VIRUS HUNTERS

By Jad Adams

AIDS The HIV Myth, 1989

The cancer viruses

It had long been observed that in a flock of chickens if one had cancer, many would get it- unmistakable swollen tumours and a wasting away of the animal. Obviously this was of some interest to poultry farmers and to people who kept a few chickens in the back yard. But cancer scientists took an interest in this humble fowl disease. Why should so many get the cancer? Was it something in their feed? Something in the air? Were they passing it on like an infectious disease? This was a problem: conventional wisdom says cancer is not infectious.

The tumour itself, if transplanted, would cause the same tumour in the recipient. Peyton Rous at the Rockefeller Institute for Medical Research examined this phenomenon in 1910. Filters were commonly used to separate bacteria - at that time the smallest known infectious agents - from the matter they were infecting. Rous pulverised a tumour, filtered it and tested the ‘filtrate, on tumour-free animals. It caused a tumour in the new fowl. There was an infectious agent in the filtrate which caused cancer.

This was a major breakthrough in medical research. It shared the distinction with other great breakthroughs in medicine of being ignored at the time. As Renato Dulbecco writes in his memoir on Peyton Rous: ‘For about forty years this momentous discovery had little impact, because the minds of scientists were not prepared to think of viruses as agents of cancer. It was expedient to say that the chicken tumour was not a cancer, but some kind of reaction to the virus more akin to inflammation than neoplasia, and perhaps a peculiarity of chicken biology. Peyton Rous soon recognised himself that the tumour would not be accepted as a cancer because it was a cell-free extract,’ (i.e. only something smaller than cells would penetrate the fiIter).

This reaction is interesting in the light of the behaviour of scientists on the establishment side of the AIDS industry when their position is challenged by new data: first, restate accepted rules as if they are fact; second, question your opponent’s powers of observation and, by implication, scientific skill; third, concede that there may be an exception in this case but it is peculiar and in no way contradicts the general rule. Attacks on the establishment position, however, are welcomed with an extension of theory which is restated to such an extent that it is difficult to extricate the facts from the theorising.

Rous identified another two chicken viruses in the following years until lack of recognition, and the demands of the First World War made him leave this work. During the war he developed a solution for suspending the red cells of blood so they could be used for transfusion. This is still in use and is known as the Rous-Turner solution.

The turning point was the independent discovery in 1933 by Richard Shope of a tumour of cottontail rabbits which seemed to be transmitted by a virus. Rous returned to studying tumours in animals, his open mind leaving him increasingly uncertain about the role of viruses in cancer over the next three decades. Viruses seemed to be changing, to be showing variation - sometimes they produced tumours, sometimes they did not. Rous’ guiding principle, as a model of good sense, is worth repeating: ‘How far should one be led by the assumption that certain tumours may be due to viruses? Only so far as to make tests with these growths. The tumour problem has withstood the most corrosive reasoning. Yet since what one thinks determines what one does in cancer research, as in all else, it is as well to think something. And it may prove worthwhile to think that one or more tumours of unknown causes are due to viruses.’

The theory was a tool of thought, not a master of it. Rous was awarded the Nobel Prize for his work in 1966. He was eighty-seven and was to die four years later. It had been fifty-six years since he made the discovery which earned him the prize.

That there were infectious diseases was not news. Chinese accounts of the tenth century BC report a disease which is almost certainly smallpox. Vaccination against the smallpox virus was known at least from the eighteenth century AD. It was not known what this infectious agent was until the bacteriologists Frederick Twort and Felix Herelle. in 1915 and 1917 respectively, identified viruses within bacteria They demonstrated that viruses were separate particles much tinier than bacteria. It is now known in fact that there are some viruses almost as large as bacteria and some bacteria as small as viruses. Identification and classification of viruses has continued through this century Because their small size was shared with some bacteria this could not be used as the distinguishing feature of them. It was thought that their inability to replicate outside a cell they were infecting could be used as a distinguishing characteristic but this too is shared with some bacteria which more commonly are complete organisms. Now viruses are characterised by their simple organisation and their means of replication: a virus is a bundle of genetic material wrapped in a protein coat. It does not contain sufficient mechanism for its own replication but must enter a cell in a host - and there are plant as well as animal viruses - in order to use part of the mechanism of the cell to reproduce itself.

Cancer research

The direction which AIDS research took is so deeply rooted in the history of cancer research in the second half of this century that it is necessary to know a little about cancer before it is possible to understand why cancer laboratories and cancer researchers took such a leading role in research into AIDS.

Knowing about chicken cancers is all very well, but common sense indicates cancer in both humans and animals relates to the division of body cells, the way they reproduce themselves. At some stage in life, almost always in later life, an organ begins to overproduce cells which invade the surrounding tissues. Often this is followed by a spread to other sites in the body by way of the circulatory systems: referred to as metastasis. Of the one hundred different forms of human cancer, each have their own age of onset, rate of growth and tendency to spread. Cancer is not reversible though it can sometimes be attacked with radiation or surgery, both of which will destroy a tumour, or far less successfully with drug treatment (chemotherapy). Very occasionally, spontaneous remission does occur and a patient recovers.

There seems to be a programme to turn on cancer at a particular age in particular people but what is it that turns the disease on? Environmental factors certainly have some effect: workers in the leather industries suffer from bladder cancer because of the chemicals they use at work; smokers suffer more lung cancer than non-smokers. Apart from this small percentage of environmentally induced cancers - and cancer is by no means inevitable, even in these circumstances - the reason why a cancer starts at a particular time in a particular individual is still a mystery.

Perhaps one of the genes of a particular organ starts to go wrong on its own and begins to overproduce. Perhaps a virus gets into a cell and converts or ‘transforms’ the genes into enemies.

Many viruses were found in animal and human tumours by scientists pursuing these theories. Most of them did not cause cancer. About twenty types of animal virus did cause cancer but they were all a very special type of virus: the oncogenic retrovirus.

Oncogenic viruses are those which give rise to tumours - oncology is the study of tumours. Retroviruses are a particular class of virus whose name comes from their genetic programme.

The genetic code - the information which instructs each cell in how to reproduce itself- is contained in DNA (deoxyribonucleic acid). DNA is present in all body cells of all species including unicellular organisms and viruses.

In this model it is best to see DNA as the ‘double helix’ - two corkscrews wrapped around each other - of coded information as first described by Francis Crick and James Watson in 1953, for which they received the Nobel Prize in 1962. RNA, for this purpose, is best seen as short strands of information, smaller segments of the information for which DNA encodes the entire sequence.

The genetic code of a retrovirus is RNA (ribonucleic acid) which is transcribed (‘rewritten as’) DNA by an enzyme called reverse transcriptase. Once the DNA is present in the cell it locks itself into the cell’s own DNA. The picture is finally presented of a virus entirely dependent on the cell’s genetic material - it can replicate only when the cell itself replicates.

This is a complex subject but it is integral to the AIDS story, so I will attempt a model which should’ it is hoped’ do no great damage to the truth. Imagine a word processor which prints those business letters which find themselves in so many wastepaper baskets - the kind which are full of cliches, stock phrases and jargon words. All those exist in the machine but they are not connected. The word processor has a series of words already made up but they are not in sentences. These stand for RNA. Words are the same as sentences, of course, sentences are just arrangements of words in an ordered sequence. The computer programme which commands the writing of the business letter is the reverse transcriptase, it transcribes RNA into DNA - transcribes words into sentences. Once this letter has been constructed, it can be reproduced as often as required but however often it is photocopied, the words and phrases will not become random again, they are locked into their order.

The retrovirus, then, is locked into a cell. It cannot reproduce without using the cell’s own reproductive mechanism. Back to the chickens.

Peyton Rous’s chicken tumour was caused by one such retrovirus, the Rous sarcoma virus. When the cell reproduces, along with the retrovirus, it overproduces. It may then cause a tumour, a massive overproliferation of cells. This is possible because the Rous sarcoma virus has an extra piece of information - an oncogene. Without this, the retrovirus would live in peace with its host until the host died of natural causes. This is the clue to the mystery of those viruses which cause tumours and those which do not: if they do not have the ‘transforming’ gene which will turn a peaceful into an aggressive virus, there will be no tumour.

The entire field is very new. Reverse transcriptase was discovered only in 1970 by Howard Temin and David Baltimore, who received the Nobel Prize for this work in 1975.

Oncogenes were discovered in 1970 by Peter Duesberg and Peter Vogt. They had long been believed to exist, but believing and proving are different things. Duesberg and Vogt defined in molecular and genetic terms the first ‘transforming’ gene which caused a tumour.

Could these steps be proof of the gathering momentum towards ascribing causes to the cancers, leading to cures for them?

The cancer research programme now received its greatest stimulus. On 22 January 1971, in his State of the Union address, President Richard Nixon declared war on cancer. He said: ‘I will ask for an appropriation of an extra one hundred million dollars to launch an intensive campaign to find a cure for cancer and I will ask later for whatever additional funds can be effectively used. The time has come in America where the same kind of concentrated effort that split the atom and took man to the moon should be turned to conquering this dread disease.’

As will have been realised from other excursions of Richard Nixon, the word hubris was not one which made frequent appearances in his vocabulary. This speech, which heralded the Cancer Act and other efforts by governments and charities worldwide, meant more money and resources were spent on cancer than on any other disease before or since. The field was awash with money. It was the time of hope and riches before the oil crisis, the research institutes were buoyant, the manufacturers who supplied them with equipment had full order books, a footnote in the annals of cancer research was a passport to a doctorate, the Nobel Prize glowed in the distance like the sun.

The cancer research programme was far from being an overwhelming success. By the mid-nineteen-eighties articles were beginning to appear in major journals such as ‘Progress Against Cancer?’ in the New England Journal of Medicine. Here authors looked dispassionately at the figures and noted that the cancer mortality rate continued to rise slowly from the nineteen-fifties to the nineteen-eighties despite the vast research effort. Moreover, there was no breakthrough just around the corner. The authors bitterly remarked: ‘We are losing the war against cancer. notwithstanding progress against several uncommon forms of the disease, improvements in palliation, and extension of the productive years of life. A shift in research emphasis, from research on treatment to research on prevention, seems necessary if substantial progress against cancer is to be forthcoming.’

One of the theories on which fortune smiled was the theory that viruses caused cancer. It had a head start on other theories, because of earlier work in the field, and it promised great things. Consequently some great minds went into the virus cancer research programme. At one time, viruses were being found in almost every tumour, particularly retroviruses. Peter Duesberg, Professor of Molecular Biology at Berkeley, was part of the virus cancer research programme. He said:

We know that mice and chickens contain fifty to a hundred retroviruses which never cause disease. Viruses seemed to be at least a plausible cause of human cancer, based on animal work, and that programme has produced a lot of good things for science but has not identified the cause of human cancer.

When you’re in the retrovirus business you can detect a retrovirus. When you look at a disease, you can look for the retrovirus. We have done that before with multiple sclerosis, we have done it with leukaemias, we have done it with sarcomas, and in almost all cases a virus was found sooner or later.

What was not emphasised by many of these laboratories was that the same viruses were subsequently always found in healthy carriers and that’s why the virus cancer programme is essentially a failure.

Most connections between cancer and viruses are mere association: hepatitis B virus is associated with a high rate of cancer of the liver many years after first infection. There may well be an infectious agent in cancer of the cervix and cancer of the penis because a person with one of these is likely to have a sexual partner at a higher risk than average of developing the other.

It is possible that a virus challenges a human organ repeatedly, damaging the liver or the cervix in frequent tiny attacks. This means the cells of the organ have to replenish themselves faster than they would in the natural course of events. The greater the number of cells replicating, the higher the chance that one will ‘go wrong’ and start replicating out of control - a cancer. If every hepatitis B infection caused liver cancer, or if every liver cancer was in a person with hepatitis B, it would all be so much easier. It was not to be so; the viruses contribute to the risk of a cancer developing, they do not cause cancers.

Robert Gallo and the human retroviruses

The only other success story of the virus cancer programme was the announcement of the isolation of the first human retrovirus - human T-cell leukaemia virus, by Robert Gallo, Chief of the Laboratory of Tumor Cell Biology at the National Cancer Institute’ Maryland’ USA.

Robert Gallo is seen as the hero and the villain of the AIDS story. He has been described as ‘champion of the single cause theory’ meaning he believes AIDS is caused by a single agent with no co-factors. He is quoted as saying: ‘Who needs co-factors when you’ve been hit by a truck?’ He pursues his theory with a vigour which is impressive even to those who do not like him. He is a skilful communicator, popular with the media and in particular the medical and scientific correspondents who are invited into his confidence; general reporters develop an immunity to charm.

Gallo was born in Connecticut in 1937. Much is made of the incident when, at the age of thirteen, he saw his sister dying of leukaemia. He took a medical degree and began as soon as he could to study leukaemia in the laboratory - his nature was too restless to allow him to enjoy work with patients. Within two years of finishing his degree he was working at the National Cancer Institute where he was to stay for more than twenty-five years.

The young Gallo was immediately interested in the virus-cancer programme, showing most enthusiasm for the theory that viruses came from outside the body to infect and cause a cancer by some as yet unknown mechanism. There was another theory of endogenous (passenger) viruses which might cause disease in the presence of carcinogenic (cancer-causing) agents, but this theory has fallen into disfavour. Gallo backed the right horse and became deeply involved in the subject of RNA viruses immediately after Temin and Baltimore discovered reverse transcriptase.

Gallo describes his own thought processes: ‘In 1970, when Temin and Baltimore came on reverse transcriptase, I was studying DNA polymerases in blood cells. DNA polymerases are enzymes that assemble DNA; reverse transcriptase is a member of this group, albeit an unusual one. Under the influence of Temin’s ideas I decided to search for reverse transcriptase in human leukaemic cells, hoping to find a retrovirus there.’

Seek and ye shall find. But it was necessary to use the correct techniques. The electron microscope, which could detect objects thousands of times smaller than those available to an optic microscope, was a cumbersome tool for the purpose, according to Gallo. Moreover, human leukaemic cells had been studied under electron microscopes and no virus particles had been identified.

Gallo and co-workers laboured to refine the test for reverse transcriptase until the enzymes could be detected in leukaemic cells. They did find what seemed to be reverse transcriptase but in such small amounts that it could easily have been some other substance mimicking the behaviour of the key enzyme. They needed a much larger supply of the cells with this questionable virus.

This was where Gallo’s real skill, and that of his colleagues, came into play. In years to come he will be known as a first-class bench scientist who made significant contributions to the development of cell lines in which viruses could be studied. A plant protein, phytohemagglutinin, had been discovered in the nineteen-sixties. It would induce white blood cells to grow in tissue culture. Gallo’s lab noticed that after such stimulation, some T cells released a growth factor. They would culture T cells to harvest this growth factor and would use it to stimulate T cells which were growing with phytohemagglutinin. Gallo now had T cell lines growing and rapidly reproducing - a perfect set-up for any experiment he chose to perform with them.

There was something of a diversion on the path to find the cause of human leukaemia. In 1975 Robert Gallo published a paper saying he had isolated a new human virus - human leukaemia virus 23.

Gallo was jubilant, it was the justification for years of dedication. ‘We got permanently growing cell lines eventually, and it was a great eureka. We succeeded ten times in ten different cell lines, and we thought we had made the discovery, the genuine article, that retroviruses exist in humans. A year or more of analysis went by. We thought it was a triumph.’

This period of research turned from being Gallo’s greatest triumph to date into his greatest disaster. When other scientists looked at this virus they discovered it was a mixture of three animal viruses: from a gibbon, a baboon and a woolly monkey.

The term for this is contamination - the human serum from a leukaemia patient had been contaminated by animal viruses. The way this can occur is well-known and laboratories go to great lengths to avoid it. Viruses are worked on in ‘hoods’ which are basically lab benches surrounded by a clear plastic shield in which a fan takes air, which may contain particles of viruses or other material, out of the lab. It is always possible for scientists to bring in contaminants from outside, despite the measures taken to avoid this, or for lab equipment used in the hoods to be contaminated or for material in other hoods in the same room to pass over and contaminate new material. One contamination is probable in a long research period, two is possible, three is unlikely.

As Gallo said: ‘I was depressed, dumbfounded, angry. It was the low point of my whole career. It was almost the last nail in the coffin of the field of retrovirology. The programme died, and all the good that came out of it, like interleukin-2, which would be so important in fighting cancers, didn’t seem to matter, to me or to the world. I became more cynical, tougher, less happy. I mean, what could it be but sabotage? One contamination can occur, but three? In fifteen years I had had one contamination from a mouse. But three?’

Robin Weiss, another leading cancer researcher who is now working in the field of AIDS, played a leading role in determining the non-human component of human leukaemia 23. He said: ‘In the late seventies everyone was laughing at Gallo, they’d say: ‘There goes Gallo again discovering another human retrovirus.’ When he went to scientific meetings people would laugh at him. Every fashionable lab was going into oncogenes. He said man can’t be the exception, man must be able to be infected with retroviruses too. He proved us wrong, he found a retrovirus which causes leukaemia.’

A leukaemia breakthrough?

The connection between AIDS and leukaemia is almost nil. There is a slight connection in that Robert Gallo and those who followed his line of reasoning connected the two for reasons which will be demonstrated. In order to render this accessible, it is worth a quick aside to define leukaemia: it is a malignant disease of the blood-forming organs marked by a proliferation of leukocytes (white cells which include all kinds of T cells among their number) and a reduced number of red cells. Leukaemia is classified according to three facts: first the character and duration of the disease; second the type of cell involved; and third the increase or non-increase in the number of abnormal cells - in effect it can be either leukaemic or aleukaemic.

Acute lymphoid leukaemia is, therefore, a disease whose onset is fast, which involves lymphocytes and is characterised by a massive increase in abnormal cells in the blood. Heredity is involved in some leukaemias and radiation is certainly a factor in myelocytic leukaemia - the higher the dose, the more likely it is to develop. Acute leukaemia will cause a tendency to bleed, joint pains, enlargement of lymph nodes, liver and spleen and an increased susceptibility to infection.

Robert Gallo and his colleagues took cells from leukaemic patients, grew them with phytohemagglutinin and interleukin-2 and managed to produce reverse transcriptase. They had found a retrovirus. They called it HTLV-I: Human T-cell Leukaemia Virus I.

They now needed to find the disease which it caused. The patients from whom the virus had been isolated had a cancer of the T4 cells accompanied by skin abnormalities. This was a well described condition (mycosis fungoides or Sezary T-cell leukaemia) and only a small fraction of patients with it had HTLV-I. The quest for the disease led to Japan where in 1977 Kiyoshi Takatsuki of Kyoto University described something he called Adult T-cell Leukaemia which killed within a few months of diagnosis and was characterised by an explosive proliferation of leukaemic cells. It was heavily concentrated in Kyushu and Shikoku, Japan’s southernmost islands. Gallo remarked: ‘Such clustering suggested the disease might be caused by an infectious agent.’

It was clear the Japanese were well on the way to describing the virus also. Yorio Hinuma of Kyoto University and Isao Miyoshi of Kochi University had grown a line of cells from leukaemic patients which were releasing retrovirus particles. In a curious dress rehearsal for the AIDS story Gallo and his team had an isolate from a patient which Hinuma and his team also seemed to have. Gallo notes: ‘All available data indicated that the virus coming from Miyoshi’s cells was identical with HTLV-I.’

Gallo claims he and his colleagues isolated the first examples of HTLV-I in 1978-9 and that the results were published in 1980 and early 1981. To delay publication for up to three years is uncharacteristic in a man not given to false modesty.

Gallo is credited with isolating and describing the first human retrovirus. Japanese and American researchers confirmed by analysing the RNA of both isolates that the Japanese and American viruses were related strains of the same virus. They could never be exactly the same because of the mutations which occur as the virus replicates, but the RNA sequence was close enough in the two isolates.

Once the virus had been described, other laboratories looked for it. It was found in black patients born in the US, Caribbean countries or South America; Caribbean-born black people in England, Africans and Japanese. What could tie these disparate regions together?, mused Gallo.

The answer he came up with was the slave trade. Miyoshi in Japan found Japanese macaques had antibodies to HTLV-I and he suggested the monkeys had the disease first and infected people. Researchers at Gottingen, Germany, and in Gallo’s lab found that many species of African monkeys had antibodies which reacted with HTLV-I. African green monkey and chimpanzee viruses were most closely related to the virus Gallo had found in leukaemic cells.

Gallo suggested:

HTLV-I originated in Africa where it infected many species of Old World primates’ including human beings. It reached the Americas along with the slave trade.

Curiously, it may well have arrived in Japan the same way. In the sixteenth century Portuguese traders traveled to Japan and stayed specifically in the islands where HTLV-I is now endemic. Along with them they brought both African slaves and monkeys, as contemporary Japanese works of art show, and either one or the other may have carried the virus.

The discovery of HTLV-I infection on Hokkaido, one of the northern islands of Japan, immediately challenged this view of events but Gallo and his colleagues have remained attached to the monkey-virus theory.

So, why is it thought that this virus causes the leukaemia? First because of the coincidence between virus and leukaemia - find one and you will find the other, Gallo says. Moreover, infected infants born in the endemic area of southern Japan have the same chance of developing adult T-cell leukaemia whether they stay there or move to another part of the world.

In presenting this as an argument that his virus does cause this leukaemia, Gallo is, in the opinion of some, going beyond the evidence. The fact that some children will invariably get adult T-cell leukaemia in time, regardless of whether they are near to or thousands of miles from the supposed centre of HTLV-I infection, argues against an infectious agent and for a genetic cause.

Gallo further notes that there is a difference in the arrangement of infection between T cells infected in the laboratory and T cells infected in a patient. In the lab culture, the virus infects different parts of the cell at random. In a given patient, the virus is always seen to infect the same chromosome in every cell. This implies the cells are all clones of the same original infected cell. ‘It also implies,’ says Gallo, ‘that the infection preceded the origin of the tumour, because if the virus had entered the cells of an existing multicellular tumour, the viral sequences would be found in a different place in each cell of the tumour.’

‘So,’ says Peter Duesberg, ‘you have a virus which infects many T cells. If one of the millions or billions of T cells infected becomes the clonal precursor of a T-cell leukaemia, many years later, we have no evidence that the virus caused the leukaemic transformation. In fact we have millions or billions of ‘control cells’ in the same patient to show that it didn’t.’

Duesberg’s criticisms of the claims for a direct relationship between HTLV-I and T-cell leukaemia mirror his criticisms of the claims that AIDS is caused by HIV. The most obvious question is why don’t people with HTLV-I develop leukaemia? There are simply too many people infected with the virus but perfectly healthy for the virus to be the cause.

The incidence of adult T-cell leukaemia in Japan, Duesberg points out, is estimated to be only 0.06 per cent based on 339 cases of T-cell leukaemia among 600,000 subjects who are antibody-positive for HTLV-I. Why is this?

Because of the latency period, responds Gallo. It will cause leukaemia, but it may take as long as forty years.

So, when will we see a controlled trial to prove your theory? asks Duesberg.

The point is that when the time from infection to the appearance of the disease is so flexible - earlier estimates put it at five years - a great deal is being left to chance. Robert Gallo would be long dead before a controlled cohort study of HTLV-I carriers could show whether his theory is correct or not.

HTLV-I needs all its genetic material for its own replication, Duesberg notes, and if it isn’t causing cancer as soon as it gets into a cell but is peacefully replicating along with the cell, where does the characteristic for starting a leukaemia come from?

In the nineteen-seventies Duesberg defined the genetic nature of retroviruses and produced a ‘genetic map’ which is true of all retroviruses. There are three genes, gag, pol and env and a series of repetitive sequences called ‘long terminal repeats’ which need not concern us here.

The gag encodes the protein core which encloses the virus’s RNA and reverse transcriptase molecules; the pol gene encodes the reverse transcriptase and the env encodes the protein ‘envelope’ in which it is all wrapped. In addition to this, Gallo’s lab discovered another gene in HTLV-I, a so-called tat gene.

Could this not be performing the ‘transforming’ function: transforming a cell the virus has entered into a cancerous cell? No, says Duesberg, unless it happens every time.

If it was a transforming gene, every infected cell should be transformed. That is clearly not the case, there are millions of carriers of that virus who do not have leukaemia. The percentage of carriers who get leukaemia is not significantly higher than the percentage of spontaneous leukaemias in virus-free people.

In cells infected with this retrovirus, transformation is an incredibly rare event and the virus has nothing to do with it. By comparison Rous sarcoma virus transforms every infected cell. That is the difference between a retrovirus which causes a disease and one which does not.

In addition he says the tat gene must be essential for viral replication: if the gene is removed by a technique called ‘deletion analysis’, the virus does not grow any more, it therefore cannot be a gene which performs a rare, non-essential function like causing a leukaemia in the host.

Even those who do believe HTLV-I is a cause of leukaemia in some people are at a loss to understand why leukaemia is caused in fewer than one in a hundred carriers. Clearly there is some other factor working as well as the HTLV-I, or perhaps HTLV-I plays no role in the cause of leukaemia at all.

Ironically, as Gallo and his team ploughed on with their T-cell virus, two other researchers started looking at interleukin-2 which Gallo’s lab had developed only as a tool for growing T-cell lines. Kendall A. Smith at the Dartmouth Medical School and Hans Wigzell of the Karolinska Institute in Stockholm investigated how interleukin-2 and its precursor interleukin-l function as part of the immune system. In doing so they made a genuine contribution to the understanding of human health and sickness. A greater understanding of the immune system as it functions efficiently has been one of the more pressing medica1 needs of the past decade.

In another mirror of the AIDS story, HTLV-I now began to be connected with a range of other illnesses in addition to human T-cell leukaemia. The problem of the widespread infection with HTLV-I with no clinical disease was solved by Max Essex suggesting that: ‘People infected with the virus are prone to other infections, perhaps because some infected T cells, although not transformed, are functionally impaired.’

It was suggested that such ‘impaired’ T cells may contribute to leukaemias of the B cells and that HTLV-I is associated with a neurological disease resembling multiple sclerosis. As Robert Gallo writes: ‘It seems clear that the overall impact of HTLV-I on public health is just beginning to be realised’ (1987). Put another way: viruses are where you look for them and they will be found in people with a range of diseases. They will also be found in healthy individuals. In a manner which also foreshadows developments in the HIV story, variants of this virus were described and diseases began to be ascribed to them. HTLV-II was discovered in 1982 by Gallo’s group in collaboration with researchers at the University of California School of Medicine at Los Angeles. It was found in a young white man suffering from hairy-cell leukaemia and subsequently claimed to be the cause of this rare form of leukaemia, though Gallo himself has been somewhat cautious in his own pronouncements about the pathogenicity of HTLV-II .

Whether or not the two HTL viruses are responsible for leukaemias, their discovery was a remarkable laboratory tour de force. Within a decade of the discovery of reverse transcriptase which allowed retroviruses to be identified, the first human retrovirus had been discovered. As Gallo himself notes, there were two preconditions for its discovery: ‘The first, a sensitive assay for the virus, was provided by the discovery of reverse transcriptase. The second was the establishment of a method for growing T cells in the laboratory.,

Given the appropriate equipment, any laboratory worker could now duplicate this procedure and retroviruses could be added to all the other viruses which could be obtained from human tissue. John Beldekas has done as much bench work of this type as any other researcher. He commented: ‘As a researcher growing a virus, I could take a cell from your body and under the appropriate laboratory conditions I could coax out a lot of viruses that you have been exposed to. That doesn’t mean you are a walking carrier that’s shedding viruses and it doesn’t mean you are potentially infectious. The carrying of these organisms we have been exposed to is called persistence - they persist within us and we can find them if we look with the right techniques.’

However impressive this lab work was, it was a poor return on the investment of billions by people who felt themselves accountable to the electorate. The discovery of a human retrovirus was the acme of the viral cancer research programme’s limited success. It was the sort of achievement other researchers applaud but in the cold light of a Senate Sub-Committee hearing it doesn’t seem so great. Cancer research funding was in trouble. The cancer laboratories around the world had vigorously pursued every line of research which might conceivably bear fruit. These were still promising and their hands were still outstretched but the situation in the nineteen-eighties was radically different from that in the early nineteen-seventies. A massive budgetary deficit meant public spending cuts in the US and world recession meant similar actions in other countries. Cancer research had had its day. The cancer laboratories hadn’t played a particularly stunning game so the politicians wanted their ball back.

AIDS arrives

Into this world of gleaming technology and dashed hopes dropped AIDS. By 1982 it became clear this was not just a local problem for homosexuals in coastal cities and the cancer laboratories began to show an interest. To return to Robert Gallo: he was head of the Laboratory of Tumor Cell Biology at the National Cancer Institute, one of twelve National Institutes of Health research establishments. Near the National Cancer Institute building in Bethesda, Maryland, is the National Institute for Allergy and Infectious Diseases into whose province the problem of AIDS would fit most appropriately. AIDS was an infectious disease, almost everyone agreed. It wasn’t a cancer, anyway. If the NIH was going to look at the problem there was already an establishment designed to do just that sort of work. Moreover, at the Centers for Disease Control in Atlanta, Georgia, where the impressive epidemiological work had been done, there was a laboratory facility working on AIDS. Gallo’s way into AIDS research was by no means obvious. In his own words, from an article in Advances in Oncology:

I hypothesised that the infectious agent was viral in origin because Factor VIII transfusions could transmit the agent and these materials are filtered in a way that should remove bacteria and fungi and because viruses are known to be more specifically tropic for lymphocytes than are bacteria or fungi. We also proposed specifically that a retrovirus causes AIDS.

In addition, the agent’s apparent restricted tropism for certain target-cell types, particularly the T4 cell, was highly reminiscent of the behaviour we had observed with HTLV-I and HTLV-II. Finally, HTLV-I and HTLV-II are transmitted by blood, by sexual intercourse, and from mother to infant. In other words, the known human retroviruses were transmitted in the same way as the hypothetical agent causing AIDS.

By the summer of 1982, we began to consider strongly the possibility that a T-lymphotropic retrovirus, either closely or distantly related to HTLV-I, was the cause of AIDS. We moved towards this conclusion because of several observations: M. Essex of the Harvard School of Public Health has pointed out to us that the feline leukaemia virus, a retrovirus, commonly causes immune deficiencies. The T4 tropism seen in AIDS has been observed with HTLV-I and HTLV-II. Both HTLV-I and HTLV-II can be mildly immunosuppressive. The modes of transmission of HTLV-I, HTLV-II and the putative AIDS agent were remarkably similar.

To put it another way: Robert Gallo had seen an opportunity for a new application of the techniques he had developed in his search for the leukaemia virus. If successful, this would give him another virus to add to the HTL ‘family’ which he had discovered

The retrovirus hunters

In his social history of the first years of the AIDS epidemic, And the Band Played On, Randy Shilts stresses the importance of Don Francis at the Centers for Disease Control. This virologist worked with Max Essex on feline leukaemia and he kept Essex informed at a time when Gallo was paying scant attention to AIDS and the ball was clearly in the CDC court.

Shilts writes of Max Essex: ‘He and Francis were among the small minority of scientists who believed that viruses would one day be linked to cancer and other serious human ailments. Together they had published eight articles on feline leukaemia as well as a controversial piece suggesting that some human lymphomas, leukaemias and cancers of the immune system might be linked to viral infections.,

Francis was arguing a retroviral cause for AIDS as early as June 1981. He had the ear of Essex, the premier animal retrovirologist, who had the ear of Gallo, the premier human retrovirologist. Because viruses had fallen out of fashion as putative cancer agents, there were few people in the world who had gone on to understand retroviruses. Here were three of them in professional contact.

International co-operation is the rule in medical research. Scientists who head important research facilities spend a great deal of their time flying to international conferences, reviewing papers before publication in scientific journals, playing host to foreign researchers who have visited to study new laboratory techniques. One such visit occurred in July 1982 when a researcher from the Pasteur Institute in Paris visited Gallo’s lab to learn how to produce a cell culture favourable to the growth of HTLV. The theory that AIDS was caused by a variant of HTLV became known in 1982 through papers circulated via the various AIDS working parties and, of course, through simple conversation between scientists. Francoise Barre-Sinoussi, Jean-Claude Chermann and Luc Montagnier of the Virology Department at the Pasteur Institute were in an ideal position to pursue this theory. They had also been involved in the virus cancer research programme and were both intellectually and technologically equipped to detect retroviruses. Barre-Sinoussi had trained at Gallo’s lab in the NCI.

One bit-part player in the drama which followed was a thirty-threeyear-old Parisian homosexual fashion designer who was feeling unwell just before Christmas 1982. He called in at the La Pitie Salpetriere hospital complaining of the now-familiar syndrome: general debility, fatigue, enlarged rubbery nodes on the neck. He had a history of several episodes of gonorrhoea and had been treated for syphilis in September 1982. He enjoyed more than fifty sexual partners a year and travelled a great deal, including travel to North America, though his last trip to New York had been in 1979.

Lab tests showed he had cytomegalovirus, Epstein-Barr virus and herpes simplex virus. The hospital had been waiting for just such a patient: almost certainly an AIDS case but one who was not so ill that his T cells were depleted and could not be encouraged to grow in culture.

A tissue sample from the lymph nodes of this patient was sent to the Pasteur Institute where Barre-Sinoussi and Chermann set about growing the lymphocytes in a culture - a complex procedure involving first anti-interferon to stop the cells from producing their own interferon and stopping the growth of a retrovirus if one were there. The next stage was to make the T cells grow, so T-cell growth factor was added, then phytohemagglutinin inducing the cells to grow larger and to divide.

About every three days there would be a test for virus - spinning the culture in a centrifuge to concentrate any virus which might be present, treating it with detergent to open up the virus and testing for reverse transcriptase. The entire procedure was, therefore, not an exploration of what unknown pathogen might be present in the lymph nodes of a man who seemed to be about to develop AIDS. The operations which were applied in the Departement de Virologie of the Institut Pasteur in January 1983 were calculated to detect a retrovirus should one be present. They were not looking for the cause of AIDS, they were looking for a retrovirus.

On 25 January 1983 reverse transcriptase was found. There wasn’t a great deal of reactivity to the reverse transcriptase assay and the reactivity varied widely over the next few weeks but fresh cells could be added to boost the harvest. It was definitely there.

Montagnier and his group submitted their results to the journal Science in April 1983 and the paper was published on 20 May - an unusually short period which indicated the urgency AIDS research had assumed in the scientific community. The paper, ‘Isolation of a T-Lymphotropic Retrovirus from a Patient at Risk for Acquired Immune Deficiency Syndrome, seemed clearly to place the newly discovered virus in the Gallo family of HTLVs. Two sentences ran: ‘We report here the isolation of a novel retrovirus from the lymph node of a homosexual patient with multiple lymphadenopathies. The virus appears to be a member of the human T-cell leukaemia virus (HTLV) family.’

This line was actually inserted at Gallo’s suggestion when he saw an early draft of the paper as part of the ‘peer review’ system. The paper itself specifically contradicted the claim that there was a direct connection between the new isolate and HTLV. A comparison was made between the two proteins of the viral core of HTLV-I and the proteins of the new virus and there was no similarity. The serum of the infected patient reacted with HTLV-I infected cells which implied that the patient had come into contact with HTLV-I or something so similar to it that the patient’s own antibodies could not tell the difference. When the sera of healthy donors was tested in the same way, however. the same reaction was observed. Here was certainly a novel retrovirus which in later publications (though not this one) the Montagnier group took to calling Lymphadenopathy-Associated Virus. It is worth noting their caution: ‘The role of this virus in the etiology of AIDS remains to be determined,’ they remarked and to note that the virus was only associated with lymphadenopathy was appropriate and commendable.

This caution contributed to the mute reception the paper received. Another significant factor was the simultaneous publication, in that same issue of Science, of three other papers, two from Gallo and one from Essex, associating HTLV with AIDS. The news pages of Science featured an article headed ‘Human T-Cell Leukaemia Virus Linked to AIDS’ with the sub-heading ‘Patients with the new immune disease show evidence of infection by human T-cell leukaemia virus. Does the virus cause the disease?’ Montagnier’s work is dealt with in one sentence. As Steve Connor remarks in his thorough investigation of this for New Scientist: ‘The very journal in which Montagnier publishes his research failed to notice the true importance of the discovery while focusing on work that turned out to be wrong.’

In keeping with the principles of scientific openness, the Pasteur Institute gave Gallo an isolate of LAV on 17 July 1983. Gallo’s lab was unable to grow it. Another sample was sent on 23 September along with a contract specifying that the American lab could not use the virus to develop commercial items. The reason for this was that the French had realised the immense potential of AIDS testing kits if, as they now strongly suspected, their virus was not only associated with AIDS but was actually the cause of it. They filed for a British patent in September and a US patent in December.

Gallo wrote to a German colleague on 27 September in dismissive terms of Montagnier’s work: ‘I have never seen the virus that Luc Montagnier has described, and I suspect he might have a mixture of two. On the other hand, some of his data are interesting but still far from definitive. We have a total now of ten HTLV isolates from frank AIDS cases in approximately forty attempts and, again, I’m still not certain what this means.’

Despite this apparent uncertainty’ Gallo was still, at least up to 12 December 1983 when a Science article was submitted for publication, convinced that AIDS was caused by HTLV. This article, actually published on 11 May 1984, is headed ‘Antigens on HTLV-lnfected Cells Recognised by Leukaemia and AIDS Sera Are Related to HTLV Viral Glycoprotein’ and it attempts to demonstrate that the proteins identified on the surface of T cells infected with HTLV are ‘recognised’ by the antibodies in the blood of leukaemia and AIDS patients.

Before continuing with this chronology it is worth looking at exactly what was being stated when the claim was made that Human T-Cell Leukaemia Virus, or a variant of it, was causing Acquired Immune Deficiency Syndrome. Leukaemia is characterised by an overproliferation of leucocytes; it is a cancer - there is an uncontrolled growth. AIDS is characterised by the death of T4 cells, a particular type of leucocyte. So one disease makes them multiply and the other makes one particular type of them die. Apart from the fact that the same type of cells are involved in both diseases, what is the connection? It is impossible now to find anyone to defend the alleged connection; in 1983 while the contradiction was acknowledged it did not preclude belief in the theory. As we have seen, even Montagnier accepted an interpolation into his own paper which claimed a connection between HTLV and LAV, which that paper disproved.

It is currently difficult to find anyone to question HIV as the cause of AIDS though many express their reservations privately. It is realistic to ask how so many scientists could be wrong about HIV causing AIDS. The answer is that it doesn’t take many, if a small number of specialists in the field take a particular line, specialists in other fields will accept it and generalists, and the laity, will follow suit.

Meanwhile in Cambridge, England, another former cancer researcher was identifying a micro-organism from the blood of an AIDS patient. Abraham Karpas of the Department of Haematologica1 Medicine at Cambridge University Clinical School identified a virus in September 1983 and wrote a quick paper on it with an accompanying photograph of a view of these particles through an electron microscope. Karpas blames himself for not actually calling it a ‘novel virus’ which would have guaranteed more attention for the paper. As it was, he had some difficulty in getting the paper published, though it was accepted by Molecular Biology in Medicine on 14 December 1983.

This still made him, however, the second person in the world to have isolated this unusual virus from an AIDS patient and to have demonstrated the reactivity of the blood of some AIDS patients to it. Karpas later called his isolate c-LAV for ‘Cambridge LAV, but did not give it this name - or any name - in the paper. Neither did he refer, even in a reference, to the work of the French team. Karpas explains that the skimpy nature of the paper was due to its having been originally submitted as a letter to The Lancet on 11 November 1983 only to be rejected five weeks later. He did not refer to the French because he was unable until 1984 to compare his to the French isolate and decide they were the same.

December 1983 was a busy month for all. On 14 December Mika Popovic of Gallo’s laboratory received a letter from the electron microscopy laboratory they used. It dealt with the analysis of thirtythree samples of blood cells, thirty-one of them negative for viruses. The other two were both samples of LAV, in both cases the comments from the lab examining and photographing them through a microscope were the same: ‘HUT 78/LAV Positive: Lentivirus. Productive lentivirus infection with all forms of virus maturation.’

HIV is probably of the lentivirus family and this is an understandable identification for the person operating the electron microscope to make. This is the proof that Gallo’s lab was successfully cultivating LAV at least in December 1983. The date and the letter became vital evidence when legal action became imminent four years later. It then became known that someone in Gallo’s lab had tampered with the letter quoted above to delete all reference to LAV; on the copy of the letter provided as part of the legal case, there was just a white space where in the unadulterated letter there is the reference to LAV.

Identifying the virus was one thing, growing it was quite another. Yet there had to be a sufficiently large amount of the virus cultivated for further experiments on it and, all importantly, the commercial production of kits which could test for the presence of the virus. The tendency of the virus to kill T cells in the laboratory (of which more later) meant it was very difficult to maintain a stable culture of infected cells. Eventually, Montagnier’s group solved this problem by dispensing with T cells and using another kind of lymphocyte, the B cell, which had been infected with Epstein-Barr virus to make the cells multiply.

Gallo’s group used a T cell line called HUT 78 in the form of a sub-group called H-9. By the end of November Gallo’s group claimed to be able to cultivate sufficient quantities of the virus to be able to make clear the distinctions between it and HTLV-I. Gallo prepared for massive publication on his team’s work. It is a standard rule among serious scientific publications - the breach of which can lead to ‘blacklisting’ by serious journals - that the results of research work should not be released prior to first publication in a scientific journal. In particular this rule is aimed at preventing a rush for publicity in the lay press with its misrepresentation and over-simplification of research results. The lay press, if it wished to report scientific findings, could do so from reports in journals with their customary caution and qualification.

In this case the usual procedure was not followed. ‘Cancer Virus Tied to AIDS May Be Disclosed Soon, was the headline in the Wall Street Journal on 16 April 1984, ‘Research Indicates AIDS Is Connected to a Cancer Virus’ on 17 April in the Washington Post. The New Scientist, quoting Gallo himself, reported on 19 April:

Researchers at America’s National Cancer Institute in Bethesda, Maryland, believe they have finally tracked down the organism that causes Acquired Immune Deficiency Syndrome (AIDS). It is a virus that affects particular cells of the immune system and is called human T-cell leukaemia virus type III (HTLV-III).

There now occurred one of the strangest tableaux of the entire strange AIDS story. The Department of Health and Human Services held a press conference in Washington, DC, on 23 April to report on a new virus which had been found by Robert Gallo.

The press conference was held in a small auditorium, too small to hold the reporters and TV crews who attended. Microphones hung round the lectern like fruit weighing down a tree and scientists crowded onto the tiny stage. Secretary of Health and Human Services Margaret Heckler even introduced a scientist who wasn’t there.

Gallo made a grand entrance, as described by David Black: ‘He approached the podium like the only kid in the school assembly to have won a National Merit Scholarship. He was fastidiously dressed. None of Sonnabend’s ratty sweaters and baggy slacks for him. He wore aviator glasses - a Hollywood touch - and his hair was rumpled, but just enough to make it look as if he had recently emerged from handling a crisis. His manner seemed to me condescending, as though he were the Keeper of Secrets obliged to deal with a world of lesser mortals.’ The moral seems to be to make sure David Black is your friend before you invite him to your press conference.

Margaret Heckler acknowledged ‘other discoveries... in different laboratories - even in different parts of the world’ but the accolade was reserved for the US: ‘Today we add another miracle to the long honor roll of American medicine and science.’

Heckler said the discovery of the virus would allow the development of a vaccine against AIDS which would be available by 1986. She resigned her post in 1985 and was sent to Ireland as Ambassador.

The press reported the ‘discovery, straight, despite the cynicism of many reporters who knew of the French work. It is amazing that in a free society government could so manipulate the media, but there were reasons, both positive and negative, for press obeisance.

On the positive side: this was a good story for America, the sort of story readers like. AIDS had largely been an American disease so far and the story of the insidious progress of the ‘gay plague’ had made thrilling reading for over a year. A new angle was welcome, particularly because it was good news about American researchers in an American lab.

On the negative side: the story of a prior claim by the French team was complex, too complex for the news media to deal with in one day or, rather, the part of the day left between the end of the press conference and their deadlines. When the news editor ask ‘OK, what’s the story’ because he or she needs to know how much space to give it’ the answer ‘An American scientist has found the virus which causes AIDS’ is the right one. ‘A press conference today announced that an American team had probably found the virus that causes AIDS but some people have been saying a French team found the virus a year ago but it didn’t get much publicity,’ is the wrong answer. That story cannot realistically be done in a few hours. Moreover, the electronic media relies on direct quotation from people like Heckler and Gallo and the simple, sharp quotes rule. Most Americans get their news from the electronic media and the electronic media is at the mercy of simplifiers.

An additional problem was the time difference between the US and France, should anyone wish to telephone the Pasteur Institute. There was also, perhaps, an erroneous conception that there would be a language barrier - in fact the leading characters and the press officers on the French side all speak adequate or good English.

An honourable exception to the shabby behaviour of the US media in general was the New York Times which, days before the press conference, featured a story in which credit for the isolation of the virus went to the Pasteur Institute. Later the New York Times commented on the ‘fierce - and premature - fight for credit between scientists and bureaucratic sponsors of research.’

One other event occurred on 23 April: a patent was filed in the US on a test kit developed by Gallo. The prestige of coming first in the race to grow this virus was now indistinguishable from the financial gain each institute would receive if they could prove they came first. The small matter of proving that this virus actually caused the disease remained.

The fourth of May 1984 found Science announcing ‘Strong New Candidate for AIDS Agent’ on its news page with the sub-heading, ‘A newly discovered member of the human T-cell leukaemia virus family is very closely linked to the immunodeficiency disease.’ The leading article announced four papers in that journal, all of which appeared with Gallo’s name attached and all of which dealt with an entity referred to as HTLV-III. This had been isolated from more than a third of patients with full AIDS and antibodies against it had been found in almost one hundred per cent of patients.

One of the articles contained a series of pictures taken through an electron microscope of three viruses in three stages of development: they showed virus particles budding from a cell membrane, free particles having separated from the membrane and free particles seen from a different angle. These were pictured for HTLV-I and HTLV-II showing the similarity between them. The third series of three pictures was labelled HTLV-III but it was not a picture of HTLV-III it was a picture of the LAV isolate Montagnier had sent to Gallo. Two years later, on l 8 April l 986, Gallo and others involved in the work published a correction in Science. Gallo explained that when he received the electron microscope pictures he simply assumed they were pictures of his HTLV. One interesting aspect of the depiction of all three together was that it showed how dissimilar LAV/HTLV-III was from the first two HTL viruses. Their cores appear pentagonal or hexagonal, the new virus looks like a rod - in fact it is cone-shaped.

The one change Gallo made to accommodate the rapidly developing understanding of the new virus was to change its name slightly from human T-cell Leukaemia virus to human T-cell Lymphotropic virus indicating a tropism (affinity for) T cells.

The proof that LAV/HTLV-III was not of the HTLV family came when the viruses underwent nucleic acid sequencing through the end of 1984. This is a procedure for working out the genetic structure of a virus. It was therefore possible to be definitive: the new virus does not have sufficient similarity to the HTLVs for them to belong to the same family.

This had long been believed to be the case and was hardly a surprise. The level of similarity between HTLV-III and LAV did surprise even case-hardened scientists, however.

Reverse transcriptase does not do a perfect job; when it converts RNA to DNA there are mutations occurring which change the virus so each isolate should be quite different. To put it another way: there should be sufficient similarities to demonstrate they are the same virus but unless they are clones, meaning they came from the same culture, there should also be differences. The differences between LAV and HTLV-III were insignificant. The differences between them were no greater than between clones of the same isolate grown in the same culture.

Gallo said this might have occurred because both isolates were, by chance, from mutual sexual partners. This would mean Montagnier’s patient with lymphadenopathy would have had to have had sex with someone in New York in 1979 and three or four years later that person in New York would have had to have a sample of serum taken in which there was unchanged virus.

Another test for the genetic similarity of viruses came up with the same answer: of twelve different viruses studied by restriction mapping (measuring specific elements of the DNA rather than all the genes), all were different except LAV and HTLV-III.

The evidence, then, that LAV and HTLV-III were the same and that Montagnier got there first is in four parts: First, it is not questioned that Gallo’s lab received isolates of Montagnier’s virus twice while they did not reciprocate. Secondly, there seems to have been some tampering with letters to delete a reference to the fact that LAV was growing in Gallo’s cell line.

The pictures in Science with Gallo’s four HTLV-III papers are also telling. Gallo claims he had pictures of his isolate as early as February 1983 giving him obvious precedence over the French. But this comment, as Steve Connor notes in New Scientist, ‘does not explain why, if he could photograph the HTLV-III virus in February 1983, he waited until May 1984 to publish pictures of the virus and even then made the mistake of publishing pictures not of HTLV-III but of Montagnier’s LAV.’

Finally, the two most sensitive methods of analysis of viral genetic material show the two isolates to be remarkably similar.

This acrimonious dispute between different teams of researchers was increasingly personified in public by the personalities of the men involved - Montagnier Gallic and aloof; Gallo hurt, defensive, emotional. Just as they had been obliged to race to be first to isolate and cultivate this new virus, now they had to defend steadfastly the importance of their discovery. They had no time for quiet reflection and could hardly have turned round to their governments, their journalists, their lawyers, to say: ‘Sorry, we got it wrong, back to the drawing board.’

The lawyers were playing an increasingly significant part. Despite Montagnier’s group having filed for US patents on the test for antibodies to the new virus before Gallo’s group did, the US Patent and Trademark Office awarded Gallo a patent on 28 May 1985. The Pasteur Institute heard nothing and had to file a complaint before the US claims court. This action, one of three which made the picture of LAV/HTLVIII yet more murky, claimed Gallo had infringed the written agreement not to use the samples of LAV for commercial purposes.

The second was the action over the patent rights to the test kit. The US Patent and Trademark Office accepted Montagnier’s prior claim in May 1986 and made the French the ‘senior party’, which meant they had prior claim and Gallo’s team had to prove they were first. The third action concerned the US Freedom of Information Act and the nondisclosure of documents from Gallo’s laboratory which the French lawyers needed to see.

The legal dispute between these institutes does not affect the central question of this book, namely whether or not the virus they isolated is actually the cause of AIDS. For this reason there will not be an account of the progress of the dispute. Most importantly, the cases demonstrated how much was riding on this virus in terms of national kudos, personal prestige for the researchers and, not least, cash. The market for AIDS testing kits based on this virus was worth $100 million a year.

The dispute was settled in April 1987 in terms which meant there were two patents on the test kits. Eighty percent of the royalties collected by both sides on their test kits were to go to a new foundation based in the US researching into AIDS. The foundation, with three French appointed and three American-appointed trustees, was to award grants to scientists working on human retroviruses - keeping it in the family, so to speak.

Part of the agreement the two parties signed was a statement that they agreed to be bound by a particular historical interpretation of the events leading to the isolation of the virus. An official history was written and all parties had to ‘agree to be bound by such scientific history and further agree that they shall not make or publish any statements which would or could be construed as contradicting or compromising the integrity of the said history.’ If scientific fraud is the worst professional crime a scientist can conceive of, probably the worst for a historian is the rewriting of history to accommodate some establishment view.

The name of the virus

The International Committee on the Taxonomy of Viruses declared in May 1986 that the virus should not be called by its previous names, it was becoming confusing and was tying up scientific nomenclature in titles related to national prestige. It was named HIV by the subcommittee working on it. The letters stood for Human Immunodeficiency Virus, thus following the usual nomenclature of microbes which is to state first which species it infects, then what it is said to do, then what kind of a microbe it is. All on the subcommittee accepted this except Robert Gallo and Max Essex but, to everyone else in the scientific world, HIV it became.

Another reason for the unification of the names was the number of people who had by now isolated it and given it their own title. Another cancer researcher, Jay Levy in California, had isolated what he called ARV - AIDS-associated retrovirus. The Centers for Disease Control had tried to please all of the people all of the time by calling theirs LAV/HTLV-III-CDC-151 but mercifully it failed to thrive in culture. A German team also had an AIDS-associated virus. If HIV is not the cause of AIDS, how did so many well-qualified scientists come up with the same microbe? Surely this is an indication that the original isolation of a microbe in a patient by Montagnier’s group was correct - everyone else confirmed it, after all.

The fact that more than one laboratory can find the virus is indeed proof that it is there, but that has never been questioned by the critics who say HIV does not cause AIDS. Not only is it there in many AIDS patients, they say, but it is also there in many healthy people who do not have and are not going to have AIDS. It was found, the claim runs, because it was looked for

This is why Robert Gallo assumes such central importance despite the probability that he did not isolate HIV first and that even his early isolates were ‘contaminated’ with the virus sent from France. Gallo’s work, at a time when other scientists had virtually abandoned the field, led directly to human retroviruses. He and his lab developed the techniques possible for detecting them, he put human retroviruses on the microbiological map. When he suggested in 1982 that AIDS might be caused by another human retrovirus he had already earned some prestige as the discoverer of HTLV-I. Other laboratories followed the lead he gave both in the quest for a retrovirus and the techniques used to detect and culture one.

John Wyke of the Beatson Institute in Glasgow, Scotland, has as much experience as anyone in hunting viruses - again from the virus/cancer research programme. He said:

The favoured approach is to look for something which is like something you know already. You say, this disease is similar in some ways to another disease and we know the cause of that so let’s look for something of the same family. Of course you use the same techniques.

If you don’t know what is there at all, it is very difficult in virology to look for something. What techniques do you use?

Of course there have been mistakes in the past, viruses have been identified as the cause of a disease incorrectly, but everyone is aware of the possibility of these mistakes and is on guard against them.

To repeat Gallo’s remark: ‘We had the technology to perform sensitive assays for retroviruses and for culturing T lymphocytes in vitro, so using it seemed to be the logical first step in our search for the AIDS agent.’

A standard principle of science is replication - this means that work in one laboratory should be able to be duplicated by another.

Once one laboratory has achieved something, like the isolation of a new microbe, it is incumbent upon other labs to validate or invalidate the work. To do this they have to use the same instruments and the same techniques, to measure their quantities of sera and reagents in the same amounts, to spin substances in a centrifuge for the same amount of time at the same speed. It is this need for replication, incidentally, which makes scientific journals so difficult for lay people to read. The basic concepts are intellectually accessible to anyone of above-average intelligence; it is the technical terminology necessary so other labs can replicate the work which is impenetrable without years of study.

The other labs proved, using Gallo’s own techniques, that there were retroviruses in the tissues of at least some AIDS patients. Perhaps it was faulty technique which meant they failed to find them in the tissues of all AIDS patients. So the original work was confirmed, and the dispute started as to which family the new virus belonged to and who had found it first. No one seemed to heed the warning in an editorial in the New Scientist: ‘The scientific journals should beware of being steamrollered by scientists who are rushing forward so quickly that they do not have the time needed to make the usual series of painstaking experiments to confirm their original thought.’

The virus hunters

If a virus were sought for the cause of a disease and misidentified as the cause for the first time in the case of AIDS, this would be remarkable. In fact this error is far from being without precedent. Viruses are ‘flavour of the century’ just as bacteria were a hundred years ago. Since the nineteen-forties we have had electron microscopes which can be used to see viruses just as in the nineteenth century there were optical microscopes which could be used to see bacteria. Concepts adjust to fit the technology available to them. At the end of the nineteenth century every disease was caused by a bacteria. Today every disease is caused by a virus.

A few examples: five years were spent hunting a virus for the cause of Lyme disease, an inflammatory condition like arthritis. Originally described in Lyme, Connecticut, where many residents are affected, the disease causes swelling in knees and other large joints with chills, fever and headache associated with the condition. It is passed from animals such as deer via their ticks to humans. The textbook in which I have just looked up the condition (dated 1983) notes it is ‘believed to be transmitted by an unidentified tickborne virus.’ It was eventually identified by Willy Burgdorfer as being caused by a corkscrew-shaped bacteria called a spirochete which was named Borrelia burgdorferi in his honour.

Similarly, a distinctive form of pneumonia was identified by clinicians but its cause was a subject of speculation which always hinged on a viral cause until an organism called Mycoplasma pneumoniae was isolated. Mycoplasma is a curious genus of micro-organisms. They are able to be grown in an artificial medium in the absence of a cell line and are therefore not viruses, for viruses cannot replicate outside a cell. They are distinguished from bacteria, however, in that they do not have a rigid cell wall.

In some cases, the very means used to attempt to detect a virus has destroyed the actual agent in culture, thus making it close to impossible to detect the agent. The case of Legionnaires, disease aptly demonstrates this. The 1976 convention of the American Legion was held in the Bellevue-Stratton Hotel, Philadelphia. Within a few days scores of the delegates became ill with chills, fevers, dry coughs and muscle pains. There were 182 cases of this odd pneumonia, with 29 deaths.

The air-conditioning system was immediately suspected as most of the cases were associated with congregating in the hotel lobby. Moreover, other cases occurred in pedestrians in the street outside who had not been associated with the hotel, the so called Broad Street disease. The only thing the street had in common with the hotel was that the same air had been in both places, moved around by the air-conditioning system.

Researchers set out to find their virus. No virus could be found in lung tissue taken from the victims. Diseased tissue was injected into guinea pigs with unhelpful results: some died, some stayed healthy and the virus couldn’t be found in the lung tissue of either group.

Another attempt at growing the virus involved injecting infected tissue into hens, eggs after antibiotics had been used to kill any bacteria which might grow in the eggs and contaminate the experiment. But they still couldn’t grow that virus.

Finally Joe McDade, a thirty-six-year-old research microbiologist at the Centers for Disease Control, went back to the slides of diseased tissue which had previously failed to yield up the secret of the microbe. This time he found it, but it wasn’t a virus, it was a bacterium which was named Legionella pneumophilia. Once one bacterium had been identified, more followed and now there are ten sub-groups of Legionella pneumophilia and eighteen other similar organisms including Legionella micdadei, named in honour of Joe McDade.

Legionella lives in air-conditioning systems, cooling towers, showers - wherever there is dirty water which can then find itself sprayed and inhaled by susceptible people. The chain of events necessary to cause illness is interesting and, in its complex interplay of social, microbiological and medical factors, sheds some light on AIDS. The water needs to be still at some times and not frequently changed: there has to be a reservoir, however small, of dirty water. The bacteria must come into contact with it. It has to be turned into a spray. It has to be inhaled by people. There have been cases in young people but most are in middle-aged to elderly men with a most commonly occurring age of fifty-seven. Death rate is highest in those who already have a heart or lung condition, are immunosuppressed or have diabetes. Smoking is also a risk factor.

We thus have a peculiarly modern disease. It is relatively recently in human history that air-conditioners and showers have existed. It is also relatively recent that people w ho have the variety of problems which predispose to infection by Legionella should stay alive and active.

Once the agent was understood, as in AIDS, retrospective diagnoses began to be made. It is now realised that ‘Pontiac fever’, in 1967 when ninety-five per cent of the staff at a US Health Department suffered breathing difficulties, was caused by Legionella. There was a leak between the ducts of the evaporating cooler system and the ventilation system in which the bacteria were growing.

Besides this complexity, there were other problems in the way of the most dedicated researcher: there was no good animal model. Laboratory animals are notoriously bad models for human disease. How could a guinea pig duplicate the physical condition of a fiftyseven-year-old American man who has mild diabetes and smokes? In what quantities should the microbes be given to the lab animal? Which animal should be used? Mycobacterium leprae, which causes leprosy, will not infect any known animal but man and the armadillo.

A cell culture can be used instead of an animal but how should the cell culture be prepared? In the early CDC search, antibiotics were used to clear the way for the culture of the all-important virus. Of course, the bacteria which were the cause of the epidemic were destroyed immediately.

Finally, there is the problem of size. It is possible to look so closely for viruses at magnifications of 100,000 times that larger particles are simply missed: a classic case of not seeing the wood for the trees.

The virus hunt of all virus hunts has been that quest for the virologist’s grail, the virus which causes human cancer. In this, of course, the most common cancers are the cancers it would be most desirable to link to a virus. The equation runs ‘cancer plus virus equals vaccine plus Nobel Prize’. The lack of success has been overwhelming.

The case of breast cancer is an interesting one, particularly because it received media attention in the nineteen-seventies through the premature announcement of promising lab results.

Viruses do seem to play a role in the mammary tumours of mice. The virus is passed on in milk to the mouse’s young. When virus-like particles were found in human breast milk, scientists warned women with a family history of breast cancer not to breast-feed their children because of the possibility of passing on the cancer virus from mother to daughter.

For a series of commonsense reasons, this was bad advice. One is epidemiological: breast cancer rates are low in countries where breast-feeding is common but are increasing in countries like the US where breast-feeding rates are low. Another is genetic: breast cancer occurs equally in women with a family history of breast cancer on both the male and the female side of the family. Another reason is biochemical: human milk may inactivate viruses. If so, it might inactivate a putative cancer virus. The last point is statistical: the ‘cancer viruses’ occur with almost as much frequency in healthy women as in those with breast cancer.

Stated in this way, the arguments against a simple connection between viruses and breast cancer seem overwhelming, but many labs, many mice, many scientists and much money were channelled into this question in the seventies. In his review of the evidence Nurul Sarkar of Memorial Sloan-Kettering Cancer Center, New York, says:

The evidence for a viral involvement in human breast cancer is contradictory and inconclusive (and) scientists have a special responsibility not to raise public hopes for a cure or a prophylaxis for breast cancer based on suggestive rather than conclusive data. In the past many scientists have expressed their own beliefs as if they were proven fact.... I think that it is important to remember that there are fundamental differences between humans and laboratory strains of animals. We should be able to accept the fact that human breast cancer may not be caused by a virus. An open-minded attitude on this question will provide the mental freedom that is essential to creative and innovative research into the cause of human breast cancer.

Inevitably, once the human retroviruses were described, researchers started looking for them in breasts and found them. Scientists at the University of Liverpool, England, reported in January 1988 a study of tissue from thirty-two women with breast cancer and twenty-seven healthy controls. Reverse transcriptase activity was found in thirty-one of the patients and three of the control group.

Examination through an electron microscope found evidence of the virus in cells of the walls of blood vessels but not in cells of the developing tumour. The researchers admitted that some of the ‘viruses, may have been misidentified natural particles (‘coated vesicles’).

Interestingly from the point of view of anyone questioning the HIV hypothesis, the scientists reporting in The Lancet suggest a mechanism by which a retrovirus could be located in a person already immunesuppressed: ‘It is possible that the virus is present in the monocyte series of cells only, plays no part in the development of the malignancy, and has merely been unmasked by the accidental immunosuppressive effect of the tumour.’

Other diseases in which retroviruses have recently been sought and found are non-A non-B hepatitis and Kawasaki disease, in which children suffer fevers, rashes and swelling of the lymph nodes.

A virus a year

If HIV is a passenger along with many other passenger viruses, it should be possible to find not only HIV but also other retroviruses. It is indeed true that now the technology is in place to detect retroviruses, laboratories all over the world are coming up with new ones. It was, in fact, the presence of more than one retrovirus in the bodies of patients which contributed to the confusion about whether ‘the’ virus in AIDS patients was really HTLV-I. Even in Montagnier’s first presentation in September 1982 he noted that fourteen per cent of his AIDS patients had been infected with HTLV-I as well as the new virus.

In 1986 Montagnier’s group isolated another retrovirus, now referred to as HIV-2, from a patient in West Africa. As Newsweek put it: ‘At first the French doctors were doubly mystified. The thirty-two-year old man was clearly suffering from AIDS. Yet he had come to Paris from the Cape Verde islands off the coast of Senegal, thousands of miles from Central Africa, from where the vast majority of the continent’s AIDS victims come. Even more curious was the fact that routine blood tests showed he had produced no antibodies to HIV, the human immunodeficiency virus that causes AIDS.’

One avenue of approach would have been: ‘therefore re-examine the HIV hypothesis’ but researchers instead went on to isolate another form of HIV. People with both HIV-2 and AIDS have been hard to come by - more than half of a group of thirty-nine prostitutes in Guinea-Bissau have HIV-2 but none have AIDS, for example.

HIV-1 and HIV-2 are about forty per cent identical though many people who believe that HIV-1 causes AIDS, like Max Essex, have doubts about HIV-2. Essex said: ‘From my perspective it doesn’t have epidemic potential, if it did we would have seen it by now.’

Max Essex was involved in another AIDS virus discovery, one which went badly wrong. In pursuit of the elusive connection between the African green monkey and AIDS, Essex in his laboratory at Harvard examined isolates of viruses from both African green monkey and West African humans. Eureka! They were the same! The family tree of how the virus jumped the ‘species barrier’ could finally be drawn, the proof of the connection between the monkeys and the human disease, long prophesied, was finally at hand. The new isolate was proudly labelled HTLV-IV (Essex had never accepted the change of ‘AIDS virus’ nomenclature to HIV).

There had been questions, and sneers, about laboratory contamination but the clinching argument came when ‘genetic mapping’ of the isolate took place. The ‘HTLV-IV’ turned out to be ninety-nine per cent genetically identical not only with an African green monkey isolate but also with a macaque virus in the same laboratory at the Harvard School of Public Health where the work was done.

Scientists from the New England Regional Primate Center at Harvard Medical School clarified the question when they explained in Nature that they isolated what they called SIV (simian immunodeficiency virus) from macaques in September 1984. Subsequently they gave Max Essex a sample of the isolate in a HUT-78 cell line. It was worked on in the same lab as that in which work with African green monkey and HIV were continuing. There was only one retrovirus and it was from the macaques; it then contaminated the other cultures in some unexplained way.

Other human retroviruses coming to the fore included SBL 6669 V-2 from the Swedish Karolinska Institute (1986) and HTLV-V from the Universities of Rome and L’Aquila (1987).

Controversy was caused in June 1987 when Gallo announced another human retrovirus at the world conference on AIDS in Washington, DC. A ‘distant relative’ of HIV-1 and HIV-2 had been found in Nigerian patients with AIDS-like symptoms.

February 1988 saw Max Essex announcing he had found populations in the Ivory Coast and in Senegal where in a total of eighty-one AIDS patients, twenty-nine did not have antibodies to HIV-1 or HIV-2. The report noted that he ‘does not rule out the possibility that there is a third human retrovirus causing AIDS in West Africa’.

The Fourth International Conference on AIDS in Stockholm in June 1988 was presented with reports of HIV-3. A new virus was isolated from a pregnant woman in Cameroon. She was healthy but her husband ‘showed early signs of AIDS’. One of the Belgian discoverers said the new virus was forty per cent similar to HIV-I.

It seems likely retroviruses will continue to be discovered at a steady rate in the foreseeable future.

Research contracts

Not everyone accepted the hypothesis that HIV causes AIDS but the dissenting voices were drowned in the clamour of competing claims for precedence and applications for research grants to study the new microbiological marvel.

Alan Cantwell was one who immediately realised that the HIV hypothesis did not answer the questions AIDS posed. He said: ‘Scientists clearly avoided the issue of what was causing Kaposi’s sarcoma in the [HIV antibody] negative patients. I wondered how a new virus could possibly cause a century-old form of cancer. There was absolutely no direct link between [HIV] infection and the development of Kaposi’s sarcoma. This fact didn’t seem to deter most AIDS experts who insisted that the new virus was the sole cause of AIDS.’

Cantwell runs through some of the theories which persisted about the cause of AIDS, then notes dolefully: ‘I continued to get some of my research work on bacteria in AIDS published in medical journals, although it was increasingly clear to me that medical editors were becoming more and more unresponsive to any research which did not conform to the idea of the new virus as the sole cause of AIDS.’

Cantwell was spotting interesting bacteria in the skin tumours of Kaposi’s sarcoma and in lung tissue affected with Pneumocystis pneumonia. Of course, he might have been mistaken in what he saw or the bacteria might be harmless, but one would at least have thought it merited consideration.

Most research which did not comply with the HIV hypothesis was simply ignored. Joe Sonnabend suffered a worse fate. In 1983 he set up a journal titled AIDS Research which was a forum ‘for basic research and clinical observations on Acquired Immunodeficiency Syndrome’. It used direct reproduction methods so that articles could be distributed fast.

AIDS Research did not ignore the HIV hypothesis. Some of its articles were directly within the field of the hypothesis, some questioned it or sections of it. Others simply dealt with new methods of treatment. There were articles about the association between AIDS and syphilis and treatment of disseminated cytomegalovirus infection and the effect of rectal insemination on laboratory rabbits.

There were twenty-one people on the board of AIDS Research when it was still an independent journal in the autumn of 1986. The Burroughs Wellcome Company then began to fund the journal, presumably out of the profits it was making from AZT, the AIDS drug, which will be discussed in more detail later in this book. The journal was renamed AIDS Research and Human Retroviruses. There were nine articles in the first edition in 1987, seven of them about HIV and two about other retroviruses alleged to be linked to it. There were fifty people on the new editorial board, only two of them had been on the AIDS Research board. Joe Sonnabend, of course, had gone.

Robert Gallo became a household name as few other scientists have done. He enjoyed public acclaim from people who could not know enough to criticise him and surrounded himself at the National Institutes of Health with colleagues whose respect bordered on adoration. One press officer told me Gallo was ‘the complete Renaissance man’ and Sam Broder, another cancer researcher, said: ‘Gallo is one of the paradigmatic figures of the twentieth century. He’s influenced things in our daily lives to an incalculable degree. Einstein, Freud - I’d put him on a list like that, I really would.’

A more balanced picture of Gallo was featured in the magazine Advances in Oncology, noting he has served for fifteen years as Chief of the Laboratory of Tumor Cell Biology, Departmental Therapeutics Program, National Cancer Institute. ‘In that position he has transformed what might otherwise have been a relatively unnoticed basic research facility into an ignescent force in the battle against AIDS.’

Or maybe not. ‘Without Robert Gallo there would have been no HIV’ is a great compliment if he is right. If he is wrong, it is a great curse.

Coda

As always, what did not happen is as significant as what did. Remember the fashion designer, the thirty-three-year-old Parisian homosexual who was feeling unwell just before Christmas 1982? Doctor Willy Rosenbaum took a sample of tissue from his enlarged lymph nodes and sent it to Montagnier’s groups at the Pasteur Institute. What happened to that patient? This was the most famous AIDS patient in history, the one from whom the ‘AIDS virus’ was isolated, which gave the discovery to Montagnier. It was the virus which was sent to Gallo’s laboratory and which was almost identical to the one Gallo claimed he had found. Five years later that patient was still alive and well and living in Paris.

When Willy Rosenbaum talked to me in July 1988, five and a half years after the patient had been to see him with lymphadenopathy, he assured me that the patient was very well. So, he added as a matter of interest, was the other patient whose tissue was taken at the same time to demonstrate that he had antibodies to the virus.

It is possible to over-interpret this information. As Willy Rosenbaum said: ‘The majority of patients who are infected have no AIDS.’ Even according to the establishment view, it is possible to accept the presence of the virus without the clinical disease. I feel it is more of symbolic importance: within five years the most famous HIV patient in the world did not develop AIDS. *