Saturday, 15 May 2010

Who discovered the AIDS virus?

By Sanjay A Pai

Once it became evident that a new disease had emerged, the race to discover the pathogen that caused it began among scientific researchers on two continents.

Every once in a while, scientists discover – or stumble across – a new disease or condition. Just some examples in the recent past include Legionnaire's disease, Swine flu, SARS and Ebola haemorrhagic fever. In fact, in August 2007, WHO announced that during the 40-year period, 1967-2007, at least 39 new pathogens (organisms causing disease) had been discovered. By far the best known of these new diseases that we have had the misfortune to encounter is AIDS.

The origins of AIDS is not known and, indeed, is unlikely to ever be known. What is known with certainty is how and when it manifested first or at least was first recognised in the United States of America.

The story of the early years of AIDS has an intriguing plot-line – mysterious illnesses cropping up in a discriminated, stigmatised population, then spreading to other groups, a government choosing to ignore the illness, death of a screen idol, the beginning of people power in influencing government spending on health issues and not least, a heated controversy over who discovered the virus that caused the disease.

In late-1980 and early-1981, physicians in California noticed an increase in the incidence of Pneumocystis carinii pneumonia (PCP), while physicians in California and New York City started seeing many cases of Kaposi's sarcoma in young male homosexuals. Neither was a "new" disease, yet physicians were perplexed by their appearance.

Kaposi's sarcoma was a form of a slow-growing tumour of the blood vessels seen mainly in older people, was common among Africans, but was extremely uncommon in America. PCP was seen at the extremes of age and in the terminally ill. For these two diseases to present in otherwise apparently reasonably healthy people was perplexing. Moreover, the Kaposi's sarcoma, unlike the type seen in Africa, was highly malignant. Seeking to find a commonality between the patients who had these diseases, scientists soon discovered that many of these patients were either gay, or were intravenous drug addicts or were Haitian.

Michael Gottlieb, physician and immunologist at the University of California Los Angeles Medical Center, and his group published a report in Morbidity and Mortality Weekly Report (30:250-252), a publication of the Centers for Disease Control and Prevention, on June 5, 1981, informing physicians about the epidemic of PCP in young, male homosexuals. Soon after, on July 3, 1981, appeared a report in the same journal, on the epidemic of Kaposi's sarcoma in gay men.

The term used for this disease initially was Gay-related immunodeficiency disease (GRID), while some referred to it as "gay cancer" or "gay plague". That this term was quite incorrect was soon obvious when it was realised, by July 1982, that some haemophiliacs who had received blood transfusions and factor VIII concentrates had also developed the disease. Factor VIII is one of the proteins in the blood, which plays a major role in clotting of blood. Absence or reduced amounts of this factor leads to haemophilia. Treatment of this condition is by giving patients large amounts of factor VIII, which is done by pooling samples from many donors. The name "acquired immune deficiency syndrome" or AIDS was now adopted.

The year 1982 saw the emergence of the disease in European countries and in Africa. By January 1983, reports had come in of heterosexuals with the same disease.

Scientists were soon involved in a race to discover the organism which caused this disease. One such group was led by Robert Gallo of the National Cancer Institute, National Institutes of Health, Bethesda, USA. Gallo was a noted researcher who had just discovered the HTLV-I and HTLV-II viruses, which were retroviruses which were known to cause some leukaemias. Retroviruses are viruses composed of RNA and which contain an enzyme called reverse transcriptase which can transcribe RNA into DNA.

Another group was that of Luc Montagnier of the Institut Pasteur in Paris, France. Montagnier headed the viral oncology unit and was doing research on viruses, particularly retroviruses, from the early-1970s, to determine if they caused cancer in humans. Their research involved working with T-cell cultures, which are pure growths, in Petri dishes, of T-lymphocytes, a type of white blood cell.

Towards the end of 1982, when AIDS had appeared on the scene, Montagnier and his group decided to investigate whether a retrovirus was the cause of AIDS. Gallo had already suggested that this was a strong possibility. The Paris group was in a position to perform this research as they were already working on the problem of retroviruses, using human T cell cultures. Using fresh lymph node (a lymph node is an oval, solid, localised collection of lymphoid cells in the body and plays an important role in the body's defence against organisms) tissue from patients with AIDS, Montagnier's group, by January 1983 had isolated a new retrovirus which they christened LAV (Lymphadenopathy associated virus). On May 20, 1983, they published a paper in Science (Barre-Sinoussi et al, 220:868) suggesting that LAV was a virus associated with the disease.

They did not make the claim that LAV was the causative organism of AIDS. It is important to note the difference between the two terms – an association only means that the virus is seen in patients with the disease. Whether it is the cause of the disease or whether it is coincidentally present, as a "passenger" is not clear. A causative relationship however, clearly shows a cause and effect relationship.

Subsequent to discovering the virus, the Paris group shared samples of the virus with Robert Gallo's group at the NCI in July 1983 and September 1983. By December 1983, Gallo's group had succeeded in cultivating a virus. In April 1984, Margaret Heckler, secretary of health and human services, USA, announced at a press conference that Gallo's group had discovered a virus called HTLV-III, that caused AIDS and that one could expect soon, a diagnostic test as well as a vaccine, for the disease. Gallo also filed a patent application for a diagnostic blood test for AIDS. Immediately, industry got into the act and applied for licences to manufacture a commercial diagnostic test.

In May 1984, Gallo and others published papers in Science (224:500), proving that HTLV-III was the retrovirus which caused AIDS.

In June 1984, at a joint press conference held by Gallo and Montagnier, it was announced that the two viruses, HTLV-III and LAV were probably the same. The similarity between the two viruses suggested that there had been a contamination (a mix-up of sorts) in Gallo's laboratory. For the next three years, there existed turmoil in the research field of AIDS while Gallo and Montagnier had a dispute over which group had actually made the pathbreaking discovery. Montagnier's group challenged the US patent in court and finally decided, out of court, to share the credit.

The dispute extended even to the name for the virus: while the French group referred to it as LAV, the American group insisted on calling it HTLV-III. Finally, the International Committee on the taxonomy of viruses, in May 1986, adopted the name Human Immunodeficiency Virus or HIV. After much controversy and bad blood, the issue was finally settled.

In what was an unprecedented event, in March 1987, it was the heads of government of the two nations who made an announcement about biomedical research and priority. President Ronald Reagan of the USA and Prime Minister Jacques Chirac of France announced that Montagnier and Gallo were to be considered joint discoverers of the virus.

The reason for the dispute extends well beyond merely the quest to be first to do something in scientific research – it involves patents, royalties and possible prizes including the Nobel prize. It is significant that both have already been awarded the Lasker award for their work on the AIDS virus. (Gallo, in fact, has been awarded two Lasker awards – the earlier one was for his work on the viral origins of cancer). The Lasker awards, established in 1945, have been termed "America's Nobels" and are among the most, if not the most, prestigious awards in medical research. Significantly, 75 Lasker award winners have gone on to win the Nobel prize subsequently.

In November 1990, a study performed by a group at Roche, on the request of the Office of Scientific Integrity at the National Institutes of Health, on archival samples from the Institut Pasteur and the NCI, showed that the virus isolated by Gallo was the same as that discovered by Montagnier. This settled the issue finally and today, it is accepted that while Montagnier's group was the first to identify HIV, it was Gallo's laboratory which first made the definitive, causative association between HIV and AIDS. Moreover, Gallo et al were the first to grow the virus in an immortalised cell line. (Immortalised cell lines are cells which are grown in culture in a laboratory under controlled conditions and which can proliferate and grow indefinitely. Most cell lines have a limited life span). Finally, Montagnier's work in retrovirology was largely dependent on an earlier discovery by Gallo for growing T-cells in cell lines in the laboratory by using interleukin-2, a cytokine or chemical messenger secreted by helper T-cells, which helps proliferation of T-cell cultures.

Remarkably, Alison Rawling of the Department of Social Work and Social Policy at Sydney University, Australia, in New Scientist (September 22, 1990), writes a fascinating account of what the scientific community seemed to believe about the actual discoverer of HIV. Rawling used the science citation index, which is a rough way of establishing how important a paper is. The citation index developed by Eugene Garfield of the Institute for Scientific Information, Philadelphia, is a useful, interesting and controversial concept and is the number of times a particular paper is quoted by scientists in the bibliography of their own research papers. (Thus, the citation index is roughly like a batting average in cricket – the higher it is, the better a batsman is likely to be. However, like with batting averages, a citation index is not fallible and has its own follies).

Rawling showed that the paper by Montagnier's group was quoted only 27 times in the first six months while the paper by Gallo et al was cited 115 times in the first six months (1983-84.) After this, during the controversy over the priority of discovery of the virus, citations to Gallo's paper reduced while those of Montagnier's group increased. Citing both papers was also a common phenomenon. However, after 1987, when the controversy was resolved and the two scientists agreed to be considered joint discoverers of the virus, one might expect the number of citations for the rival groups to be roughly equal. Yet, Rawling found that the scientific community has quoted Montagnier's paper more than that of Gallo.

Theories are not lacking for the origin of HIV. There was, some years ago, a strong belief that accidental contamination of the cell lines used for the production of the vaccine against polio may have led to a virus "jumping" from animals to man, but this was later disproved.

Some suggest that HIV is the result of biological warfare research having gone awry. Peter Duesberg, noted scientist at UC Berkeley, California, USA, believes that HIV does not cause AIDS and that the cause is yet to be discovered. This theory, however, is not considered seriously by most investigators.

(Sanjay A Pai, is Consultant Pathologist and Head, Department of Pathology and Lab medicine, Columbia Asia Hospital, Yeshwantpur, Bangalore.)

InfoChange News & Features, March 2008

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