AIDS and HIV: Science, Politics, and Controversy, 1981-1993
As an expert on retroviruses it was natural for Varmus to become engaged in research on human immunodeficiency virus (HIV), the retrovirus that causes AIDS, in the years after it was first isolated by French researchers in 1983. He regarded scientists' experience combating AIDS as an example of the profound though often serendipitous role of basic science in understanding disease. Four decades of rapid advances in cell biology, virology, and genetics--including those made by Varmus and Bishop through their research on the genetic origins of cancer--had yielded insights into the life cycles of retroviruses. Knowledge of how retroviruses proliferate by copying their genes onto the chromosomes of the cells they attack made it possible to understand quickly the reproductive pattern of HIV and to begin to devise treatments. "We were trying to understand retroviruses because we were trying to understand cancer," Varmus explained. Yet, without these earlier genetic studies of other retroviruses, "we would have been many years slower figuring out what to do about treatment of HIV."
In his own research, Varmus focused on the basic biochemical and genetic properties of HIV which allow the virus to commandeer human cells for the purpose of self-replication. He conducted studies of how HIV genes are inserted into the genome of the cells they were first shown to infect, T-lymphocytes, key components of the human immune system. In particular, he studied the role of the protein integrase, an enzyme produced by HIV and other retroviruses that enables their genetic material to be integrated into the DNA of infected cells. Integration follows synthesis of the double-stranded DNA form (the proviral form) of retroviral RNA by the viral DNA polymerase, reverse transcriptase. Integrase then acts to insert proviral DNA into the host chromosomal DNA, a step which is essential for HIV replication and which therefore presents one potential target for drug intervention against the virus.
Varmus became involved not only in AIDS research, but in the politics of the disease, even before he had to respond to the demands of AIDS sufferers and activists as director of the National Institutes of Health in the 1990s. He stepped into an ongoing scientific and political controversy over the discovery of the AIDS virus and the use of this discovery when, in March 1985, he became chairman of a subcommittee of the International Committee on the Taxonomy of Viruses charged with the task of developing a uniform nomenclature for the virus, which until then had been called by several different names. The work of the subcommittee, which resulted in the designation human immunodeficiency virus, or HIV, touched upon sensitive issues of priority of discovery, scientific ethics, professional reputation and ambition, and national pride that were at the center of the larger controversy.
In January 1983, Luc Montagnier and collaborators in his laboratory at the Pasteur Institute in Paris, Françoise Barré-Sinoussi and Jean-Claude Chermann, found a retrovirus in the lymphoid tissue of a homosexual AIDS patient which they called LAV, for Lymphadenopathy Associated Virus, and which they assigned to the genus lentivirus. They suspected that LAV was the etiological agent of AIDS, although they did not rule out that other co-factors had to be present to cause the disease. They published their findings in May. In July and again in September Montagnier sent samples of LAV to Robert Gallo, an expert on retroviruses at the National Cancer Institute in Bethesda, outside Washington, D.C.
All along, Gallo was pursuing his own hypothesis regarding the cause of AIDS. In 1974, in his research on cancer-causing retroviruses, Gallo had discovered the first two lentiviruses in humans, HTLV-1 and HTLV-2 (for Human T-cell Lymphotropic Virus), which are associated with adult T-cell leukemia and lymphoma. In December 1983, he published four papers stating that AIDS resulted from an infection by a retrovirus similar to HTLV, which he claimed to have isolated and which he called HTLV-3. Gallo and Montagnier had agreed to share samples of the AIDS virus, publish jointly, and announce their findings together. Nevertheless, at a news conference on April 23, 1984, Margaret Heckler, the Secretary of Health and Human Services, and Gallo declared--in Montagnier's absence--that Gallo had isolated the virus that causes AIDS, that its name was HTLV-3, and that a blood test to screen patients and the nation's blood supply for the virus would soon be commercially available. The Pasteur Institute had previously filed a patent application for such a test. On the day of the news conference, Gallo filed a patent application of his own, which was soon granted by the U.S. government, while the Pasteur Institute's application was denied. A test, based on Gallo's patent, that probed for antibodies to protein antigens on the surface of the AIDS virus was developed in 1985, and remains the primary means for detecting the virus.
However, pictures of HTLV-3 shown by Gallo at the news conference bore little resemblance to images of HTLV-1 or HTLV-2, and suggested that it belonged to an unrelated family of retroviruses. Instead, the pictures proved identical to images of Montagnier's LAV virus. Further studies confirmed that Gallo's AIDS virus was in fact LAV, and raised suspicion that Gallo had improperly used Montagnier's viral isolate while failing to give Montagnier credit for first discovering the virus. In his defense Gallo claimed that Montagnier had applied methods for isolating the virus that had been developed in the course of Gallo's work on T-cells, that the virus Gallo had found had been inadvertently contaminated with Montagnier's sample, that Gallo was the first to prove the etiological relationship between the virus and AIDS, and that he had devised the blood test using a virus that he and his group had isolated independently. The controversy over the priority of discovery and the patent for the blood test was fought out in scientific journals, high-level diplomatic negotiations, and the courts. Montagnier and Gallo agreed in 1987 to share credit for the discovery, but allegations against Gallo have continued.
In lessened but nevertheless significant form, these issues played into the international effort, headed by Varmus, to decide on a name for the AIDS virus and its distinct types. Between March of 1985 and May 1986, Varmus solicited proposals for names of the virus from members of the subcommittee in the United States and abroad, as well as from other prominent virologists. Soon, more than a dozen names were under discussion. Gallo continued to insist on the designation HTLV-3, while Montagnier proved willing to consider alternatives to LAV.
Varmus repeatedly polled committee members regarding their preferences and weighed the results. He analyzed intricate matters of virology, such as the molecular differences between HTLV-1 and 2 and the AIDS virus, as well as between its immunorepressive properties and those of other viruses. He reviewed naming conventions and precedent. And he mediated discussions of issues that went beyond the laboratory, such as the impact inclusion of AIDS in the name would have on health policy and the relationship between clinicians and patients at a time of widespread public anxiety over the disease and stigmatization of people with AIDS. By May 1986, members of the subcommittee, including Montagnier (but not Gallo) proposed in a letter to the prominent journal Nature that the new virus be called human immunodeficiency virus, or HIV, with enumerated sub-categories, HIV-1 and HIV-2, respectively, for the common type of the virus and a second, much less common and less easily transmitted type also first isolated by Montagnier. To reach consensus, Varmus had to rely on his scientific expertise as much as his sense of discretion and diplomacy, qualities that would serve him well in his future career as NIH director.