Virolution. Frank Ryan
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developed cancer, and it even happened in the absence of developing cancer. Subsequently, it became clear that the immunosuppression was related to the strain of retrovirus … [This assumed a more societal importance when] it became clear that Gallo had identified the first human retrovirus.’3
The virus to which Essex was referring is now known as the human T-cell leukaemia virus, or HTLV-1, which causes T-cell leukaemia, a cancer involving the white blood cells known as lymphocytes, which play a key role in the body’s fight against viruses, and indeed against any form of foreign invasion of the blood or tissues. The story actually goes back to 1976, when a Japanese researcher, Dr Kiyoshi Takatsuki, was studying a newly discovered form of leukaemia, in which the cancerous cells had nuclei so dramatically convoluted that they looked like the bunched up petals of flowers. Takatsuki noticed that almost all of the sufferers came from Kyushu, a large island to the southwest of Japan, so he travelled to Kyushu where he found that doctors in the local hospitals were treating many people with this bizarre leukaemia. At this time nobody knew the cause of this disease, but they decided they would call it “Adult T-cell Leukaemia”.4 Then, in 1979, as Essex had just remarked, Robert Gallo and his collaborators at the US National Institutes of Health found the causative virus in the blood of a 28-year-old man from Alabama, who was suffering from a lymphoid cancer of his skin. Two years later, Japanese virologists Yorio Hinuma and Mitsuaki Yoshida isolated the same retrovirus from the Japanese leukaemia patients. This virus, which is now known as human T-cell leukaemia virus one, or HTLV-1, was the first human retrovirus to be isolated.
‘This was before AIDS was recognised?’ I asked Essex.
‘Before AIDS was recognised. It was probably about the time that, or shortly after, AIDS was already present in Americans but before it was recognised and appreciated as a clinical entity.’
We had arrived at what appeared to be a key moment in the early investigation of AIDS and I encouraged him to talk about it further.
‘There was a workshop in Seattle. It was contacted by our National Cancer Institute, in collaboration with the Japanese, to see how important such human retroviruses might be. I was invited to co-chair it … I went there with Gallo and about four or five people from his lab, together with six or seven Japanese investigators working on these viruses, such as Hinuma, Miyoshi, Yoshida and Takatsuki – the people who defined the leukaemia. It became clear during the discussion that there were lots of things that really needed to be done, and they just weren’t happening. The first thing I suggested doing – and was encouraged to do myself – was to question whether or not some of those viruses, like the human T-cell leukaemia virus, might be immunosuppressive, the way retroviruses of cats were, because they infected the same T-lymphocytes.’
‘Which immune cell in particular is infected by the HTLV-1 virus?’
‘The T4 lymphocyte – exactly the same cell as AIDS. It’s not absolutely clear that it’s through the same receptor, but it’s definitely the same cell. You find all the same transmission strategies, such as sex, and mother to infant, although HIV is a little more effectively transmitted cell-free by blood.’
Even today, HTLV-1 infection remains an important source of disease in Japan, America, in the Aborigines of Australia, Peru, Colombia, Ecuador, Africa and the Caribbean – and the Inuit of Northern Canada. As Essex explained, it is transmitted in the same way as AIDS, although the pattern of transmission varies from country to country. In Japan it is mainly transmitted from mother to child through breast-feeding, while in America, Australia and South America it is mainly through sexual intercourse and through contaminated needles, syringes and blood products. The disease pattern also resembles AIDS, with most of the deaths resulting from immunosuppression. A small percentage of sufferers get progressive nerve damage, and in the very long term it can cause cancers such as leukaemia and lymphoma. A closely related virus, HTLV-2, infects intravenous drug users in America and the Caribbean, which is also associated with nerve damage.
I listened attentively as Essex moved deeper into the heart of the preliminary investigation of the AIDS pandemic.
‘So we were studying HTLV from the standpoint of immune suppression and then, with Gallo, we put forward the hypothesis that retroviruses should be considered as a possible cause of AIDS. It was at that time too, let’s say ’82 – after the clinical syndrome of human AIDS had been announced, and before any human viruses had been claimed for discovery – that the head of the New England Primate Centre, a guy named Ron Hunt, called me. He said that he had seen immunosuppression similar to human AIDS, and to the immunosuppression we had described in cats, in his monkey colony at the Harvard-associated facility about 50km away from the medical campus. He asked me if I would come out and talk to them and make some suggestions about how they might find the cause. I went out there and had discussions with Ron, and with Norman Letvin and two or three others, and I made the suggestion that we look at blood and tissue samples. We found that there was a virus in the animals that had developed lymphoma, and in the ones that were housed with those that developed lymphoma, even though they might not have lymphoma. We showed that it was a retrovirus on serology and by electron microscopy.’
I should explain that the afflicted monkeys were not African monkeys – they were Asian macaques. I asked him if the antibodies they were finding in the macaques in the monkey colony suggested that they were infected not with the human virus, HTLV-1, but with a related retrovirus.
‘Right. It showed that a lot of the monkeys that had lymphoma – and some of the ones that did not have lymphoma but were in the same facility, and were immunosuppressed – had a virus that was cross-reactive with, and morphologically similar to, HTLV-1 in Japanese people. Then, when [HIV-1] the actual cause of AIDS was discovered,5 we already had samples of the causative virus [of the monkey immunosuppression] in our laboratory, and we then asked ourselves whether or not the sick monkeys had a virus exactly like [HIV-1] – and whether or not it clustered with the development of immunodeficiency.
‘I collaborated with Ron Desrosiers and Norm Letvin, with the work in my own laboratory coordinated by Phyllis Kanki, who was a doctoral student of mine at that time. We found that the monkeys that had the AIDS-like immunosuppression, and some of the ones with lymphoma too, were infected with a new virus, which we initially called STLV-III. Later, of course, it was called SIV.’6
SIV is the simian immunodeficiency virus, and its discovery would play a major role in our understanding of the origins of AIDS. But there was an additional, important extrapolation that came from its study. At this time nobody knew where AIDS had come from, geographically or virologically.
‘As soon as we realised there were viruses related to HIV and HTLV in monkeys, it seemed likely these viruses must be coming from Africa, and perhaps the common link with the human AIDS virus would be African. A year or two earlier, Belgian and Dutch researchers published work on the clinical recognition of AIDS in African people. So we said, “Gee, maybe we should look at people in Africa who are high risk for this sort of infection – like female prostitutes and male patients attending STD clinics, and perhaps infectious disease patients – and see if they have a virus that fits somewhere within the spectrum between the monkey viruses and the human viruses.” So we looked at blood samples from these high-risk people and found some cross-reactive antibodies and subsequently we also found actual virus.’
Which virus was he now speaking about?
‘People were clearly infected with a virus very closely related to the monkey virus, in fact virtually indistinguishable from it. And this new virus was clearly related to HIV-1 – but it was also clearly distinguishable from HIV-1.’
Like HIV-1, this second human retrovirus would subsequently be isolated by Luc Montagnier at the Pasteur Institute, and identified as the second human immunodeficiency virus, or HIV-2. But what now interested me was the very close evolutionary link between HIV-2 and the virus Essex’s group had earlier discovered, the simian immunodeficiency virus, SIV.
‘What has been shown since then is that the monkeys in West Africa have a range of SIV viruses. Some of these viruses, from monkeys in exactly the endemic area we were studying, and from mangabeys in particular, have a simian immunodeficiency virus that is indistinguishable