The New Face of AIDS
- Jon Cohen
The 11th International Conference on AIDS, to be held in Vancouver, Canada, next week, comes at a time of guarded optimism on some aspects of the 15-year battle against the disease. This represents a change from 3 years ago, when Science last did a special issue on AIDS, with a focus on European researchers (28 May 1993). This special section, focusing largely on the United States, looks at the changing culture of AIDS research (p. 1876); the AIDS marketplace (p. 1880); the story behind the discovery of a promising new class of drugs (p. 1882); and a surprising recent meeting on antiviral therapy (p. 1884). We also present the viewpoints of leading researchers on HIV pathogenesis (p. 1885), drug treatments (p. 1886), and vaccine research (p. 1888).
[Web Site] Additional AIDS Resources
AIDS Community: The Changing of the Guard
- Jon Cohen
photo A decade ago, the world of AIDS research was more like a collection of fiefdoms than a typical field of science. The leading researchers were tumor virus hunters who had known each other for many years. They were split into camps whose leaders provided their collaborators—most of them tumor virologists—with viral samples, reagents, and the latest information. Early on, the different camps cooperated closely, even coordinating the publication of their findings, which sped the discovery of HIV and the proof that it caused AIDS. But, even before the discovery of HIV was announced, the harmony between the camps gave way to vicious feuds—feuds that earned the world of AIDS research a reputation for having a particularly nasty terrain.
Today, the landscape of the AIDS research world appears much different and, by most accounts, considerably less hostile. The field is now so large that no one lab controls anything. And the community itself has been transformed: The reign of the tumor virologists has been eclipsed by a younger generation of researchers who have spent their entire independent careers trying to tackle tough, detailed questions about HIV and AIDS. As Beatrice Hahn, 41, a molecular b iologist at the University of Alabama, Birmingham (UAB), puts it simply: “The culture has changed.”
The culture has shifted in part because this new guard of leading scientists has grown up together and seen the high cost of discord in the research community and the benefits of cooperation. “There is a younger generation at the forefront who don't have the egos, and it's very enjoyable,” says Didier Trono, 39, a leading molecular biologist at the Salk Institute for Biological Studies. Richard Koup, 39, an immunologist at the Aaron Diamond AIDS Research Center (ADARC), has noticed the change, too: “It's really quite amazing how little real fighting or hatred there is, which distinguishes this era from the previous one.” UAB oncologist George Shaw, 42, says his peers also have high regard for each other: “Many of the investigators of this era would not dream of doing anything to hinder even their fiercest competitor.”
Scientifically, the ascendancy of this new generation of researchers is abundantly evident. The work of scientists in their 30s and 40s fills the top journals and is among the most frequently cited in the field. They are the foundation—and the soul—of w orld-class AIDS programs at places like ADARC and UAB. They are selected to give the choice talks at the biggest conferences, such as the upcoming international AIDS meeting to be held in Vancouver, Canada, next week, and they organize Keystone and other prestigious get-togethers. “The torch has been passed … and that's how it should be,” says UAB retrovirologist Eric Hunter, 48.
It's not just in the research arena that leaders of the new guard are making an impact: They are also helping shape the politics of the AIDS program. Most notably, these younger researchers, working with AIDS activists, played a pivotal role in persuading Congress in 1993 to revamp the Office of AIDS Research (OAR) at the National Institutes of Health (NIH). And they provided much of the muscle for a subsequent sweeping review of the NIH's AIDS research portfolio that OAR has just completed (see p. 1878).
These changes in the culture of the AIDS community reflect the maturing and expansion of the field itself. “There are not two or three major camps as there were before,” says virologist David Ho, 43, who heads ADARC. “You could probably name a dozen groups” making major contributions. And the glory stakes are lower than they were when the virus was discovered: No longer is there any expectation that findings will quickly lead to effective vaccines or therapies. “I think everyone was trying to hit a home run in the beginning,” says molecular biologist Steven Wolinsky, 43, of Northwestern University. “Quick answers just aren't going to be there any longer.”
The realignment of the culture is less apparent to the old guard, however. “It happened without us thinking about it,” says Robert Gallo, the tumor virologist whose former lab at the National Cancer Institute (NCI) first proved that HIV causes AIDS. Others, such as Duke University's Dani Bolognesi, a tumor virus veteran who became a leading AIDS vaccine researcher, say the lines between the eras are blurry. “I don't see the old passing into the new so much as it all being better integrated,” says Bolognesi. He points out, for example, that Gallo, who recently left NCI to run a new Institute of Human Virology at the University of Maryland (p. 1877), is still making discoveries that shape the field. Jay Levy of the University of California, San Francisco, another tumor virologist who independently discovered HIV, says “AIDS is still an area where there are camps. Unfortunately, I don't see any difference.”
Ho and others are quick to acknowledge that competitive juices still flow strongly when different groups home in on the same target—such as the race to unravel the connections between HIV and chemokines (Science, 21 June, p. 1740). But the rivalries that clouded the field for a decade have dissipated. James Mullins, 44, a molecular biologist at the University of Washington, Seattle, who got caught in some of the early storms, has much enjoyed the climate change over the past few years. “I started sleeping a lot better,” says Mullins, “and I know many people did.”
The Birmingham and Manhattan projects
The new guard of AIDS researchers, who started out when the epidemic was first recognized 15 years ago, have climbed their way through the hierarchy and are now making their mark in many institutions. Nothing exemplifies the shift in the world of AIDS res earch so much as the new prominence of ADARC and UAB. These two powerhouses have become “remarkable forces” in AIDS research, says Bolognesi.
One gauge of just how remarkable they have become is their impact on the AIDS literature. A database of AIDS research papers put together by the Institute for Scientific Information in Philadelphia assesses impact by tallying the number of citations autho rs receive per paper. The database shows that for authors publishing 25 or more papers between 1993 and 1995, six of the top 15 researchers come from ADARC and UAB (see table). And their rise has been rapid: If the same analysis is done for publications in an earlier slice of time, 1988 to 1992, none of them even ranks in the top 25.
In parallel with their meteoric rise in the citations index, ADARC and UAB have displayed many other similarities. Both strongly link clinical and basic research, focusing on pathogenesis (how HIV causes disease). They both embrace a wide range of experti se, allowing clinicians to team up with primatologists, molecular biologists, immunologists, vaccinologists, retrovirologists, and, in the case of UAB, epidemiologists and behavioral scientists. And, although everything isn't lovey-dovey at both instituti ons, success has allowed them to grow at a blinding speed.
The UAB AIDS program started in 1985, when the school recruited Hahn and her husband Shaw. At the time, Hahn and Shaw were postdocs with Gallo, who was then embroiled in a vicious dispute with the Pasteur's Luc Montagnier over who discovered HIV. Shaw's P h.D. adviser, Albert LoBuglio, had joined UAB (he is now head of its cancer center) and made an offer to lure Shaw to Birmingham—a move some UAB researchers argued against. “The last thing they wanted was to touch people out of Gallo's lab,” recalls Hahn. But the offer was made and accepted, and UAB scored a double recruitment.
Hahn and Shaw soon began to publish their work in high-profile journals. “The science worked,” says Hahn. “We were able to be very productive outside of the sheltered structure of a big lab.” They also began to attract a cadre of other researchers. One im portant convert to AIDS research was Hunter, who previously worked on Mason-Pfizer monkey virus. “There's an enthusiasm here that by working together we can actually have an impact on AIDS research and on the disease itself,” says Hunter, who has headed t he NIH-funded Center for AIDS Research at UAB since its inception in 1988. Other converts were Casey Morrow, who switched from polio research to AIDS vaccine work; mucosal immunologist Jiri Mestecky; and pediatrician Richard Whitley. In addition, the grou p recruited many younger scientists who were just starting their independent careers, including Michael Saag, 40, who did a postdoc in the Hahn-Shaw lab and is now a top AIDS clinical researcher.
Today, UAB's AIDS program has a $25 million budget and a large faculty. Its 55 principal investigators, who are spread across several different departments, include such notable recruits as primatologist Patricia Fultz, drug-resistance specialist Victoria Johnson, epidemiologists Sten Vermund and Richard Kaslow, pediatrician Grace Aldrovandi, and behavioral scientists Ralph DiClemente and Laura Leviton. “One reason it is working here is that there's no sense that ‘This is my area, this my work, you stay o ut of it,’” says Fultz.
ADARC's $6.7 million budget means it has a considerably smaller program than UAB. And because many of the researchers do work in overlapping areas, the internal competition can get intense—separate papers on chemokine receptors just came out in the 20 Ju ne issue of Nature, for example, from different ADARC teams. Another difference with UAB is that ADARC, based in New York City, houses its diverse array of AIDS researchers under one roof—which begs a comparison to the Manhattan Project. “Well, we are in Manhattan, aren't we?” quips biochemist John Moore, 39, one of 11 staff investigators at the center.
ADARC was the brainchild of author and biologist Lewis Thomas, who encouraged Irene Diamond to invest money from the foundation that was set up with real estate profits made by her late husband Aaron into a basic research AIDS center. In 1989, the nascent center contacted Ho, who, after studying at Harvard University with virologist Martin Hirsch, had moved on to the University of California, Los Angeles. “I was actually a little surprised,” says Ho. “I was 36 at the time, and to head up something like th is, I just thought they were going to pick a more senior figure.”
Ho got the job, and with $11 million from the foundation and another $3.3 million from New York City, the center officially took over the seventh floor of the city's Bureau of Laboratories building in April 1991. (ADARC was then affiliated with New York U niversity, but last month was transferred to Rockefeller University.) “The place has developed more or less along the lines we had planned,” says Ho. “We have people with a lot of different backgrounds converging, and so we can do things extremely quickly .” ADARC's accomplishments can also be measured by its steady growth: In September, the center will nearly double in size when it completes the refurbishing of yet another floor of labs, and in short order plans to grow from 70 employees to 120.
As with the UAB researchers, the ADARC scientists depend heavily on each other for everything from reagents to know-how—and they are encouraged to work with outside groups, too. “That's the spirit of this place,” says Ruth Connor, 33, who concentrates on pathogenesis questions. Eric Delwart, 37, who studies the genetic diversity of HIV, says his generation has learned from the battles that marred the field for so many years: “We don't want to repeat it.”
Angling for results, not prizes
The success of younger investigators at leading AIDS research institutions such as ADARC and UAB helps to explain the cultural shift that is taking place throughout the field. But larger forces are also contributing to these changes. For one thing, the sc ience of HIV and AIDS has become vastly more complex. Although dramatic progress has recently been made in drug therapy, few scientists still entertain fantasies of finding the cure. Vaccine developers have also been humbled over the years. “In the beginning, people had more of the feeling that they'd be an overnight hero who would solve the problem and get great rewards,” says Salk's Trono. “This concept has changed because of the difficulty in solving the problem. Each of us can contribute someho w, but none of us on our own can do it.” UAB's Vermund, 42, adds: “There is this older culture that was very much tied up in Nobel Prize angling, and this got in the way of what the true mysteries were in the field.”
The scientific challenge, in effect, has matured the culture. “Back in the early years, every day counted,” says Joseph Sodroski, 41, of the Dana-Farber Cancer Institute in Boston, a virologist who did his postdoc with William Haseltine, who helped identi fy many of HIV's genes. “As the field matures and you get into structural biology, the development of vaccines or effective therapy, [you realize] those long-term questions are likely to be around for a number of years. It encourages people to feel cooperative.” Molecular biologist Mario Stevenson of the University of Massachusetts agrees. “Previously, when there were camps and big names taking chunks of the field, the research was not as inclined to look at very specific and fundamental issues,” says Stevenson, 39. “The field is more sophisticated now. There isn't this camp sense or mentality anymore, and people are more willing to interact.”
To David Baltimore, a Nobel Prize-winning retrovirologist who shifted into AIDS research relatively recently, the culture is becoming more civil because the questions being asked today have less immediate medical relevance. “I've learned that the more med ically relevant the question, the worse the social behavior,” says Baltimore. “When something is really hot and has direct medical relevance, people's behavior is atrocious. If you're working on something like Drosophila, people are much more colla borative and better behaved.”
Michael Emmerman, 37, a molecular biologist at the Fred Hutchinson Cancer Research Center of Washington in Seattle who did a postdoc in Montagnier's lab, says: “There are more people trained in this kind of biology and more people watching every step you make.” And many of these people, he notes, grew up together: “We're at the same time in our careers and we knew each other as postdocs and now know each other as assistant and associate professors.”
With the passing of time, the bitterness of the early disputes between the Gallo and Montagnier labs—which even ensnarled the leaders of their countries—has faded. The old battles live on in memory, and “it was an unfortunate period,” concedes Anthony F auci, head of the U.S. National Institute of Allergy and Infectious Diseases. “Not taking any sides about who's right or who's wrong, it lent a flavor to the field of ‘Gee, what a strange, bizarre field this was.’” Now, says Fauci, some young researchers have never heard word one about it: “I have young people coming into the field who don't even know what we're talking about. It's an era that passed them by.”
Although the hallmarks of the early AIDS research culture—vicious credit spats and backbiting—are less common today than they were a decade ago, the field is still highly competitive. And this means that the threat of divisiveness is ever present. Many of the younger researchers now leading the field remain on guard against an outbreak of the old ways. “It's not like the younger generation is immune,” says UAB's Vermund. Some have even witnessed backsliding lately. “In the past few years, I've attended conferences where I've seen clique, allegiance stuff popping up,” says the University of Washington's Mullins. “I've actually talked to people about it to help them remember history. We don't want to get back to that.”
But researchers of both the old and new generations seem to recognize that the main thing they must contend with is not the research culture, or peer competition, but their own ignorance. Despite recent progress in deciphering how HIV is structured and ho w it functions, the virus still has the upper hand, leaving plenty of unanswered scientific questions up for grabs.
AIDS Community: The Rebirth of Robert Gallo
- Jon Cohen
Baltimore-An area at the center of this city, called the Inner Harbor, is often cited as a model of urban renewal. Once in dire straits, it has been reborn as Harborplace, a mecca for natives and tourists alike. Robert Gallo is hoping that it will be a fitting venue to launch a second career. The retrovirologist recently ended a 30-year stint at the National Cancer Institute (NCI)—where his lab first published convincing evidence in 1984 that HIV causes AIDS—to run a brand-new institute just a few blocks from Harborplace. Known as the Institute of Human Virology (IHV), its launch, combined with a recent landmark paper Gallo co-authored, provides ample evidence that at least some old-guard researchers are still a force to be reckoned with.
“I have a desire to leave something behind when I die,” says Gallo, 59. That's an odd thing for Gallo to say, considering that he has been credited with speeding the development of the HIV blood test, which has saved lives. His NCI lab was also celebrated for discovering the chemical messenger interleukin-2 and the two human tumor leukemia viruses—the first of which proved that a human tumor virus really exists. If that weren't enough, Gallo and Fiorenza Cocchi, working with Paulo Lusso from Italy's San Raffaele Scientific Institute, on 15 December 1995 published in Science (p. 1811) a discovery about the role natural anti-inflammatory chemicals called chemokines play in the suppression of HIV—a finding that has opened up the hottest new area in the field (see p. 1885 and 21 June, p. 1740). But Gallo, a man who attracts scientific controversy in almost equal measure to his scientific achievements, is restless to prove himself once again. And IHV is the vehicle.
Set in a refurbished department store warehouse that boasts 100,000 square feet of usable space framed around a giant atrium, IHV—which will focus on battling AIDS and other viral diseases—is Gallo's dream come true. He has shed the bureaucratic shackles of the NCI, where he was the subject of a long-running scientific misconduct investigation into his role in the discovery of HIV. Among the material benefits of relocation: IHV will soon have its own clinic, so Gallo will no longer be forced to rely on clinical specimens from chance collaborations. The center is part of the University of Maryland (UMd), which will allow Gallo to interact with students—another plus, he says. Because IHV will have its own biotech partner, Omega Biotherapies, investigators will be able in theory to develop new treatments quickly (and also make money). “It's one of the most impressive facilities I've ever seen,” says Dani Bolognesi, a Duke University AIDS vaccine researcher. Gallo has “an opportunity there to do wonders.”
IHV is still in its infancy. But 12 scientists have already come on staff in four areas: Gallo is overseeing basic researchers, former NCI researcher William Blattner heads the epidemiology division, ex-Army AIDS researcher Robert Redfield heads the clinic, and Ed Tramont, the one-time head of the U.S. military's entire AIDS program, leads the vaccine division.
In addition to spending $52 million on the building and equipment, the state of Maryland has promised IHV $13 million over 4 years. “These became the carrots to attract [Gallo], Redfield, and Blattner,” says Tramont, who heads UMd's Medical Biotechnology Center and put the deal together. Another new hire is Mikulas Popovic, a virologist who aided Gallo's discovery of HIV and, likewise, was a subject of the misconduct investigation. (Both Gallo and Popovic were cleared of wrongdoing.)
Gallo, being Gallo, is not content with simply starting IHV, which he hopes will employ about 500 people. He's already thinking about expanding to a second IHV in Pasadena, possibly affiliated with the California Institute of Technology. “What attracts me is it opens up many more clinical possibilities and goodwill between the West Coast and East Coast,” says Gallo. Clearly, some of the old guard in AIDS research are ready for anything but retirement.
AIDS Politics: OAR Gets by With a Little Help From New Guard Friends
- Jon Cohen
In October 1994, a group of leading young investigators attending the Cent Gardes AIDS colloquium near Paris had a heart-to-heart talk with Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases (NIAID), in a challenge to the old ways of doing business. David Ho, head of the Aaron Diamond AIDS Research Center (ADARC) in New York, recalls that he and a dozen others told Fauci they felt that his staff at NIAID, the hub of AIDS research at the National Institutes of Health (NIH), was too heavily directing their research. “We sat with Tony and said, ‘It's rather unusual for so many middle officials at NIH to dictate to us what to do. Let more of the science be driven by extramural scientists,’” says Ho. “It was a great meeting,” says Fauci. “Ten, 20 years from now when people talk about how things evolved, that meeting has to come down as important.”
One reason Fauci describes the meeting as “pivotal” is because it led him to aggressively solicit “more input from younger researchers in the trenches who have the ideas.” But it was a symbolic moment as well. The meeting reflected a changing of the guard in AIDS research, as young researchers establish themselves as leaders in the field (see main text) and the center of gravity in U.S. AIDS research shifts away from NIH. That shift became evident to the outside world earlier this year when NIH's Office of AIDS Research (OAR)—a body shaped in large part by young researchers—completed a massive review of NIH's $1.4 billion AIDS portfolio. Its main recommendation: Extramural researchers should have more control.
Indeed, the recent history of OAR itself speaks of the growing political power of the new guard. The young researchers played an instrumental role in convincing Congress to pass legislation in 1993 that gave the then-obscure OAR the power to oversee the NIH's entire AIDS research portfolio. Not only did several prominent younger researchers like Ho lobby for the change, but they worked with AIDS activists who masterminded the OAR overhaul, which included replacing Fauci as its head with immunologist William Paul.
Mark Harrington, 36, a member of the Treatment Action Group, co-author of a critical review of the NIH's AIDS research program in 1992 that served as a reform manifesto, says activists like himself and younger researchers bonded as the clinical-trials network took shape in the 1980s. “It's there where we first met,” says Harrington. “We came up against the same powers-that-be that they mentored with and had to gain their independence from.” He says the younger researchers were more willing to have activists involved in designing trials: “They were closer to us. There were no barriers.”
The 1993 legislation also directed OAR to conduct a top-to-bottom review of NIH's AIDS research; again, younger researchers played a leading role. The same ones who met with Fauci at Cent Gardes were among the 114 members of the six subpanels that conducted the OAR review. And they were not the only representatives of their generation. “Take all the panels together, they're largely this generation [of younger researchers],” says Ho. The review, which OAR plans to release in full by next week, calls for sweeping changes (Science, 15 March, p. 1491).
Whether Congress will give OAR the muscle the new guard is seeking is a big question right now, as a House bill passed last week removed the office's ability to control the AIDS budget (Science, 21 June, p. 1733). Virologist Joseph Sodroski of the Dana-Farber Cancer Institute in Boston, a participant at the Cent Gardes meeting with Fauci, is confident that the OAR review will lead to important changes. “It looks to me like there's a sincere effort with people at the NIH to be more critical,” Sodroski says. Another participant of the Cent Gardes gathering, who asked not to be named, is more circumspect. “The old guard has maintained its position and has not really responded to the change and has protected their own turf,” this scientist says. ADARC biochemist John Moore, who also attended the Cent Gardes powwow, has deep misgivings as well: “I came out of the meeting very optimistic, and that optimism has completely disappeared.”
Paul, OAR's director, says he understands the young guard's concerns: “They've been good citizens, and they want to make sure that they don't get caught in that old saying, No good deed goes unpunished.” But he notes that even if the House language makes it into law, it gives OAR the power to move 3% of an institute's funds to any other program, without limiting the recipient. The report, promises Paul, won't be a paper tiger.
Money Matters: The Marketplace of HIV/AID$
- Jon Cohen
Thirteen years ago, when the public was just learning about a new disease called AIDS, the scientists tracking down the virus that causes it were already thinking about how their research could be marketed. French and American groups eventually claimed to have “co-discovered” HIV independently and in different ways. But in one respect their approach was the same: Shortly before announcing their discoveries, both rushed to file patents that described how to determine whether a person's blood harbored the virus. And thus they gave birth to the HIV/AIDS industry.
Today, the U.S. Patent and Trademark Office has awarded more than 1500 patents related to HIV and AIDS, and the Food and Drug Administration (FDA) has approved eight anti-HIV drugs, with a ninth in the wings. Companies are making millions of dollars on tests that screen blood for evidence of HIV and immune-system damage. And, while a few companies are interested in developing an AIDS vaccine, none has yet proved its worth.
Around this field of experimentation a vast body of business literature has grown up—an abundant, if not always reliable, source of information on the HIV/AIDS marketplace. Some of it consists of free reports written by Ph.D. or M.D. stockbrokers. Typically, these offer an HIV/AIDS 101 overview and, with little subtlety, attempt to persuade investors to place bets on this or that company. Other commissioned reports, which can sell for $5000 or more, aim to inform companies more objectively about how they should position themselves in the volatile and unpredictable HIV/AIDS marketplace. Even these vary in quality and reliability—not surprising, given that even government epidemiologists can't say whether the number of HIV-infected people in the United States is closer to 630,000 or 900,000. Still, these reports are important, in part because they inform the largest source of funding for AIDS research: private investors.
One comprehensive study, for example—a just-published review of the entire HIV/AIDS market sold by the financial analysts Frost & Sullivan Inc.—says that the industry targeted on HIV's nine genes and 17 proteins rang up $1.3 billion in sales last year. Just over half of that amount went to drugs designed to treat the opportunistic infections associated with AIDS. The rest of the money, $617.5 million, is linked to other parts of the virus, as shown in the illustration of HIV and a discussion of market forecasts below.
Drug Development: Protease Inhibitors: A Tale of Two Companies
- Jon Cohen
photo Last January, as Merck & Co. prepared to reveal data from a human trial of its new anti-HIV drug indinavir, Edward Scolnick, the head of the company's research labs, was beside himself with glee. The data on this inhibitor of the HIV enzyme protease, which the virus depends on to assemble itself properly, would cause “a complete paradigm shift,” predicted Scolnick. The trials showed that indinavir, when used with two other anti-HIV drugs that attack a different target, could reduce the amount of HIV in people so dramatically that the most sensitive tests could not detect any virus in more than 85% of the patients. “It's dynamite,” said Scolnick, predicting that this treatment would be “analogous to the first triple drug therapy for tuberculosis.”
It will take years to tell if Scolnick was right. But the data on indinavir and another protease inhibitor made by Abbott Laboratories called ritonavir have already caused a paradigm shift both for people living with the virus and for those studying it. The new results are dispelling a funk that has pervaded the AIDS field because of the mediocre success of drugs like AZT that target HIV's reverse transcriptase (RT). But these protease inhibitors, both of which were licensed by the U.S. Food and Drug Administration (FDA) in March, are a different story. Their early successes suggest that the hundreds of millions of dollars invested in AIDS drug studies may at last be paying off, and they have given a shot in the arm to a field that was desperate for some good news.
photo Merck and Abbott are but two of a dozen companies making protease inhibitors. Hoffmann-La Roche actually won the race to market, licensing a rapidly metabolized—and thus less effective—drug called saquinavir in December 1995. Agouron's nelfinavir may be licensed by early 1997, and Vertex/Glaxo, Nikko Kyoto, and Pharmacia & Upjohn all have products in human trials. At least half a dozen other companies have compounds in the preclinical phase. But it was the data from the clinical trials of the Merck and Abbott drugs that started researchers giddily talking about the new era of “guarded optimism.” And it was data from these trials that spurred the FDA to approve these drugs in record time.
The story of how Merck and Abbott sped their protease inhibitors from the lab bench to the pharmacy shelf is a study in contrasts, revealing how two front-runners ran the race with significantly different corporate, scientific, and political strategies. Now both face the same question: How long will their drugs' effects last?
Blood pressure, sweat, and tears. The work on protease inhibitors at Merck and Abbott owes much to pre-existing efforts to develop inhibitors of renin, another protease that regulates blood pressure. In 1987, the year both companies began searching for drugs that could find a chink in HIV's armor, AIDS researchers were just beginning to understand the critical role that protease played in making viable copies of the virus. HIV replicates by weaving its genetic material into that of a host cell's, which produces the proteins that can form new infectious virions. But protease must cut the freshly minted proteins into the proper size to make them work. So researchers tried to find a compound that could jam itself between the blades of the protease scissors and block the replication process. Chemists at both companies knew their mission was formidable.
Developers of renin inhibitors had wrestled with an identical, vexing problem: The part of the scissors that had to be jammed was hydrophobic, requiring a molecule that did not like water. But any drug that is not water-soluble would be difficult to take by mouth. Says Abbott chemist Dale Kempf: “We recognized very early on that oral bioavailability would be the key issue with HIV protease inhibitors as a whole.” But their work with renin gave Merck and Abbott scientists a head start on HIV protease inhibitors. “Intellectually, the approach wasn't out of the blue,” says Merck virologist Emilio Emini.
Although similar scientific challenges face the companies, upper management pursued them differently. Merck, a pharmaceutical Goliath that last year grossed $16.7 billion, went all out in January 1987. To Merck's Scolnick, developing an AIDS drug was critical for the U.S. biomedical community. “There was an enormous amount of pressure to do something about AIDS,” says Scolnick. “The community at large, academic and industrial, was on the line. … The backlash would be enormous if nothing was delivered.”
Abbott, which made less than 15% of its $8.2 billion in revenues last year from pharmaceuticals, did not get into the AIDS drug development business at all until May 1987. It launched a protease program in 1988, when it won a grant from the National Institute of Allergy and Infectious Diseases to do so. Abbott put just three chemists on the protease team. Kempf, who says he had heard that Merck had a few dozen chemists on its team, says “I remember walking down the hallway one day and someone giving me their condolences.”
Both companies soon met big obstacles. “It turned out to be a lot harder than we expected,” says Scolnick. Calamity struck at Merck in December 1988, when biochemist Irving Sigal, a leader in the protease program, died on the infamous Pan American Flight 103, which was blown up by a terrorist bomb. Other setbacks were more routine, as experiments built up hopes, then dashed them.
One of Merck's first big successes came when researchers discovered and published in the 16 February 1989 issue of Nature the three-dimensional structure of HIV's protease, a key advance. The molecule resembles a set of butterfly wings joined at an active site—the part responsible for snipping HIV proteins. With this computer image in hand, scientists could fine-tune the design of protease inhibitors, attempting to make a compound that would clog the active site.
Getting the design to work in a living system—rather than just in a computer model—is another thing, however. More often than not, the protease developers resorted to the standard way of finding a drug that works: trial and error.
Two giant leaps. For many months, all the scientists could manage were small steps. But in the 1990s, their protease research suddenly took two giant leaps.
After testing a few dozen renin inhibitors off the shelf, the Merck team found one that was potent against HIV and began tinkering with it, adding a chemical here and taking one off there. “Some of these compounds were as soluble as sand,” says Merck chemist Joseph Vacca. Once they had the protease structure, they saw places to add soluble molecules that they hoped would not hurt potency. They finally created an inhibitor that had good activity in the test tube, L-689,502, and, in March 1990, tested it on eight dogs. The animals suffered serious liver damage. L-689,502 was history, but Merck had at least learned some new manufacturing tricks.
At about the same time, an Abbott team was making progress on a parallel track. Led by John Erickson, chemists Daniel Norbeck and Kempf published in the 3 August 1990 issue of Science details of their first-generation protease inhibitors. By January 1991, they were in the clinic with what seemed a promising candidate. But the molecule was so large that the drug's oral bioavailability was pathetic.
The trial-and-error process continued over at Merck, which by then had attracted the attention of AIDS activists. In March 1991, the company made the then-unusual move of forming a community advisory board with these often strident agitators, who wanted to play a role in the company's drug-development effort. “The price of cooperation is tremendous criticism,” says organic chemist Paul Reider, who oversees the scale-up production of drugs. Nine months later, Merck chemists Vacca, Joel Huff, and Bruce Dorsey synthesized L-735,524. Now known as indinavir, or by the trade name Crixivan, the drug had high potency in the test tube and moved into animal studies that summer. No red lights flared. “It was remarkably clean in toxicity tests,” says Emini.
Early in 1992, Abbott synthesized ABT-538, and in August, Kempf presented data from rat studies at an in-house meeting. Not only was the drug, now known as ritonavir (trade name Norvir), incredibly potent, it stayed in the rats' systems for 6 hours—as compared to 90 minutes with the next-best candidate. “It was unbelievable,” says Norbeck.
In 1993, both indinavir and ritonavir began the climb from small safety tests to larger trials. Abbott, which the year before had been pilloried by AIDS activists for not allowing its preparation of HIV antibodies known as HIVIG to be tested (Science, 17 July 1992, p. 316), began trials in France in an “out-of-the-way site,” says John Leonard, head of AIDS clinical development at Abbott. “We were trying to be off the beaten path. Abbott was very sensitive to activists at that time.” Their drug often caused bouts of nausea. It also interfered with a critical liver enzyme, cytochrome P450, which was a double-edged sword: It slowed down the metabolism of ritonavir, causing it to remain active longer, but it interfered with the actions of many other drugs. Still, the data looked so positive that Abbott launched trials all over the world in sicker patients to see whether the drug could help them lead healthier, longer lives.
Despite the promising start, by January 1994, Merck was getting worried about indinavir. Within 6 months of starting treatment, patients were developing resistant strains of HIV. “We were pretty depressed at that point,” says Scolnick. “Had the next set of studies had similar results, I would have pulled the plug.” There was reason to hope, however. Virus levels had been knocked down so low in one patient, number 142, that researchers could no longer cultivate virus from his blood. And his count of white blood cells known as CD4s, used as an index of immune function, was rebounding steadily. The researchers asked themselves: If we can do it with one patient, why not others? Maybe the dose was too low. Merck's researchers increased it by 50%, and viral levels in the other patients started to drop and stay down. Merck quickly decided, like Abbott, to launch full-scale trials.
Ailing activists, seeking “compassionate use” of indinavir outside the trials network, began clamoring for the difficult-to-make drug. It was a demand the company could only partially meet. “We thought we had enough drug all the time, but the ante kept getting raised,” says Reider of his scale-up team
After 7 months, Abbott had data from a placebo-controlled study with 1090 patients showing that the drug, in combination with RT inhibitors, could cut the number of cases of AIDS-related disease and death in half. On 29 February 1996, the company asked an FDA advisory committee for permission to market ritonavir. After deliberating into the evening, the committee gave a thumbs up.
The next day, Merck presented the committee with results from three of its indinavir studies involving more than 550 people. The most impressive data came from the trial that had excited Scolnick, reporting that 24 weeks after starting indinavir plus the RT inhibitors AZT and 3TC, 20 of 22 people (90%) had no detectable HIV. CD4 counts had also seen significant rises.
Later that day, on 1 March, the FDA approved ritonavir and the advisory committee gave indinavir its blessing. Only 72 days had passed since Abbott had filed its request, setting a new FDA speed record for drug approval. And on 14 March, the FDA approved Merck's indinavir, a mere 42 days after the company's filing.
Coming up next. At the international AIDS conference in Vancouver, Canada, next week, ritonavir and indinavir are destined to be the stars. Researchers, health care providers, and media from around the world will celebrate the new era of therapy that these drugs have ushered in. But expressions of optimism are likely to be guarded, for sobering limitations still exist.
Ritonavir causes nausea in one-fourth of the people who take it (although it may be reduced by a new dosing schedule), and it interferes with the action of 23 drugs—a staggering list for physicians and patients to remember. Indinavir, which Merck has had trouble producing in adequate supply (a new plant comes on line this fall), causes kidney stones 4% of the time, and it must be taken three times a day either 1 hour before or 2 hours after a meal. Both drugs are expensive, now retailing for more than $6000 a year. And both must be taken every day, in combination with other anti-HIV drugs, forever. “Triple therapy is tough for people to take for 20 or 30 years,” acknowledges Scolnick.
Long-term use raises another problem, the most profound of all: viral resistance. When people forget—or refuse—to take their pills, they give drug-resistant HIV mutants a chance to multiply. Even at full dosage, resistance becomes more likely to occur the longer people stay on the drugs. And, as with AZT, people infected with protease-resistant strains will one day transmit them to others.
Inarguably, the protease inhibitors have pushed the resistance horizon out into the distance, as studies to be unveiled in Vancouver will show. One study will also show that the less bioavailable protease inhibitor saquinavir packs a surprising wallop when combined with ritonavir, suggesting that new, powerful combinations may soon be found.
Whether protease inhibitors will sustain today's excitement with enduring antiviral protection is something that will be revealed only with the passage of time. But for the moment—and it is one of the brightest moments in many years—the glass is at least half full.
Antiviral Therapy: Eradicating HIV From a Patient: Not Just a Dream?
- Elizabeth Pennisi,
- Jon Cohen
In 1993, Science polled 150 top AIDS researchers, asking them to list the outstanding questions hampering the search for a cure or a vaccine (Science, 28 May 1993, p. 1254). The key obstacle then facing vaccine developers—determining which immune responses can protect a person from HIV—remains. “We're no further than we were 3 years ago,” says David Ho, head of New York's Aaron Diamond AIDS Research Center (see p. 1888). But work by Ho and others has brought scientists much closer to answering two questions that topped the 1993 list regarding the search for a cure: Why does the immune system collapse, and how can HIV replication be controlled?
Indeed, a new understanding of HIV pathogenesis that has emerged over the past 18 months has led AIDS researchers to pose what was recently an unthinkable question: Can HIV be eradicated from an infected person? “If you would have asked me in January 1996, can we eradicate HIV, I would have laughed in your face,” says Julio Montaner, co-director of the Canadian HIV Trials Network and co-chair of the international AIDS conference to be held in Vancouver next week. But not now. Montaner and more than 80 colleagues, in fact, attended a conference in Washington, D.C., 2 weeks ago that focused on just that question.*
The excitement infusing the field stems from a mix of stunning results from both basic and clinical researchers. On the basic front, the labs of Ho and of George Shaw at the University of Alabama, Birmingham, showed last year how new, powerful anti-HIV drugs could uncover key mysteries—and their work has helped alter how researchers now discuss the disease process. In the clinic, Montaner and others have shown how new combinations of anti-HIV drugs can reduce viral levels in the blood so dramatically that it cannot be detected with the most sensitive tests (see p. 1886). “We're talking about complete suppression and the prospect of eradication,” pathologist Douglas Richman, of the University of California, San Diego, said at the meeting.
Ho and Shaw's work, in the 12 January 1995 Nature, has received much attention because it blew out of the water the popular notion that the long lag time between HIV infection and disease meant that the virus lay quiescent in the body for years. As Ho and Shaw demonstrated, billions of HIVs were being made and removed from the blood every day during that supposed latent period. HIV's genetic material thus passes through about 180 generations per year, says John Coffin of Tufts University, a staggering replication rate that establishes a large pool of mutants shortly after infection occurs. This leads Coffin to challenge the popular idea that HIV mutates its way around drugs; instead, he says anti-HIV drugs exert Darwinian forces that simply select for pre-existing viral mutants that can foil them.
That Darwinian point of view has recently led AIDS researchers to challenge another truism: the idea that HIV steadily confronts the immune system with ever more mutants until finally it wears down, and viruses can escape immune detection. In this view, viral diversity is bad. But molecular biologist Steven Wolinsky of Northwestern University and co-workers published a study in the 26 April issue of Science (p. 537) that reaches the opposite conclusion. They found that people who develop greater diversity shortly after infection fare better. In essence, extensive diversity reflects how the rapidly replicating virus behaves when confronted with a strong—not a weak—selective force such as the immune system. “This model predicts that if you treat early, when there's relatively limited diversity, you can abrogate infection,” says Wolinsky.
“Treat early” was one of the mantras at the D.C. meeting. John Sullivan, a pediatric immunologist at the University of Massachusetts Medical Center in Worcester, reported that his group has treated two 10-week-old infants, who were both clearly infected at birth, with a potent three-drug cocktail. Now, after 1 year, HIV is no longer detectable in these infants, and they have even begun to lose antibodies to the virus—a sign that eradication might have occurred. At Aaron Diamond, staff investigator Martin Markowitz and co-workers last August began treating recently infected adults with potent triple combos. If after 9 months, no HIV is detectable, and antibodies are declining, some patients may opt to stop taking the drugs.
Part of Markowitz's study includes looking for HIV in lymph nodes, which can harbor virus even when none is detectable in the blood. The fact that stalwart HIVs can hide out makes some researchers question whether anti-HIV drugs by themselves are, in most situations, powerful enough to eradicate the virus. “We have all the hoopla about antiviral drugs, and you get any virologists aside and they'll say this is not how we're going to win,” contends retrovirologist Jay Levy of the University of California, San Francisco. To clear all the virus from the body, Levy says, “it's high time we look at the immune system.”
Several researchers are evaluating a combination of strategies that links antiviral approaches with efforts to boost the immune system—which, after all, has a black belt in virus killing. Immune-based approaches under way include: using interleukin-2; using HIV vaccines; and removing people's white blood cells known as CD8s, expanding them (or engineering hardier ones), and then returning them. Blocking molecules on the surface of CD4 white blood cells known as chemokine receptors, which HIV apparently uses to infect cells, is a new, exciting possibility (see pp. p. 1885 and p. 1955). Levy has evidence that CD8s secrete still another as yet unidentified factor that can stop HIV in an infected cell from copying itself.
Even if researchers can figure out a way to remove every last vestige of HIV from some people, that doesn't mean patients will be cured. “It doesn't necessarily follow that dropping viral burden to zero will result in immunoreconstitution,” Louise Market, an immunologist from Duke University Medical Center in Durham, North Carolina, said at the meeting. Market and others suspect that one reason the immune system does not completely rebound in these powerful new drug studies is because HIV damages the thymus. Pediatrician Richard Hong of the University of Vermont has started treating patients with both triple-drug combos and thymus transplants. Market has a similar study in the wings.
In the past 3 years, AIDS researchers haven't solved all the questions of how to control HIV replication and prevent immune collapse. But they have discovered enough key pieces of the puzzle to see at least the outline of the answers.
↵* “Can HIV be eradicated from an infected individual?” sponsored by Antiviral Therapy and the University of Amsterdam, 12-13 June, Washington, D.C.