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Chapter 29

The Discovery of HIV and the Development of Screening Tests


29.1 This chapter describes the discovery of the Human Immunodeficiency Virus and the scientific research that led to the development in the UK of screening tests for infection.

29.2 In 1986, the name 'Human Immunodeficiency Virus' (HIV) was adopted by the Varmus Committee.[1] Until then the virus had been known in French-inspired sources as lymphadenopathy-associated virus or immunodeficiency-associated virus (LAV/IDAV) and in US-inspired sources as human T-lymphotropic virus type III (HTLV-III). It was shown in 1984 that the viruses were the same.[2]

The first human retroviruses

29.3 By the 1970s, retroviruses had been found in cats, horses, sheep, goats and other mammals and were well known to veterinary clinicians and pathologists.[3] In 1977, Japanese researchers investigating human diseases identified a retrovirus as the causative agent of an unusual leukaemia. Development work proceeded in the USA and the retrovirus was isolated in 1981 by Dr Robert Gallo (the principal US researcher in the area) and his colleagues at the National Institutes of Health (NIH) in the USA. They called it human T-lymphotropic virus type I, HTLV-I.[4] A second retrovirus was then isolated and called human T-lymphotropic virus type II, HTLV-II.

29.4 The identification of a human retrovirus in 1977 was a 'slightly revelatory moment' for those researchers who had been expecting such a discovery but it was very much a revelation for those who had not known what retroviruses were and now came to realise that there was a new class of viruses capable of infecting humans and causing disease. Against this background, the concept that a pathogenic retrovirus was a possible disease-causing agent in humans became very prominent and topical amongst specialist virologists interested in AIDS.[5] Professor Andrew Lever, Professor of Infectious Diseases at Addenbrooke's Hospital, Cambridge, said that some virologists and infectious diseases specialists would have speculated, in the immediate aftermath of the first reports of AIDS in haemophilia patients, that a retrovirus similar to HTLV-I might 'fit the bill' for AIDS.[6]

Institut Pasteur and LAV

29.5 Scientists at the Institut Pasteur in Paris, led by Professor Luc Montagnier, were among those who pursued that speculation. On 20 May 1983, an article was published in the journal Science reporting that researchers at the Institut had isolated a novel retrovirus from cultures of T-lymphocytes (a type of white blood cell which plays a central role in cell-mediated immunity) derived from the lymph nodes of a homosexual patient ('Patient 1') with signs and symptoms thought to precede AIDS.[7] The patient had multiple lymphadenopathies (swollen or enlarged lymph nodes). They reported that it appeared to be a member of the HTLV family. It was later recognised as identical to that subsequently isolated by Dr Gallo and his team at the NIH in 1984. Neither of the expressions 'LAV' or 'IDAV' appeared in the Science article. Rather, the article dealt with the possible classification of the virus as a member of the HTLV family and the differentiation of the new virus from the known viruses, HTLV-I and HTLV-II.

29.6 The tentative conclusion of the article was that the virus belonged to a family of T-lymphotropic retroviruses that were horizontally transmitted in humans and might be involved in several pathological syndromes, including AIDS. The conclusion was uncommitted on the issue of whether the new virus was the aetiological agent causing AIDS. The 'antigen overload' alternative[8] was explicitly acknowledged. The article stated:

The role of this virus in the etiology of AIDS remains to be determined. Patient 1 had circulating antibodies against the virus, and some of the latter persisted in lymphocytes of his lymph node (or nodes). The virus-producing lymphocytes seemed to have no increased growth potential in vitro compared to the uninfected cells. Therefore, the multiple lymphodenopathies may represent a host reaction against the persistent viral infection rather than hyperproliferation of virus-infected lymphocytes. Other factors, such as repeated infection by the same virus or other bacterial and viral agents may, in some patients, overload this early defence mechanism and bring about an irreversible depletion of T cells involved in cellular immunity.[9]

29.7 The full significance of the French discovery was not widely acknowledged in 1983. Later, Professor Montagnier commented:

Our results were still controversial ... and we had difficulty in obtaining the funding needed to better characterize the virus and develop a blood test. The tide only turned in France when Robert Gallo and his group in the United States made a similar discovery. In the spring of 1984, Gallo published more convincing evidence that HIV causes AIDS.[10]

29.8 Despite the hesitancy expressed by Montagnier, there was growing interest in the scientific community in the hypothesis that transmission of a virus caused AIDS, and for some specialists the Montagnier discovery was significant. After the publication of their paper in Science, however, the French scientists struggled to persuade some others in the field that the virus they had isolated was indeed the cause of AIDS.

29.9 In 2008 the Nobel Prize for Medicine was awarded to Luc Montagnier and Françoise Barré-Sinoussi (co-author of the Science article) for their discovery of the virus that causes AIDS. There had been controversy as to whether they or Dr Gallo's group had priority. In the opinion of Professor Robin Weiss,[11] the answer was clear: the French group published first.[12] It is not necessary to examine the merits of the controversy over priority any further in this Report.[13] Inevitably, however, against that background there were mixed reactions among scientists to the French paper. Professor Lever said that some were very convinced by it but that others were convinced only after the Gallo publication.[14]

29.10 As noted in Chapter 11, AIDS Aetiology, some Scottish scientists may have been persuaded by Montagnier. However, the impression given overall is that, leaving aside all national prejudices, internationally there was cautious scepticism among many opinion leaders about the French research, until Gallo's announcement. The Montagnier/Barré-Sinoussi team did not have a long track record of discovering viruses.[15] Their work did not have the international esteem required to spark the scientific research and development that followed the work of the Gallo group.

National Institutes of Health and HTLV-III

29.11 Dr Gallo and his group announced their discovery on 23 April 1984.[16] They reported the presence of antibodies to HTLV-III in a majority of patients with AIDS and at the same time announced that they had isolated human T-lymphotropic retroviruses from patients with AIDS. Preliminary details were published in two articles in Science on 4 May 1984.[17] It was announced that a retrovirus belonging to the HTLV family and designated HTLV-III had been isolated from a total of 48 subjects, some with AIDS, some with 'pre-AIDS' and some without symptoms but in risk groups. The authors concluded that HTLV-III might be the primary cause of AIDS.

29.12 Gallo's announcement was a turning point in developing knowledge worldwide. The evidence that people who had AIDS-like symptoms had antibodies against HTLV-III was more compelling circumstantial evidence that the virus was associated with the disease than finding the virus itself in somebody with the illness. In the latter case, the virus could have been a 'passenger', a virus to which the real AIDS virus had made the person more susceptible. Gallo's work was a major contribution to developing knowledge.[18] In time, the isolation and characterisation of the AIDS retrovirus enabled retrospective studies to be carried out on stored frozen blood samples from haemophilia patients, using tests for antibodies to the virus.

29.13 With the development of HTLV-III testing, following US research leading from Dr Gallo's work, further cases of infection emerged and the discovery laid the basis for the general consensus that has prevailed ever since.

29.14 There was soon intense research activity and an avalanche of technical papers. The characterisation of the virus as a 'true' member of the HTLV family was discussed.[19] The development of cell systems for the reproduction of HTLV antigen, a necessary step in developing antibody tests, was researched in May 1984.[20] The high incidence of antibodies specific to HTLV-III in patients with AIDS and pre-AIDS was identified, supporting the suggestion that HTLV-III was the primary cause of AIDS.[21]

Scientific response to LAV/HTLV-III in the United Kingdom

29.15 The work of Dr Gallo's group in isolating the HTLV-I retrovirus responsible for the rare form of leukaemia reported in Japan had led to research in the UK. The work done was important in relation to later research on HIV. Professor Lever said in his report:

[M]uch of the research work that had been undertaken in isolating and characterising HTLV-1 was absolutely critical in facilitating the rapid discovery and identification of HIV. The discovery and usage of certain cell lines for isolating viruses and the discovery of growth factors for human cells were all essential prerequisites for retrovirus isolation. If HTLV-1 had not been identified when it was then the identification of HIV might have been delayed by several years.[22]

29.16 For present purposes, research collaboration between Professor Robin Weiss at the Chester Beatty Cancer Research Institute and Professor Richard Tedder at the Middlesex Hospital, in a project to develop a serological assay for the detection of antibodies to HTLV-I, became particularly significant.[23] Professor Weiss provided Professor Tedder with infected serum and Professor Tedder's laboratory worked to develop the detection of antibodies to HTLV-I. By late 1983, this work was well advanced. As will be seen later, they subsequently used the expertise they gained in that research to develop anti-HTLV-III tests when it became clear that this virus was associated with AIDS.

29.17 Earlier in 1983, Professor Tedder and his virology colleague Dr Philip Mortimer of the Public Health Laboratory Service (PHLS) both thought that AIDS looked like a transmissible viral infection. They had a meeting with a Department of Health and Social Security (DHSS) official, early in 1983. They explained their views about AIDS, including its similarity to Hepatitis B in terms of the group affected and the likely means of transmission, in order to see if they could assist by exploring the hypothesis that AIDS was a transmissible viral infection. Their overture was, however, rejected, and they were discouraged from promoting the 'transmissible agent' theory of the cause of AIDS.[24]

29.18 The official government line at the time was that there was 'no conclusive evidence' that AIDS was transmitted by blood products.[25] The rejection of the scientists' approach had an important bearing on what later transpired. Briefly, development work proceeded in the non-government sector. Through their organisations, Professor Tedder and Professor Weiss obtained the intellectual property rights to their discoveries, initially in respect of HTLV-I, and were able to shape the approach to the development of screening. Progress was to be determined by the scientists, not by the UK Government.

29.19 In France, the Institut Pasteur proceeded to develop an antibody screening test based on the LAV isolated by the work of Montagnier and Barré-Sinoussi. Professor Tedder and Professor Montagnier were in contact and, in the autumn of 1983, a courier brought to London a sample of IDAV, the name given at the time to the current version of the first French isolate. IDAV and LAV-I were both epidemic HIV-1 viruses and were in time to be identified as the same, for practical purposes. A ferry and trains were delayed and the courier left the flask in a security locker at Waterloo Station. When it was collected, the virus had died and could not be resuscitated.[26] Professor Weiss obtained more of the French virus in February 1984 but the London scientists had effectively lost some months of research work.

29.20 Professor Tedder's comments capture the position:

[W]e would have been six months ahead of where we were in September 1984 in terms of the early epidemiology. We might have had a British isolate, a UK isolate, much earlier. We might have been able to work with commerce much earlier.

As a scientist, it grieves me that we lost six to nine months on the field. Had we been publishing the [Cheingsong-Popov] 1984 September paper in January 1984/February 1984, we would have presaged the entire Gallo and Montagnier disclosure in the Science paper of May 4th. We would have not only demonstrated the virus, in reality we would have had the break on epidemiology. And I really - I look back and some things happen and some things don't. This young man carrying a bottle of LAV1 in his hand, nobody to meet him, leaving it in a lock-up on Waterloo Station, such are things fairy stories are written about, you know? Such is life ....

I still weep about it. But, you know, we didn't do badly in the end.[27]

29.21 For the purposes of this Inquiry, speculation on what might have been is not productive. However, the anecdote illustrates an important aspect of the reality of cutting edge scientific research in areas that attract the attention of several groups of researchers: priority may be determined by chance events. There is no necessary logical progression that allows one to transpose one team's success onto another's failure and reach conclusions about what ought to have happened, as distinct from what might have happened.

29.22 As events unfolded, Professor Weiss' laboratory was the first in the UK to become involved in investigating HIV when they did eventually receive the French isolate of the virus from Dr Montagnier in February 1984.

The propagation medium and the selection of test format

29.23 At this point, it is convenient to say something about the science of testing since it has an important bearing on the differences between, and the relative merits of, the test developed by Professors Weiss and Tedder and the tests developed in the USA.[28] In simple terms, and in the context of AIDS, the early tests were looking for the antibody to the virus. An antibody is a protein produced by the body in response to an antigen, which can be thought of as a 'foreign invader'.[29] The formation of an antibody in response to an antigen is a defining characteristic of an antigen. The human immunodeficiency virus - HIV - is an antigen. It stimulates the human body to form HIV antibodies. The screening systems developed at this early period targeted the HIV antibodies produced rather than the antigen. In most infections, the formation of antibodies signals the eradication of the infection.[30] Unlike antibodies produced against many other infective agents, however, the production of HIV antibodies does not indicate the eradication of the disease.[31] The presence of HIV antibodies was consistent with continuing disease.

29.24 HIV is an intracellular parasite and can only propagate (grow) by getting into human white blood cells.[32] Once Professor Weiss had received a sample from Professor Montagnier in February 1984, it was necessary to propagate the virus in order to produce antigen for the test. The choice of cell line was important. That required the selection and use of appropriate white blood cells - a specific cell line - as a medium for propagation.

29.25 When the HIV virus is released from a cell line it may carry with it components of the cells making up the line. These components may themselves cause reactions when introduced into a human recipient, eliciting their own antibodies. The cell line (known as H9)[33] used in the production of virus for the early US enzyme-linked immunosorbent assay (ELISA) tests was very efficient: large volumes of HIV antigens could be grown in it. However, the envelope of the cells making up the cell line (their 'lipid membrane') contained proteins other than HIV that could elicit antibodies when administered to some patients. The HIV antibody test produced using this cell medium was therefore responsive not only to HIV antibodies specifically but also to antibodies found in some normal, healthy people who had received a blood transfusion or an infusion of platelets, for example.[34] The test would register positive for antibodies in the case of these individuals whether or not they were infected with HIV. As a result, the risk of false positive results with tests using reagents produced by the H9 cell line was high: the cell line in which the virus was grown was itself responsible for false positive results.[35] The risk was inherent in the basic technology adopted at this early stage.[36]

29.26 Professor Weiss' team used a different cell line, the 'CEM' cell line,[37] on the advice of a colleague, Professor Mel Greaves.[38] This avoided problems encountered with some of the tests developed in the USA. They developed the CEM cell line initially for research into HTLV-I. The CEM cell line used (and provided by them to the Institut Pasteur on licence)[39] did not express the antigens (in addition to HIV) typically produced by US technology.[40] As demonstrated by the research reported in the Cheingsong-Popov paper referred to at paragraph 29.14 above, it was less prone to false positive results and in fact yielded almost no false positive results in the 1984 research exercise reported.[41] A factor contributing to its success in that respect may have been that the proportion of infected individuals in the donor population was lower in the UK than in the USA[42] but the technology does appear to have been fundamentally more satisfactory at this early stage than that typically employed by US pharmaceutical companies.

29.27 The second difference that needs to be noted is the difference between radioimmunoassay (RIA) and ELISA tests. Professor Tedder's research work, once virus-infected material had been provided to him, led to an RIA which was considered to be working by 4 July 1984, at least for laboratory purposes.[43] In RIA systems, radioactive isotopes are used in the detection of the target antibody. By contrast, in an ELISA the detection element is provided chemically by an enzyme. Although this initial RIA turned out to be highly successful in the UK research studies, the Inquiry heard evidence that around this time (1984-85) the general scientific climate was turning against RIA testing because of the use of radioactive materials and the safety of staff involved in testing.[44] In the event, no commercial company developed an RIA for the detection of HIV antibodies[45] and Professor Tedder's RIA was to give way later to an ELISA test.

29.28 A third, and highly technical, distinction relates to the test format and the difference between a so-called solid phase test and a competitive test. The distinction lies in the functioning of the tests. It is relevant in this Report only to the extent that it came to have a part in assessing the respective merits of the US solid phase tests and the Middlesex Hospital/Chester Beatty competitive radioimmunoassay test developed by Professors Weiss and Tedder (the MH/CB assay) in a competitive market.

29.29 All of the US tests under development were solid phase ELISA tests. To be fully effective, the virus antigen had to be 'pure'. For practical purposes it was assumed that virus antigen and only virus antigen was adsorbed (condensed on the active portion of the test kit). However, as has been described in relation to the cell line typically used in the USA, the material that is applied in the solid phase test may contain antigens other than those to which the test is directed. As a result, the US model was exposed to the risk of attracting non-relevant antibodies and thereby producing false positive results.

29.30 The commercial companies involved in developing the US tests used large vessels to propagate the virus and then purified the virus from the 'soup' in which the cells were growing. The virus then had to be further purified, pelleted and further cleaned up physically by processing through a density gradient (a centrifuge used to isolate and purify cells, viruses and sub-cellular particles). A great deal of work was involved and the complexity of the process added to the time required for development of effective test kits.[46]

29.31 By contrast, the competitive test format used in the MH/CB assay did not require 'pure' antigen. It used relatively high volumes of serum and was inherently more specific in application than the US test format. It attracted criticism in the 1980s, however, on the ground that it was relatively insensitive.[47] For present purposes, the technical distinctions between the two approaches need not be developed further. It is, however, important to note that they were distinct and that the UK developments were able to proceed without challenge from the USA on intellectual property grounds.

United Kingdom research: the initial phase

29.32 The research projects of Professors Tedder and Weiss in England, and the Institut Pasteur in France, were making progress over substantially the same period as the US research discussed below. When Professor Weiss obtained LAV from Professor Montagnier in February 1984, his laboratory was concerned to investigate the prevalence of the infection and the risks associated with it.[48] At that time, virological research into the disease was at an early stage of development. LAV/HTLV-III infection was a threatening and dangerous condition and funds were diverted by the two scientists from other areas of their respective institutions' research in order to begin the study. They proceeded without funding from either the Medical Research Council (MRC) or the DHSS.[49] They did not await the development of administrative solutions.

29.33 Dr Gallo also provided Professor Weiss with isolates of HTLV-I, HTLV-II and, in mid-1984, provided HTLV-III for research purposes.[50] The US and French isolates had both been provided in terms of Material Transfer Agreements, a common format between research laboratories that restricts their use to research, stipulates that the provider accepts no liability and stipulates that the material must not be used for commercial developments.[51] The isolate provided by Dr Gallo was HTLV-III B, the same isolate as was provided to all scientists interested in the investigation. Montagnier provided the current version of LAV-1. Professor Tedder and colleagues started developing antibodies using the Gallo isolate and continued with that source material almost exclusively until, in about November 1984, Professor Weiss' group had produced a British isolate against which Professor Tedder's team could develop antibodies. A British test was trialled in November 1984. They propagated the antigen in CEM cells which produced better quality virus and a very high level of viral antigens trapped in the cells.[52] In this way, they continued to produce antigen until spring 1985. In 1984 there was little to choose between the French and US isolates and the choice of the Gallo material for research seems to have been a matter of chance.[53]

29.34 The Cheingsong-Popov article of 1 September 1984 set out the first published results of that research.[54] In carrying out the project, the MH/CB RIA assay to detect antibodies to HIV developed by Professor Weiss and Professor Tedder was used.

The MH/CB assay for anti-HTLV-III

29.35 There were issues for the Inquiry whether any delay in the provision of funding by the UK government, or the US government's attitude to the use of the Gallo isolate (referred to later at paragraphs 29.41-29.43), hampered progress in developing a British screening test. It appears clear from their evidence to the Inquiry that neither factor prevented or hindered progress by Professor Tedder and Professor Weiss in laboratory-based development of the assay. As noted later, funding for scale-up to industrial production became an issue, however.

29.36 For them, it was an incredibly difficult and busy time, with resources stretched almost to breaking point.[55] In some respects, in attempting to meet the demands on them, Professor Tedder and his colleagues acted in a way that would have been constrained by modern employment practices.[56] Professor Tedder said that Dr Rachanee Cheingsong-Popov on one occasion left the maternity hospital where she was in the early stages of labour to finish a procedure in a radioimmunoassay. She gave birth to her first son two hours after returning.[57] Professor Tedder was to complain in strong terms about the lack of support and funding before the end of the year (1984)[58] but that did not inhibit the progress of their work. The scientists were pursuing their own project not only unsupported but also uninhibited by government oversight.

29.37 In the event, the prototype MH/CB competitive assay was ready for laboratory application on 4 July 1984. At that stage, they were ready to carry out epidemiological studies.[59] On 16 July 1984, Dr Ian Fraser of the Bristol Blood Transfusion Service wrote to Dr Alison Smithies, DHSS, outlining what was proposed.[60] He reported that a screening test for AIDS was likely to be available within the next eight weeks or so for trial, first at Edgware and then at Bristol and Manchester.

29.38 At that stage the DHSS did not have an isolate that could be provided to a commercial manufacturer in the UK for the development of a test. The MH/CB test was beginning trials but, from the summer of 1984, Professor Tedder and his colleagues believed that they needed a much larger number of donors to be tested than those dealt with in their paper to ascertain the prevalence of HTLV-III in the donor population. For this, they required to involve a wider range of centres. Widening the project involved risk and would require control. The National Blood Transfusion Service (NBTS) was reluctant to introduce general testing because of the risk of attracting individuals seeking access to 'AIDS tests' for personal purposes.[61] Targeted subsets had proved problematic in other contexts. It was important to avoid attracting 'window donors', individuals who thought they had been recently exposed, who were, as Professor Tedder put it, 'bad news' for the blood component issue but could have been 'devastating' for blood products.[62] There was, however, a clear need to expand the research.

29.39 It was at this stage that DHSS officials made contact with their US counterparts to ask permission to use Gallo technology for screening in the National Health Service (NHS). The DHSS was aware of the development of the RIA by Professors Weiss and Tedder from isolate supplied by Dr Gallo 'for research purposes only'. Among other aims, the DHSS was keen to commence screening of donated blood for the virus, initially at two or three Regional Transfusion Centres. To do so, as the DHSS saw it, it was necessary to obtain further supplies of the virus from the USA.

29.40 On 10 August 1984, a DHSS official, probably Dr Walford or Dr Smithies, wrote to the Assistant Secretary for Health in Washington DC. The letter narrated the work of Professor Tedder and Professor Weiss, and the anticipated publication of their research, and stated:

We are anxious to extend the screening test initially to two or three of our Regional Transfusion Centres in order to establish the incidence of carriers amongst donors in a varied donor population. To do this further supplies of antigen are required over and above those that could be regarded as purely for research purposes which was the understanding on which [Dr Weiss] received the isolate from [Dr Gallo] in the first place. I am writing to request your agreement to our using the virus isolate originally provided by Dr Gallo to scale up production of the antigen.[63]

29.41 It was stressed that the intention was for the isolate to be used mainly for NHS purposes. Permission was refused on 14 November 1984.[64] It was now clear that, outwith the boundaries of the Material Transfer Agreement entered into by Professor Weiss and Professor Tedder, the NHS was denied the Gallo isolate by the US government.

29.42 The precise date on which the MH/CB assay was ready for routine use is not clear. It was reported to the Advisory Group on AIDS on 27 November 1984 that Professor Weiss had a UK isolate and cell line suitable for assay[65] but the information appears to have lacked clarity. Dr Brian McClelland, Director of the Edinburgh and East of Scotland Blood Transfusion Service, reported that he could get no clear picture of when or how a serviceable assay would be provided. Having regard to the then pending patent application in the names of the Middlesex Hospital and the Chester Beatty Laboratory,[66] it would have been highly unlikely that Professor Weiss and Professor Tedder would have disclosed details of their test. Professor Weiss wrote to the DHSS on 3 December 1984 confirming that he had a local independent isolate of the AIDS retrovirus.[67] An RIA from this isolate was also developed at the Middlesex Hospital.[68] Professor Weiss suggested that the use of US reagents should be stopped and that scaling-up of their methods should be developed independently. He also reported continuing discussions to expedite the development of reagents.

29.43 The Inquiry was initially concerned to establish whether the unwillingness on the part of the US Department for Health and Human Services to allow the US isolate to be used for blood donor screening in the UK delayed the introduction of screening in this country. In fact, Professor Weiss advised the Inquiry that, by the time the reply was received from the US government, an independent isolate had already been developed by his team. Neither Professor Weiss nor Professor Tedder considered that the refusal by the US government delayed the development of a test for use in screening blood donors in the UK.[69]

29.44 As regards HTLV-III antibody screening, Professor Tedder advised the Haemophilia Reference Centre Directors on 10 December 1984 that the Gallo cell line was available for research although the US government had made the isolates difficult to obtain. Looking forward, the testing of donors for HTLV-III antibody required either mass commercialisation of a British test or application of a US commercial test when that became available.[70]

29.45 The approach of Professor Weiss and Professor Tedder differed from the US approach in a number of significant respects, as already discussed. Their work was now at a critical stage. In order to provide a test for general use, the laboratory-based work had to be scaled-up to industrial levels for commercial manufacture and marketing.

Scaling-up the MH/CB assay for routine use

29.46 On 18 December 1984, Professor Tedder wrote to Dr Smithies:

i. We urgently need to be able to scale-up ... the Middlesex Hospital/Chester Beatty radioimmunoassay (MH/CB RIA).

ii. The MH/CB RIA has been designed to be compatible with the current BTS hepatitis testing. Pilot studies are of the utmost priority in selected centres to confirm this is indeed the case.

iii. Until the MH/CB RIA has been routinely used for a considerable time, it is very important that reactive sera are referred to a designated laboratory for confirmatory testing and that donors and their blood products are followed up.

iv. There is an initial need to monitor the efficiency with which the MH/CB RIA and the forthcoming commercial kits detect anti-HTLV III.[71]

29.47 He sought financial support and commented that his Dean (Professor Sir John Pattison) and he, 'must emphasise that we see the necessary UK commitment to this problem increasing over the next few years' but that the hospital would not be able to take up the work without support.[72]

29.48 On 31 December 1984, Dr Smithies, DHSS, drafted and circulated a position paper on 'AIDS and its prevention in the UK' in response to a request from the Chief Medical Officer (CMO).[73] She commented on the response on 14 November 1984 from the US government to the request for permission to make wider use of the Gallo isolate and noted that, by the time the response had been received, Dr Weiss had succeeded in isolating the virus from a British patient. She noted that negotiations had been opened with Wellcome (Wellcome Diagnostics, a UK pharmaceutical company) to use the UK isolate to develop a UK test, and that Wellcome had sub-contracted CAMR Porton, who had the appropriate containment facilities, to produce the antigen.[74] The advantages of the UK test were noted: with luck, it might be available at about the same time as the US commercial tests; it was suitable for use in RTCs which already had experience of the RIA format; it was also more sensitive and specific than the US tests; and it was likely to be less expensive.

29.49 In addition, Dr Smithies prepared a draft submission to Ministers seeking approval for the introduction of an AIDS screening test. In sending the paper to Dr Richard Alderslade, DHSS, for consideration by the CMO, she wrote:

The UK test is currently being used at the Middlesex Hospital and at the Central Public Health Laboratory, Colindale to detect antibody carriers among patients thought to have AIDS or the AIDS related complex, haemophiliacs and male homosexuals attending STD clinics.

Scale up of production of the reagent is necessary before the test can be applied more widely.[75]

29.50 In the event, testing of patients (particularly haemophilia patients) was already widespread by the end of 1984. From the researchers' point of view, that might have been characterised as an extension of the research project. From the clinicians' point of view it was an aspect of patient care. It had revealed that a significant proportion of English and Welsh haemophilia patients and at least 33 Scottish haemophilia patients were positive for the AIDS virus.[76] Professor Tedder's letter of 18 December 1984 had sought funds for development to promote donor screening, not testing of patients.

29.51 It appears that the distinctions between 'research' testing of assays for HTLV-III by Professor Tedder and subsequent testing of wider groups, for example the haemophilia population, for antibodies to HTLV-III/HIV, may have become blurred by the beginning of 1985 so that 'patients' were beginning to be screened rather than 'research subjects' evaluated. This was probably increasingly the position in relation to the use of the initial tests based on Gallo/Montagnier isolates and subsequently in the evaluation of the test based on the UK isolate from December 1984. By early 1985 the majority of UK haemophilia patients had been tested for HTLV-III in a piecemeal fashion, without a developed protocol having been worked out and promulgated. It seems likely that, because testing arose in this way, many of the issues around informed consent and counselling which were soon to emerge were not dealt with and haemophilia doctors found themselves in possession of important information about their patients with which they were ill-prepared to deal. Practical response on the ground had run beyond official guidance. These issues are dealt with in Chapters 32 and 33.

29.52 In addition to the two papers referred to at paragraphs 29.48-29.49, Dr Smithies prepared a further paper dated 4 January 1985 for the Research Liaison Group (a joint NBTS/BPL research group).[77] In it she supported Professor Tedder's application for funding.[78] She narrated the work of Professor Tedder and Professor Weiss in developing the MH/CB RIA, its compatibility with the BPL Hepatitis B RIA (then routinely used to screen blood donors for Hepatitis B); and the role of Wellcome, and stated:

There has been a Patent application in the names of the Middlesex Hospital and the Chester Beatty Laboratory ... and commercial exploitation is likely.

The MH/CB RIA is thus a product of the co-operation of British Science and British Industry. There is general agreement that it is the most sensitive RIA for HTLV III presently available.[79]

29.53 As noted above, the MH/CB RIA was, in fact, the only RIA developed for the HTLV-III antibody.[80] Dr Smithies drew heavily on Professor Tedder's representations in supporting further work, which she said was strongly supported by the Medical Division of the DHSS. In relation to the anticipated arrival of commercial kits, she commented that Middlesex Hospital would be uniquely qualified to assess them when they arrived.

29.54 The expectation of officials at this stage (January 1985) appears to have been that the joint venture between academic researchers and a drug company[81] would lead to an RIA, developed in the UK, becoming available about the same time as the US ELISA tests would become available.[82]

29.55 In terms of technology, Professor Tedder commented that Dr Smithies' information was already out of date, possibly encouraged by his letter to her of 18 December 1984. The group had already begun work on an ELISA with Wellcome in October or November 1984. His letter appears to have been drafted in the light of experience of the approach most likely to be productive of funding.[83] On the other hand, protection of intellectual property rights in the MH/CB assay and related work would have been a legitimate reason for caution in disclosing information, given the initial refusal by the DHSS of support for research in response to the threat of AIDS.

29.56 The scientific research and initial development work necessary to produce a specification for a commercially marketable product had been done. Outstanding was the development work required to scale-up the project for industrial manufacture and general supply.

29.57 As Dr McClelland explained to the Inquiry, there is a 'huge difference' between an assay which works well in a laboratory in the expert hands of research scientists, and a test which can be used for hundreds of thousands of tests daily in the sort of working environment surrounding the screening of donors.[84] The achievement by Professors Weiss and Tedder of a functioning assay did not mean that there was immediately a test ready for use in screening blood donors in the UK for the AIDS virus. Much further work was needed and that required collaboration with Wellcome and their sub-contractors CAMR Porton.

29.58 The scaling-up of the project and progress towards commercialisation are discussed in Chapter 30, Screening of Donated Blood for HIV.

1 The Varmus Committee was convened by Dr Harold Varmus, Chair of the Retrovirus Study Group within the Vertebrate Virus Sub-committee of the International Committee on Taxonomy of Viruses: - last accessed 23 December 2014

2 Cheingsong-Popov et al, 'Prevalence of antibody to human T-lymphotropic virus type III in AIDS and AIDS-risk patients in Britain', The Lancet, 1 September 1984; 477-480 [LIT.001.0417]; Preliminary Report, paragraph 8.92

3 Professor Lever - Day 26, page 14

4 Professor Lever's Witness Statement [PEN.015.0517] at 0518

5 Ibid [PEN.015.0517] at 0518; Professor Lever - Day 26, page 13-14

6 Professor Lever - Day 26, page 16; Professor Lever's report [PEN.015.0517] at 0518. HIV was thought to belong to the sub-group of retroviruses called 'lentiviruses,' although Professor Lever stated that the most recent research suggested that, while certainly a retrovirus, HIV does not properly belong to the sub-group of lentiviruses: Day 26, page 25.

7 Barré-Sinoussi et al, 'Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS)', Science, 1983; 220:868-871 [LIT.001.0058]

8 Discussed in Chapter 11, AIDS Aetiology.

9 Barré-Sinoussi et al, 'Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS)', Science, 1983; 220:868-871 [LIT.001.0058] at 0060

10 Montagnier, 'A History of HIV Discovery', Science, 2002, 298; 1727-1728 [LIT.001.3767]

11 Professor Weiss was, at the time in question, employed at the Chester Beatty Laboratories, London. He is currently Emeritus Professor of Viral Oncology at UCL Medical School.

12 Day 48, page 173

13 The debate is more fully set out in John Crewdson's book Science Fictions.

14 Professor Lever - Day 27, page 30

15 Professor Lever - Day 26 pages 69-70

16 Preliminary Report, para 8.84

17 Gallo et al, 'Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS', Science, 1984; 224: 500-503 [LIT.001.3769]; Popovic et al, 'Detection, Isolation, and Continuous Production of Cytopathic Retroviruses (HTLV-III) from Patients with AIDS and Pre-AIDS', Science, 1984; 224 (reprint Plasma Quarterly Summer 1984) [SNB.004.9457]

18 Professor Lever - Day 26, pages 71-72.

19 Schupbach et al, 'Serological analysis of a subgroup of Human T-Lymphotropic Retroviruses (HTLV-III) Associated with AIDS', Science, 1984; 224: 503-505 [LIT.001.0685]

20 Popovic et al, 'Detection, Isolation and Continuous Production of Cytopathic Retroviruses (HTLV-III) from patients with AIDS and Pre-AIDS', Science, 1984; 224 (reprint Plasma Quarterly Summer 1984) [SNB.004.9457]

21 Sarngadharan et al, 'Antibodies reactive with human T-lymphotropic retroviruses (HTLV-III) in the serum of patients with AIDS', Science, 1984; 224 [LIT.001.5515]; Gallo et al, 'Frequent Detection and Isolation of Cytopathic Retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS', Science, 1984; 234: 500-503 [LIT.001.3769]

22 Professor Lever's report [PEN.015.0517] at 0518

23 Professor Tedder - Day 49, pages 3-4; Professor Tedder's Witness Statement [PEN.017.1831]

24 Professor Tedder - Day 49, pages 97-98. For discussion on the 'transmissible agent' hypothesis concerning the aetiology of HIV/AIDS, and competing hypotheses at the time, see Chapter 11, AIDS Aetiology.

25 Extract from Hansard, 14 July 1983 [SGH.002.6720] at 6721. See Chapter 9, Knowledge of the Geographical Spread and Prevalence of HIV/AIDS 1, paragraphs 9.108-9.110

26 Professor Tedder's Witness Statement [PEN.017.1831]; Professor Tedder - Day 49, pages 6-7

27 Professor Tedder - Day 49, pages 62-63

28 Ibid, pages 37-48 and 50-60. Professor Tedder explained to the Inquiry these different features of testing kits and this summary is derived from his evidence.

29 See paper produced by Dr Peter Foster [PEN.013.1309], Glossary at 1310.

30 Dr Cuthbertson - Day 46, page 5

31 Ibid page 6

32 Professor Weiss - Day 48, page 165

33 A sub-line of the leukaemia tumour line.

34 In particular, the Class-II Major Histocompatibility Complex (MHC-II) antigens (MHC Class II antigens). These are found also in women if they have had children with DR4 positive partners: Professor Weiss - Day 48, page 167

35 See discussion of this at paragraph 29.29

36 Professor Tedder - Day 49, pages 45-46

37 The CEM cell line is associated with some forms of T-cell leukaemia and Hodgkin's disease, a cancer originating from lymphocytes.

38 Professor Weiss - Day 48, pages 168-169

39 Ibid page 170

40 Professor Weiss' report [PEN.017.1261]

41 Professor Weiss - Day 48, page 159

42 Ibid page 159. Professor Weiss suggested that this was probably true, not only in those contributing to commercial blood banks but also among volunteer donors in the USA at this time.

43 Professor Tedder - Day 49, pages 15-16

44 Ibid pages 65-67; Dr Dow's Witness Statement [PEN.017.1680] at 1681; Dr Mortimer's Witness Statement [PEN.017.1761]; Professor Cash - Day 48, page 136

45 Dr Dow's Witness Statement [PEN.017.1680] at 1681

46 Professor Tedder - Day 49, page 10

47 'Sensitivity' is a function of the test's ability to capture all cases of infection with the target pathogen. 'Specificity' is a function of the test's ability to identify only the target pathogen.

48 Professor Weiss' Statement [PEN.017.1261] at 1263; Professor Tedder - Day 49, page 6

49 Professor Tedder - Day 49, pages 69-70

50 Cheingsong-Popov et al, 'Prevalence of antibody to human T-lymphotropic virus type III in AIDS and AIDS-risk patients in Britain', The Lancet, 1 September 1984; 477-480 [LIT.001.0417] at 0418 regarding ascertainment of prevalence of the virus in patients with haemophilia.

51 Professor Weiss - Day 48, pages 5-13, and 171

52 Professor Tedder - Day 49, pages 11-12

53 Professor Weiss - Day 48, page 170; Professor Tedder - Day 49, page 14

54 Cheingsong-Popov et al, 'Prevalence of antibody to human T-lymphotropic virus type III in AIDS and AIDS-risk patients in Britain', The Lancet, 1 September 1984; 477-480 [LIT.001.0417]

55 Professor Tedder - Day 49, pages 78-79

56 Ibid page 79

57 Ibid page 70

58 Ibid page 79; Letter to Dr A Smithies, DHSS dated 18 December 1984 [DHF.001.8856]

59 Professor Tedder - Day 49, pages 15-16

60 Letter [DHF.002.9126]

61 Professor Tedder - Day 49, pages 71-72; Professor Tedder's report [PEN.017.1831] at 1833.

62 Professor Tedder - Day 49, pages 72-74

63 Letter [DHF.001.5619]

64 Crewdson, Science Fictions, pages 188-189 [PEN.017.0568] at 0592-0593. See position paper 'Aids and its prevention in the United Kingdom' (undated and without appendices) [DHF.002.0431] at 0432, para 4. Date is probably 31 December 1984 - see [DHF.002.0430]. See also letter from Department of Health & Human Services, Bethesda, Maryland to Chester Beatty Research Institute dated 19 December 1984 [DHF.001.8858]

65 Dr McClelland made notes of the meeting [PEN.012.1938] at 1939

66 Referred to in [DHF.001.9036], dated 4 January 1985: see paragraph 29.50.

67 Letter [DHF.001.8805]

68 Letter dated 18 December 1984 from Professor Tedder to DHSS [DHF.001.8856]

69 Professor Weiss - Day 48, page 172; Professor Tedder - Day 49, pages 12-14

70 Notes of Meeting [SNF.001.3850]

71 Letter [DHF.001.8856]

72 Ibid [DHF.001.8856] at 8857

73 Covering letter [DHF.002.0430]; position paper [DHF.002.0431]

74 Formerly the highly secretive MOD technology park DSTL Porton Down, the establishment closed as an MOD facility in 1979 and re-opened in 1980 as the Centre for Applied Microbiology and Research (CAMR) within the Public Health Laboratory Service (PHLS).

75 Letter [SGH.002.7303]

76 The number of seroconversions in Edinburgh among recipients of the implicated batch was 18, as explained in the Preliminary Report, paragraph 8.207. See also Chapter 10, Knowledge of the Geographical Spread and Prevalence of HIV/AIDS 2.

77 BPL, The Blood Products Laboratory, is the manufacturer of NHS blood products in England and Wales.

78 Covering Letter [DHF.001.9040]; Paper [DHF.001.9036]

79 Paper [DHF.001.9036]

80 Professor Tedder - Day 49, page 82

81 There was pride in this cooperation between British science and British industry - see paper of 4 January 1985 [DHF.001.9036] as quoted above.

82 See draft position paper 'Aids and its prevention in the United Kingdom', 31 December 1984 [DHF.002.0431] at 0432

83 Professor Tedder - Day 49, pages 81-82

84 Dr McClelland - Day 50, page 5

30. Screening of Donated Blood for HIV >