The Gathering Storm

By Sarah Abrams

In 1978, as a third-year medical student doing his first clinical rotations at University of New Mexico Hospital, Richard Marlink was shown a patient with an extremely rare form of cancer. The attending resident explained that this malignancy, known as Kaposi’s sarcoma, typically was found only in older men of Mediterranean descent and was usually quite benign. He ended his talk by telling Marlink and his colleagues that this was probably the only case of Kaposi’s sarcoma they would see in their careers. He couldn’t have been more wrong.

As an intern at St. Vincent’s Hospital in New York City in the early 1980s, Marlink began seeing other patients with the characteristic bruise-like lesions of Kaposi’s sarcoma. These cases, however, were different from the one he’d seen as a medical student: the majority were young adults most of whom had other severe symptoms, including weight loss, swollen lymph nodes, pneumonia, and diarrhea. Few ever recovered. Marlink, now executive director of the Harvard AIDS Institute, based at the Harvard School of Public Health, recalls the frustration he and his colleagues felt as they saw patient after patient for whom none of the standard explanations applied. "We knew there was a syndrome," says Marlink today, "but we didn’t know what to do about it."

Richard Marlink, Executive Director of the Harvard AIDS Institute

By the time this mysterious new syndrome had a permanent name—acquired immune deficiency syndrome (AIDS)—thousands of people had already died from the disease and millions of apparently healthy people were carrying and silently spreading the virus that caused it. Since then, the AIDS epidemic has claimed at least 6 million lives worldwide, and an estimated 25 million people are now living with the virus. Within a decade, according to some estimates, as many as 100 million people may be infected. In certain areas of the world and certain populations, the epidemic has wreaked particular havoc. Over 90 percent of the world’s AIDS cases occur in Sub-Saharan Africa, North America, and Latin America. In the United States, where the disease first devastated the gay community, AIDS is now the leading cause of death for all African Americans under the age of 55. In Uganda, researchers estimate that one-in-four adults is now infected with the virus, perhaps foreshadowing a secondary epidemic of children orphaned by the disease. And in Thailand and India, skyrocketing infection rates portend an Asian epidemic that may exceed in scale and intensity anything seen to date.

Yet mortality and morbidity figures, no matter how staggering, can’t fully describe the impact that AIDS has had on the world. Not since the 1918 influenza epidemic has an infectious agent cut such a broad swath of destruction around the planet. But whereas influenza struck hard and fast and then passed on, AIDS has infiltrated the social body, exposing weaknesses and blindspots and challenging long-held beliefs about disease susceptibility and control. At the same time, AIDS has to a large degree revitalized the field of public health, exposing the limits of curative medicine and rejuvenating the search for preventive vaccines and effective behavioral interventions and creating a sense of urgency and global solidarity in the face of a mounting crisis.

Right from the start, faculty and alumni of the Harvard School of Public Health has played a key role in confronting the epidemic. From laboratory discoveries that have set the direction for AIDS vaccine and treatment research to important epidemiologic, data analysis, and human rights work, the School has been a major participant in the fight against AIDS.

In many respects, Max Essex was an unlikely hero in the AIDS saga. A veterinarian and virologist by training, Essex had spent most of his career studying the animal virus FELV, which causes cancer in cats. In the early 1970s, he had discovered that this virus also severely impaired the cats’ immune system.

By 1982, Essex, now chair of the School’s Department of Cancer Biology, was also researching the human T-cell leukemia virus (HTLV-1). Like FELV, HTLV-1 caused immune suppression—people infected with HTLV-1 had three times the rate of infection with bacteria and other viruses as uninfected people. Essex was struck by the similarities between symptoms of FELV, HTLV-1, and this new disease, and he was one of the first to suggest that the mysterious agent causing AIDS was, like FELV and HTLV-1, a retrovirus. Essex’s insight accelerated the discovery of the AIDS pathogen, now know as the human immunodeficiencyvirus (HIV), by the National Cancer Institute’s Robert Gallo and the Pasteur Institute’s Luc Montagnier the following year. For his role in identifying the cause of AIDS, Essex shared the 1986 Albert Lasker Medical Research Award—the nation’s most prestigious medical research award—with Gallo and Montagnier.

"Max catalyzed the notion that retroviruses were something to contend with, that they were disease-causing agents in animals, and that they could play an important role in humans," said Gallo in a 1988 interview in the hsph Alumni Bulletin. "He went beyond standard biological thinking about animal models. He looked at the importance of retroviruses broadly and widely."

Other important discoveries followed. In collaboration with scientific colleagues, Essex confirmed that the AIDS virus could be transmitted through blood transfusions. Further studies showed which viral antigens were most useful for blood bank screening. Working with a young research associate Tun-Hou Lee, S.D.’82, now professor of virology at the School, Essex discovered glycoprotein 120 (gp120), an envelope protein that plays a key role in HIV transmission and is seen as a promising target for an HIV vaccine.

In 1985, Associate Professor Phyllis Kanki, S.D.’85, Francis Barin, then a postdoctoral fellow at HSPH, and Essex uncovered evidence of a second AIDS virus, now known as HIV-2, when they found cross-reactive antibodies in West African sex workers. With Marlink and other French and Senegalese collaborators, a major research and training program was created that continues today. Their work has revealed that HIV-2 causes disease more slowly and spreads less readily than the more virulent HIV-1, and that people with HIV-2 are 70 percent less likely to become infected with HIV-1.

"Once we understand how this happens, we’ll know how to manipulate the immune system just as evolution did," Essex says. Because of "the utility of this discovery," Gallo ranked Essex’s work on HIV-2 among his major achievements.

Essex has said that the emergence of AIDS created a sense of urgency in his research that he still feels today. "With AIDS, I think we all felt that putting in the extra hours could make a big difference," he told a Boston Phoenix reporter last October. AIDS also awakened him to the global dimensions of infectious disease, and he has spent much of the last decade continent hopping from North America to Africa to Asia in an effort to finally outßank his adversary.

While laboratory scientists would be instrumental in identifying the causative agent of AIDS, some of the first clues about the nature of the epidemic were provided by hsph graduates working on the front lines of the epidemic. Don Francis, S.D.’79, had recently graduated from the School and was working in the Centers for Disease Control’s (CDC) hepatitis program when the first reports of gay-related immuno-deficiencydisease (GRID) began trickling in. The CDC and state public health officials had long been interested in the health problems of gay men because rates of sexually transmitted diseases, primarily gonorrhea, syphilis, and hepatitis B, among this population were so high. To find out why, CDC enlisted cohorts of gay men throughout the country to answer detailed questionnaires about their lives and sexual practices. Because they received treatment free of charge, says Francis, these men were "remarkably willing to answer a bunch of stupid questions from epidemiologists."

Max Essex, Mary Woodard Lasker Professor of Health Sciences and Chair of the Harvard AIDS Institute.

The data collected proved invaluable in understanding the transmission patterns of this new disease. Although no one knew what was causing the disease, once it was established that grid, like hepatitis B, was being transmitted through blood and sexual fluids, Francis felt sure it would also begin showing up in other vulnerable populations: recipients of blood transfusions and injection drug users. (Serum samples gathered from these cohorts in the 1970s and early 1980s would also shed light on HIV’s long incubation period.) It was Francis who called Essex, his former teacher, to alert him to this new disease.

As the epidemic took off, Francis’s boss, CDC Director William Foege, M.P.H.’65, appointed James Curran, M.P.H.’74, then head of the agency’s venereal diseases research branch, to head a national AIDS initiative. Curran quickly moved forward on establishing effective data collection and prevention programs. He also set up a national AIDS hotline to provide information to an increasingly alarmed public. Despite these efforts, Curran and other government officials and academics soon came under fire from AIDS activists for responding too slowly to the epidemic. Francis, who eventually resigned from the CDC in frustration in 1985 when Congress rejected his proposal for a comprehensive AIDS prevention program, says the CDC was continually undercut by the Administration’s lack of commitment to fighting AIDS.

"We were told to look pretty and do nothing," he says. "The (Reagan) Administration didn’t want to do anything for anybody. It lost all perspective for public health."

Curran has since been recognized by AIDS activists and medical experts alike for his clear, decisive leadership during a period in which the unknowns far outweighed the knowns. In his 1988 chronicle of the epidemic’s early years, And the Band Played On, journalist Randy Shilts wrote: "Under Curran’s leadership, the CDC had done an admirable job of collecting AIDS data. He had guided CDC AIDS research on a course that he felt was the best that could be done in a conservative administration."

"Curran pushed the CDC and the public health service hard to recognize the impending epidemic," says the Harvard AIDS Institute’s Marlink. "He organized much of our epidemiologic and prevention response."

Another alumnus who would play a central role in the AIDS struggle on the international front was Jonathan Mann, M.P.H.’80. Mann was working as an epidemiologist and assistant director of the department of health in New Mexico when Curran tapped him to serve as assistant to the director in charge of international activities in Kinshasa, Zaire. Working with Zairian, Belgian, and American colleagues, Mann established Project SIDA, providing training programs that drew upon the resources and skills of each country and collecting the first and most comprehensive scientific information on AIDS in central Africa. In 1985, Mann organized the first African AIDS Conference in the Central African Republic city of Bangui. The following year he left the CDC to develop and run the Global Programme on AIDS (GPA) at the World Health Organization (WHO). Under his leadership, the GPA’s staff expanded to over 200 and its budget grew from $20 million to over $100 million by 1990, making the GPA the largest single program at who.

During his years at both the CDC and WHO, Mann emerged as a pre-eminent spokesman for international health strategy reform in AIDS control, emphasizing the need for greater government involvement in AIDS research and prevention and increased attention to regional and local needs in establishing programs. But above all, Mann spoke out for the rights of those infected and against the discrimination to which they were subjected. To combat the disease effectively, he believed, human rights issues must become a priority.

In the fall of 1990, Mann returned to the Harvard School of Public Health as professor of epidemiology and head of the Global AIDS Policy Coalition, established to track the epidemic worldwide. Under the direction today of Daniel Tarantola, the program is at the heart of monitoring the pandemic, circulating information through articles, AIDS textbooks, interviews, and participation at conferences.

By 1987, the number of AIDS cases reported to the World Heath Organization was over 100,000. While experts recognized AIDS as a global phenomenon, tracking the disease was complex, as the pandemic evolved, changed, and rapidly expanded. In countries where infection had once been spread predominantly through homosexual contact, infection rates among heterosexuals were on the rise. Minorities and marginalized populations—such as intravenous drug users—were especially vulnerable. And the disease was making inroads into countries once labeled as low-risk.

Within the AIDS research community, early hopes for a swift solution had given way to the sobering prospect of a long, arduous struggle against a highly adaptable killer. After the initial, promising burst of discoveries about HIV, the pace of research had inevitably slowed. With each new finding, the puzzle of HIV/AIDS seemed to grow more complex. Every aspect of this seemingly simple organism—its sugar-coated outer shell, which cloaked it from the body’s defenses; its sloppy reproductive apparatus, which generated a continuous series of new mutations; the discovery of different subtypes of the virus—favored its continuing survival and spread. Frustrated researchers stopped talking cures and vaccines and began calling for more basic research on the virus itself.

In an effort to spur a new push toward a solution to the crisis, President Derek Bok and Dean Harvey V. Fineberg convened a group of AIDS experts from the School of Public Health, the Medical School, and Harvard’s affiliated teaching hospitals to discuss how to integrate and advance Harvard’s diverse AIDS-related activities. "If we are to meet the challenge of AIDS," Fineberg said at the time, "we must mobilize all the intellectual and academic resources at Harvard’s disposal." The discussions resulted in the creation of the Harvard AIDS Institute, which drew together the University’s formidable body of AIDS expertise included leading figures in virology and vaccine research (Essex and Lee, the late Bernard Fields of Harvard Medical School), AIDS treatment (Massachusetts General Hospital’s Martin Hirsch, the Deaconess Hospital’s Jerome Groopman, and others), epidemiology (Professor Nancy Mueller, Marlink, Kanki, and others), molecular biology (William Haseltine and Joseph Sodroski at Dana Farber Cancer Institute), statistical modelling and clinical trials design (Professor Steven Lagakos and Associate Professor Victor De Gruttola, S.D.’86) and AIDS law and policy (Lawrence Gostin, Harvey Fineberg, and the late William Curran).

Officially unveiled in 1988, the Institute, under Essex’s direction, has been a catalyst for research and training on AIDS. As hoped, the Institute’s creation helped accelerate AIDS research across the university (Harvard ranked first among academic institutions in the number of papers its researchers published on AIDS between 1988 and 1992). The Institute has also succeeded in focusing attention on AIDS and AIDS research locally, nationally, and internationally, through Institute-sponsored lectures and forums and conferences—including large panel discussions as well as informal, brown-bag lunches. In addition, the Institute has served as a bridge between the academic world and the broader public realm of AIDS activists and advocates.

"From the very beginning, Dean Harvey Fineberg saw AIDS as a public health issue and believed that there was a role for the public health advocates," says Larry Kessler, executive director and one of the founders of AIDS Action Committee (ACC), Boston’s leading service and advocacy organization for people with AIDS. Kessler also credits Essex, Groopman, and other Boston-area physicians and researchers with recognizing early on the need to integrate clinical treatment with the services offered through AIDS Action’s "social safety net" —particularly in light of the few treatment options available at that time. As the disease has proliferated, the connection between the advocacy group and the research institution has only become stronger, says Kessler. Each organization had something valuable to teach the other. "While we learned about immunology, the docs learned about the psychosocial issues," says Kessler. It was a relationship that would also prove critical when volunteers were needed for clinical trials of new drugs: Harvard researchers turned immediately to AAC, whose clients trusted the organization to steer them in the right direction.

"We don’t even have to work at it," says Kessler of AIDS Action’s continuing "good connection" with the Institute and School. "It’s in the fabric of what we do."

By 1987, when the first anti-HIV drug, AZT, was approved by the Food and Drug Administration the demand for safe, effective treatments had reached a fever pitch. Desperate for answers, people with AIDS demanded more attention from government, scientists, and the pharmaceutical industry, clamoring in particular for quicker access to experimental drugs. In 1989, the analysis of AIDS drugs received a big boost when the National Institutes of Health selected Harvard’s Statistical and Data Analysis Center (SDAC) to analyze and interpret data from most of the federally funded clinical trials of AIDS drugs around the country. Over the next eight years the center would help analyze over 300 clinical trials involving some 37,500 people and provide critical insights about the treatment of AIDS.

Phyllis Kanki, Associate Professor of Pathobiolgy, has helped shed light on HIV-2, HIV-1's less virulent cousin.

By the early 1990s, the emerging picture was that of a relentless epidemic involving shifting demographics. Nearly 2.5 million people had died from the disease, and more than 12 million people were now infected with HIV, a 120-fold increase from a decade earlier. Women now represented 40 percent of the total AIDS cases. Experts were describing the epidemic as "dynamic, unstable, and volatile." While the great majority of AIDS cases continued to be found in Africa, the United States, and Latin America (90 percent of all adult AIDS deaths to date), the infection rate was rising dramatically in Asia, where the disease had been virtually unknown a decade earlier. By the end of the century, experts now warned, Asia could become the epicenter of AIDS.

Two events that took place in 1992 dramatically underscored the need for international collaboration in responding to the pandemic. The first was the Eighth International Conference on AIDS, co-sponsored by the Harvard AIDS Institute. The second was publication of AIDS in the World, the first effort to define the epidemic’s global contours, by the School’s Global AIDS Policy Coalition.

The Eighth International AIDS Conference will be remembered as much for the political drama that preceded the conference as for the scientific material presented at the conference. U.S. laws refusing entry to HIV-infected individuals prompted a showdown of sorts between the Bush Administration and conference planners, who threatened to move the conference overseas if the laws were not lifted. Two years earlier, at the Sixth International Conference on AIDS, the normally soft-spoken and reserved Essex had strongly condemned the government’s stand: "This policy...threatens the free and open exchange of information which is critical to international efforts to conquer the AIDS epidemic. There is no sound public health justification for these restrictions."

Ignoring appeals from activists, academics, and foreign governments, the U.S. government refused to lift the ban, and the Institute, in partnership with the Dutch Foundation, moved the conference to Amsterdam, naming Jonathan Mann as conference chair. AIDS activists and the international scientific community cheered Harvard’s principled stand. AIDS Action’s Kessler, whose organization had been involved in planning the conference, says that while his organization was excited to see the world come to Boston for the conference, he supported Essex’s decision to move the conference to ensure that people with AIDS would be able to participate. Despite the eleventh hour change of venue, the conference drew more than 10,000 scientists, clinicians, and activists, a remarkable show of solidarity in the midst of a mounting global crisis.

The full scope of this crisis was brought into sharp relief with the release of AIDS in the World by the School-based Global AIDS Policy Coalition. Edited by Mann, Daniel Tarantola, and Thomas W. Netter, the book detailed, region by region, the status of the pandemic and the global response to it. Describing the epidemic as "spinning out of control" the report’s authors predicted major AIDS epidemics in Asia and Oceania and projected that, by century’s end, as many as 100 million people would be carrying the AIDS virus.

The publication, updated and revised in 1996, helped crystallize some of the key principles of HIV/AIDS and related risk behavior to larger societal issues. It also breathed a new sense of urgency and purpose into AIDS research. "We tried to plead for an expansion of the response to AIDS," said Tarantola, "to define what needed to be done from a societal perspective—what social interventions needed to take place." The conceptual approach found in both editions, said Tarantola, was employed in two important development efforts. As a result of the publication, the United States Agency for International Development (UNAID) moved from looking at prevention to looking at treatment issues, and the unAIDS (the Joint United Nations Programme on HIV/AIDS) strategy broadened from condom distribution and AIDS education and treatment into an expansion of these strategies to look at social issues.

Almost 10 years after its creation, the Institute continues to bring the research conducted at Harvard and elsewhere to bear on the epidemic and to create solutions for ending the epidemic. Recent research yielded significant information about HIV-1 subtypes, of which there are no less than 10. Essex’s laboratory found that subtype E, the cause of an explosive rise in HIV-infection in Thailand, is spread very efficiently through heterosexual intercourse, unlike subtype B, the subtype found most frequently in the United States and Western Europe.

The Institute’s search for a vaccine, under the leadership of Professor Tun-Hou Lee, is also progressing. Based on a process called "selective deglycosylation," in which sugar molecules are selectively deleted from gp120’s surface, this work could lead to vaccine trials within a year. In editorials, Essex has continued to push for development of a cost-effective preventive vaccine that can help relieve the growing AIDS burden in developing countries.

But where the Institute continues to do the most good, says Marlink, is in the role of advocate—inßuencing and pushing for important AIDS-related issues. A good example, he says, is hai’s Madison Project, which helped propel the government to establish a national AIDS research agenda. Under the auspices of the Harvard AIDS Institute, some of the country’s leading AIDS experts, government officials, and activists—including Essex, Larry Kessler, Robert Gallo, and National Institute of Allergy and Infectious Diseases head Anthony Fauci—assembled in two separate sessions in 1992 to design a model for establishing a national AIDS research program. The group’s work, says Marlink, provided the incentive for federal action in establishing the Office of AIDS Research.

Today, Institute faculty are working to have the same impact on vaccine research and testing in developing countries, one of the Institute’s highest priorities. The Institute recently held the fourth of six, three-day long conferences, at which leading AIDS researchers met to discuss strategies for developing a world-wide AIDS vaccine, a project that Marlink says combines two of the Institute’s greatest strengths: its discoveries on the basic mechanisms of the AIDS viruses—the different subtypes and types—and its international collaborations.

Institute faculty are also concentrating on ways to curb the epidemic in two of the United States’ most vulnerable groups: African Americans and young people. Today, the African American community is losing more of its young members to AIDS than to any other cause of death, before heart disease, cancer, and homicide. With the help of African-American leaders such Henry Louis Gates, Jr., head of Harvard’s W.E.B. du Bois Center for African American Studies, medical school psychiatrist Alvin F. Poussaint, and Children’s Defense Fund founder Marian Wright Edelman, the Institute recently launched Leading for Life, an educational campaign focused on stopping the epidemic from making further inroads into communities of color.

To stem the tide of HIV infection in America’s youth (one-half of all HIV infections in the United States are in people under age 25), the Institute recently teamed with the Center for AIDS Prevention Studies at the University of California at San Francisco to convene a group of youth-focused media and marketing experts to develop new marketing approaches to HIV prevention. Together they discussed such strategies as condom advertising on cable and network television and incorporating responsible sexual health messages into film, radio, and television programs geared toward young people.

Less than two decades after the first cases of AIDS were reported, almost 6 million people have died from the disease, one million of whom were children. Approximately 22 million people are now living with HIV or AIDS, and, last year, over 3 million new HIV infections occurred. Some recent trends appear encouraging: In some industrialized countries, in parts of Africa, and among some populations in Thailand, HIV prevalence is either decreasing or stabilizing. AZT has been shown to block a majority of perinatal HIV transmission. And new combination therapies using powerful protease inhibitors have delayed many deaths from AIDS. But the battle against AIDS is far from over. More than 90 percent of the people affected by the disease cannot afford existing treatments, and development of vaccines to stop the disease’s further spread is still several years away.

Until then, the School’s researchers, faculty, and alumni will continue their vanguard efforts, tracking the epidemic, devising better prevention strategies, uncovering the most effective drug treatments, searching for a vaccine, and pushing to keep AIDS at the top of national and international policy agendas. As a principal player in the AIDS effort over the last two decades, Jim Curran, now dean of Emory University’s Rollins School of Public Health, sees the School’s contributions to curbing the epidemic as indispensable.

"From the dean down, the School has provided important leadership in controlling this disease," says Curran. "From its public policy and human rights work to its work in the laboratory and AIDS modelling, its contributions are irrefutable."