He got my attention and I began to listen to them.”
Mark Harrington, a leading player in ACT UP until he started his own advocacy organization, Treatment Action Group in New York City, was the only openly HIV-infected person to speak at the gathering. “Apologies if we ever went overboard,” said Harrington, who, after a pause, added “Dr. Fauci.” He explained that activists condemned government health officials—and indeed staged massive, theatrical protests at NIH and the U.S. Food and Drug Administration (FDA)—because they believed the science was too shrouded in secrecy and promising drugs were approved too slowly. They also insisted that affected communities should have input about the research agenda itself, a battle they won, inspiring many other disease advocates. Harrington then told the entire gathering, “I would like to thank you all and everyone who works with you from the bottom of my heart and on behalf of the world’s 37 million people that are still living with HIV and also on behalf of all those who didn’t make it, because they, too, lived longer and had hope because of the efforts that you made.”
When Barré-Sinoussi gave her presentation near the end of the meeting’s second session, she noted that she was the first woman speaker to take the podium. This drew loud applause and hoots. “Things have changed over the years, but still you can see that males are always the first,” she said. “I’m joking, of course.” Well, yes and no.
The attendee list was skewed in other ways, too. Only a dozen participants were from outside the United States, and age was the butt of as many jokes as Donald Trump. “There are some young people in the audience—and by the way my definition of young is that you’re under 70,” said Samuel Broder, who did pivotal work at NCI on the first approved anti-HIV drug, azidothymidine (AZT). Flossie Wong-Staal, who worked with Gallo at NCI, noted that she recently sent an email and it auto-corrected her name to “fossil.” Michael Worobey, an evolutionary biologist at the University of Arizona in Tucson who studies the origin of the AIDS epidemic, made a point of being one of the youngsters, apologizing for not having any interesting anecdotes about what he was doing in 1981. “I was 8,” he said. “I skinned my knee rollerskating.”
Most notably absent from the meeting was Montagnier, who shared the Nobel with Barré-Sinoussi. Gallo, one of the conference organizers, told me they couldn’t locate him. (Montagnier has been ostracized by many of his former AIDS research colleagues for promoting several controversial ideas since his HIV discovery, including the contention that water contains memory via electromagnetic DNA imprints.)
Neither Gallo nor Barré-Sinoussi mentioned the blood test patent dispute or the intense competition between their teams. Barré-Sinoussi did describe an evening in Paris in 1984 when they reviewed data from a study that compared the ability of both labs to detect the virus in blinded samples from AIDS patients and controls. “It was so hot and strong a discussion that we decided to go to a cabaret,” she said. “It was a difficult period but we had a nice time all together.”
I asked Barré-Sinoussi why she sidestepped the controversy. “For me, this is a meeting of the scientific history,” she said. “I have no problem with Bob [Gallo].” I told her I didn’t see how you could separate the science from its historical context. “It’s not interesting to me,” she said. “I don’t care who was first. I care that there’s a solution for patients.” She told me a story about a conference in France in the mid-1980s, when a few people living with HIV confronted her. “They said, ‘Whatever you will say we will not believe you scientists because you’re more interested in fighting each other than taking care of us,’” she recalled. “Emotionally, that was terrible for me. It was so awful.”
Warner Greene, who worked at NCI when AIDS surfaced and now is at UCSF, had a most diplomatic take on how Gallo, Barré-Sinoussi, and others were recounting the history. “It’s a wonderfully refreshing view in cordial terms of what were remarkably turbulent times,” he said.
Since AZT first won FDA approval in 1987, the field has brought nearly three dozen other antiretroviral drugs to market. They have converted HIV infection from a death sentence to a chronic, manageable disease. These same drugs also can prevent viral spread from an infected mother to her baby, as well as transmission between sex partners. They are even taken by people who don’t have HIV to prevent infection, a proven strategy called Pre-exposure prophylaxis. But a cure and a vaccine remain elusive. “Our challenge really is to put the genie back in the bottle,” said David Baltimore, one of the few old-time retrovirologists to have taken up HIV/AIDS research, which he does at the California Institute of Technology in Pasadena. “It is impressive to see how much can be learned in 35 years of research and how we take a challenge that’s put up by nature and apply science to it. Of course it also reminds us that probably the greatest failure of modern molecular biology is that we haven’t been able to control HIV and that we’re still in the midst of an epidemic.”
Several talks at the meeting gave updates on cure research, which moves forward inch by inch, but Baltimore said he thought a vaccine would be a more important tool to bring the epidemic to an end. His own lab has pursued the finding that some rare antibodies have unusual power to stop the virus and, importantly, work against a huge range of mutant strains. Despite a great deal of effort into developing vaccines that can teach the body how to make these so-called broadly neutralizing antibodies, progress has been slow, so Baltimore’s group has taken another tack: In a technique he calls vectored immunoprophylaxis, they stick genes for the antibodies into a harmless adeno-associated virus, which makes the antibodies instead of relying on the body to do so. Another group has already launched human trials with this approach, and Baltimore’s team hopes to follow suit soon.
The quest for a more traditional vaccine has been frustrating and contentious, as a debate about a vaccine trial set to launch next week in South Africa showed. The $130 million trial, which plans to enroll 5400 people at high risk of becoming infected by HIV, is funded jointly by NIAID, the Bill & Melinda Gates Foundation, and the South African Medical Research Council. It retests a vaccine strategy that in 2009 showed a modest 31% efficacy in a trial held in Thailand.
The placebo-controlled study will test a one-two punch strategy. The first round uses canarypox virus to deliver several HIV genes. This is followed by a vaccine that only contains HIV’s surface protein, gp120, plus an immune stimulant called an adjuvant. Analyses of the people protected in the Thai study found that they had higher levels of specific antibodies that can bind to the surface protein. But because these binding antibodies do not prevent the virus from infecting cells in test tube experiments, critics of the Thai study say that they make an unconvincing case for protection.
It was the adjuvant that sparked the fiercest controversy, however. One panelist, NCI’s Genoveffa Franchini, suggested the formulation might even make people more vulnerable to infection. As Franchini and co-workers reported 30 May in the online issue of Nature Medicine, they tested the vaccine strategy used in Thailand in rhesus macaques and found that the binding antibodies did correlate with protection. But the group also conducted a head-to-head comparison of two different adjuvants used to juice up the immune response to the gp120 component of the vaccine. Monkeys given the vaccine along with the “alum” adjuvant used in the Thai study were protected. Not so the monkeys that received an adjuvant known as MF59.
The South African study is using MF59, not alum. “If MF59 is doing the same thing that it’s doing in the macaques then you’re going to end up having no protection and you won’t know why,” Franchini said, urging the designers to add an arm to the study that includes alum. She suggested MF59 might even overstimulate the immune system and create more target cells for the virus to infect. “There’s this oath that we take when we finish up medical school: Don’t harm,” she said. Lawrence Corey of the Fred Hutchinson Cancer Research Center in Seattle, Washington, who heads the NIH-funded network overseeing the study, countered that they hadn’t ignored Franchini’s data but noted that another monkey study had different results. “People of good faith will have different answers,” Corey said, stressing that the human experiments are the way to arrive at the real answer.
Ronald Desrosiers, a virologist now at the University of Miami in Florida who did pioneering AIDS vaccine studies in monkeys when he used to head Harvard University’s now defunct primate research center, thinks the South African study is a waste of money and flatly rejected this line of logic. “Every single vaccine that’s tested in monkey can’t be tested in people,” Desrosiers told me. “Monkey trials let you do a rank ordering of what to test.” He was so riled by this discussion that he walked out of the conference hall.
I gave a presentation after the formal conference had ended and the auditorium doors were opened for a “public event” that included me, Swedish filmmaker Staffan Hildebrand, and former NIH historian Victoria Harden. I spoke about the history and future of HIV/AIDS media coverage. Four of my 49 slides, most of which showed headlines from newspaper and magazine stories, recounted the main plot points in the French/U.S. controversy, including a protracted U.S. government probe that found Gallo guilty of scientific misconduct for misreporting a technical detail in his landmark 1984 papers and a subsequent ruling by an appeals board that dropped all charges.
I retook my seat in the front row next to Greene. Gallo immediately came over, asked Greene for his seat, and proceeded to tongue lash me. Gallo was outraged by my presentation, which he thought portrayed him unfairly and discounted the fact that he helped the French group. He started loudly ticking off the minutiae of the debate. Gallo is hot-blooded and I have been on the receiving end of his anger before, which often abates when he is reminded of the facts. He and I made peace before I left, but in retrospect, I wish I had seen historian Harden’s talk before I gave my own. I would have framed it differently.
Harden stressed that there is no single history of the HIV/AIDS epidemic: There are many, and there will be many more. There is a history written by journalists like me, among them—I wish I had reminded Gallo—one who in 1993 wrote a full-throated paean in The New York Times Magazine subtitled “The Vindication of Robert Gallo” that proclaimed him a “hero.” Gallo and other researchers have written memoirs. There are histories written by activists, relatives of people who died from AIDS, and denialists who did not believe in the “HIV/AIDS hypothesis.” There is the history that was told in PowerPoint presentations and barroom gabfests here at CSHL this autumn in the autumn of the careers of many pioneers, whose conflicts with each other long have been eclipsed by their collective accomplishment and their continued efforts to make HIV, once and for all, a thing of the past.
And there is the history written by future historians, who, Harden stressed, always get the last word.