A briefing document prepared for the Royal Society
and Association of British Science Writers
by Wendy Barnaby
March 1995
Is there a crisis in AIDS research? Professor Robin Weiss, Director of Research at the Institute for Cancer Research in London, opened the meeting by saying there was a feeling around in the media that AIDS research is not getting anywhere. In fact, in comparison, say, with work on cancer, multiple sclerosis or rheumatoid arthritis, AIDS researchers are making very good progress in understanding the syndrome. The problem is that HIV is spreading even faster, and the research being done is not yet stopping people contracting HIV or preventing those infected from going on to develop AIDS.
There is no crisis in AIDS research, but there is a world crisis about AIDS. Data from the Centre for Infectious Disease in Atlanta show that over the decade 1982-92, death from AIDS in adult males between the ages of 22 and 44 in the USA have risen from 0 to 50 per 100 000 population. It is now the leading cause of death for young men. The slope for women is just as steep but began to rise six years later. As far as the developing world goes, the World Health Organization estimates - with wide confidence limits - that by the turn of the century, there'll be more new cases of HIV infection in India than in all of Africa.
Historically, there has been fast progress in AIDS research. In May 1981, a few gay men presented to their physicians with Kaposi's Sarcoma or Pneumocystis pneumonia - two symptoms which are extremely rare in immuno-competent young men. By the end of 1981, this new immune deficiency disease was recognized as being infectiously transmissible. By May 1983, HIV was isolated as one of several candidate agents responsible for AIDS, and in May 1984 it was recognised as the cause. Within three months there were reliable and sensitive research assays for antibodies to the virus in blood. This gave the possibility of providing mass screening tests. Professor Weiss said he had not known of any other medical diagnostic that translated from a research tool to covering the whole of the developed world's blood donations as a diagnostic test within 12 months. In 1985, the first drug - AZT - was taken off the shelf. This again was fast progress, even if AZT has proved disappointing as a single type of drug because the virus rapidly evolves resistance to it.
The big puzzle currently is to know precisely how HIV causes AIDS. This is
something that scientists have been arguing about for a long time. Clearly, the
virus destroys the immune system, but the main question is whether AIDS is
primarily an immunological or a virological disease. It is becoming increasingly
evident, especially with two papers in a recent edition of Nature (vol
373 no 6510 of 12 January 1995) that the virus is continually active and is
driving the whole disease. When a person first becomes infected, the immune
systems gets the better of the virus. However, it is not completely cleared. It
takes, on average in the western world, nine years
before symptoms develop. There's been a misconception that the virus is latent
during that time; but in fact it is not - and this is a new insight. It takes a
long time for it to destroy the immune system because the immune system is
almost equally good at destroying HIV. At any one time there may be some
thousand million virus particles in a body - considered a low level - but there
is a tremendous rate of turnover: something like 500m viruses every day, so that
the overall burden remains high. Moreover, there is also a high turnover of
T-helper lymphocytes. Many HIV-infected lymphocytes are rapidly killed, either
by the virus itself, or by other T-killer lymphocytes reacting to it, but new
lymphocytes are produced which in turn become infected by HIV. Thus there is a
subtle balance of power, which eventually the virus wins. Researchers need to
know more about this to understand what's going on in the bodies of infected
people before designing a practical means of stopping it.
Another very recently-reported discovery concerns Kaposi's Sarcoma. It's been a puzzle to know why gay men with HIV infection have a high chance of developing KS, whereas it's virtually unknown in haemophiliacs with AIDS. The epidemiological picture shows that KS must be caused by a microbe that is not HIV, but perhaps only becomes manifest in the presence of HIV. That's beginning to look as though it's true. A paper published on 16 December 1994 in Science announced that a new virus, a member of the herpes family, looks to be strongly associated with KS. This could still be a red herring, but it looks more like the real thing. It could lead to major advances in the treatment of the subset of people with AIDS who develop KS.
There is a tremendous amount going on, scientifically, but there is still an enormous mountain to climb before much practical action can be taken to prevent AIDS.
Issues in the treatment of HIV Dr Janet Darbyshire, Head of the Medical Research Council's HIV Clinical Trials Centre at University College London Medical School, addressed two issues. The first was the evaluation of new drugs and therapeutic strategies as quickly as possible - a difficult balancing act between responding to the demands of pressure groups and patients to have new drugs available quickly, and making sure the therapies are not being introduced before their toxicity as well as their benefits are understood. The second was how best to use the drugs currently available.
One of the difficult problems posed by HIV is the very variable clinical picture which ranges from mild opportunistic infections, such as oral thrush, and mild neurological symptoms, to severe disease including tumors. AIDS is not one single disease. Improvements in survival are due not only to antiretroviral therapy (HIV is a retrovirus), but also to early diagnosis and treatment of opportunistic infections as well as their effective prevention. The time-scale is such that to look just at survival, or even delay in developing AIDS, would mean investigating treatments for many years. This is extremely difficult when people feel that they're deteriorating and would like to change to some other treatment. One of the great priorities at present is to develop laboratory markers of disease which can be used as "surrogate endpoints" to enable treatments to be evaluated more quickly. The aim is to reduce the length of the trial so that it only lasts weeks, months or a small number of years to discover what would otherwise have taken years to know if survival were the endpoint. However, it has to be clear that the treatment being tested for its effect on the surrogate endpoint also influences the real endpoint - survival, say, or delay in disease progression. The activity of a new treatment can be measured by using the number of CD4+ cells in the blood as a surrogate marker. (These are T-helper cells: lymphocytes which are particular targets of HIV.) But the effect on CD4 count alone is not sufficient to assess the clinical benefits of a therapy. The focus now, however, is on measuring viral load, which is a more direct way of measuring what an anti-retroviral drug can do; and it is hoped that this will provide a better way of selecting therapies.
Because the patient's quality of life is important, the risks associated with different drugs must also be taken into account. Adverse effects can be serious or non-serious; but feeling nauseated, for example, or having headaches is important on a daily basis. Some drugs can interact with each other, and there can be long-term toxicity including the risk of cancer.
With the drugs presently available, the key issues are when to treat; what to treat with, for how long - and then what? The main drug presently available is Zidovudine, AZT. It prolongs life in people with AIDS and severe AIDS-related complex (ARC). It appears to delay progression of the disease in the short term, but it seems to lose its efficacy after 6-12 months at least in part because the virus develops resistance; and if it's taken early in the asymptomatic phase it gives no additional value over taking it later on. The drug has potentially serious side effects, particularly on bone marrow. Most people would agree that treatment should be given in the symptomatic phase, but many would argue that treatment should be given much earlier, even at the acute infection stage, if it can be identified. This however means committing the patient to a long course of treatment, using up the short term benefit of currently available therapies. The evidence from the Concorde trial over an average of more than three years follow-up is that there is no advantage in treating early.
As more drugs become available, one strategy might be to use them separately, one drug at a time. A better option may be to use combinations of drugs in the hope of stopping the virus becoming resistant to the drug. The hope for combination therapy is that it might be more beneficial either by an additive or synergistic effect and possibly by preventing the emergence of resistance.
The other drugs licensed at the moment are didanosine (ddI) and zalcitabine (ddC). Like AZT, they inhibit the reverse transcriptase (RT), an enzyme specific to HIV, which translates the viral RNA into DNA. Neither has had a placebo-controlled trial, as it was considered unethical to withhold therapy from patients if AZT was available, but ddI appears so far to be about the same order, or perhaps a little less effective, than AZT. ddC appears to be less effective but may help patients resistant or intolerant to AZT. All of these drugs have some effect but they don't provide a cure, and all have side effects. The next group of drugs also inhibit reverse transcriptase of HIV but in a different way, and are known as non-nucleotide RT inhibitors. Unfortunately resistance develops very rapidly to this group of drugs so their role is only likely to be in combination therapy.
All these drugs work by inhibiting reverse transcriptase. The ideal combination may include drugs which target different stages of the cycle. HIV protease inhibitors look promising but resistance also develops against them. The first, Sequinavir, from Roche, appears to have more activity in combination than as monotherapy.
At the moment, then, there is no cure for AIDS. It can however be controlled in the short term with existing drugs and hopefully in the longer term by developing strategies which will make best use of existing drugs. It is important to evaluate therapies properly and not to create undue excitement about any therapy which may look promising before it is properly tested.
HIV variation - significance? Dr Peter Simmonds of the Department of Medical Microbiology in the University of Edinburgh explained that the lab he works in is particularly interested in two aspects of HIV variation: those relevant to vaccine design and to the progress of the disease. Variation itself means different things. A virus may vary in its genotype - its genetic constitution. HIV has an RNA genome and is composed of various nucleotide bases which together code for different viral proteins. It can also vary in its phenotype: the way in which the genotype interacts with its environment. Thus different viruses will grow differently and appear differently to the immune system. Changes in the genotype affect the phenotype.
Geographically, HIV-1 is extremely varied in its nucleotide sequence. Different parts of the world have different subtypes of HIV-1. In the UK, most of Europe and the US, HIV-1 appears mostly as subtype B; but there are also subtype A to I. These differences affect the properties of the proteins coded for, which will probably mean significant variation in how these viruses appear to the immune system, which will have major implications for the design of vaccines. Within subtype B, there are also measurable different strains of the virus. This can be useful: a new subject called molecular epidemiology can identify a particular virus and establish whether one person infected another. This was the technique used in the Florida case in which an HIV+ dentist who died of AIDS was found to have infected several patients. Variation also occurs through mutation of the virus within a particular person. The virus can diversify genetically by about 10% over 10 years. Considering that the genetic constitutions of humans and chimps, as different species, only differ by about 2%, this is a remarkable amount of genetic drift. HIV also differs genetically according to which part of the body it infects.
Most research on variation is focussed on the outside of the virus, the so-called envelope. It surrounds the core region which contains different viral proteins and the RNA genetic material. On the envelope sits the protein and gp120, which the immune system responds to. It is responsible for the reaction which occurs when HIV tries to infect a cell: gp120 attaches itself to a molecule called CD4 on the cell surface. Some lymphocytes express CD4, which is why HIV infects them. When the immune response produces antibodies against HIV, it is a particular part of gp120 that they target, rendering HIV ineffective. This is obviously important for the development of a vaccine. The particular target area changes over time, however, and so there is in effect a race between the virus mutating to escape from the immune system and the immune system responding and trying to catch up.
HIV varies in its replication rate: it can be fast or slow. It also varies according to whether or not it causes infected cells to fuse together into giant cells which rapidly destroy lymphocytes: the so-called cytopathic effect, observable sometimes when cells are grown in culture. Another variation concerns the specificity of HIV's targets. Some HIV targets only lymphocytes, others, macrophages as well. This targetting ability, known as cell tropism, can change over the course of infection.
At the moment, there is some understanding of these different types of
variability during the course of infection. As a person
progresses to AIDS, there is a catastrophic loss of CD4 lymphocytes. In patients
without symptoms, HIV targets both lymphocytes and macrophages and does not
cause either to fuse together in giant cells. As AIDS becomes established,
however, giant cells are formed but the HIV - now mutated - only seems to attack
lymphocytes. Why this is so is not understood: it doesn't seem to make sense,
biologically. As far as transmission of the virus goes, it doesn't seem to
matter whether the person transmitting it has HIV which will cause cells to fuse
together, or not: the transmitted form does not cause this sort of fusion. This
is not yet understood either. The route of transmission - sexual or blood-borne
- may also affect which type of virus grows. Clearly there are many questions
for researchers to answer before understanding can be translated into more
efficient drugs or vaccines.
Immunity to HIV amongst African prostitutes Dr Sarah Rowland Jones, of the Molecular Immunology Group at the Institute of Molecular Medicine - part of the University of Oxford - described the extent of HIV as a world-wide problem. By far the greatest burden of HIV currently falls on Africa, where there are 10 million infected people in sub-Saharan countries. Many Africans die of wasting, chest infections and chronic diarrhoea, long before they develop the conditions associated with AIDS in the west. Africans have fewer resources and drugs to pit against the disease. There is an urgent need for a vaccine to be used in developing countries, but most drug companies are only interested in developing one for western countries who are able to pay for it, and they therefore concentrate on the strains of HIV common in the west rather than those in Africa.
Most successful vaccines against other infections operate on the basis that there is some degree of natural immunity to the virus. This has not so far been the case with HIV, but is an important line of investigation. Some people have been exposed to HIV and yet have remained uninfected: many babies born to infected mothers; health workers with needle-stick injuries with known HIV-infected blood. Is this because they were lucky and didn't receive any infectious HIV viruses, or could some of them be immune to it?
The immune system tackles viruses in two main ways. The first uses antibodies, which are effective against viruses in the bloodstream and which target the outer envelope of the virus. This changes very rapidly as HIV mutates, however, The second line of immune attack are the cytotoxic lymphocytes, or killer T-cells, which identify HIV-infected cells and destroy them. They can do this because an infected cell displays viral protein fragments on its surface, and these are recognised by the T-cell and trigger its response. As the viral protein fragments of HIV change less rapidly than the envelope, the T-cell response may be a better approach to developing a vaccine.
Dr Rowland Jones's research has been to see whether T-cells play a part in people exposed to HIV but not infected. Her studies have been located in the Gambia, where about 2% of adults are infected and where the Medical Research Council provides excellent laboratory facilities. Until recently, HIV-2 was the dominant virus in West Africa. It is only about 50% genetically related to HIV-1, and much more closely related to SIV, the virus which infects monkeys. It seems to be a less virulent strain than HIV-1, and less easily transmitted. She was interested to see whether people who had developed immunity to HIV-2 might have some protection against HIV-1, which is now spreading rapidly in the same area.
Prostitutes who had been working for more than 5 years and had consistently been HIV-negative, in spite of only occasionally using condoms, were examined. Only six women with a particular genetic marker (HLA-B35) were suitable for tests; and of these, three were found to have high levels of HIV-specific killer T-cells for over a year, and of the remaining three, two had detectable levels of killer T-cells against HIV-1 and HIV-2. This indicates that they have been exposed to at least one of these viruses, but have not become infected. How? This is not yet known. One possibility is that, by chance, the women made T-cell responses to those parts of HIV-2 that are similar to parts of HIV-1, and that this also protected them against HIV-1 when they were exposed to it later on.
It is possible that this work and other studies might shift the emphasis on vaccine development away from antibody-based work to stimulating a T-cell response. There are many approaches to candidate vaccines currently being developed and it is hoped that the more promising leads will be tested within the next few years.
Speakers
Professor Robin Weiss
Institute of Cancer Research
Chester Beatty Laboratories
Fulham Road tel: 0171 352 8133
London SW3 6JB fax: 0171 352 3299
Dr Janet Darbyshire
MRC HIV Clinical Trials Centre
University College London Medical School
Mortimer Market Centre
Mortimer Market tel: 0171
380 9991/3
London WC1E 6AU fax: 0171 380 9972/3
Dr Peter Simmonds
Department of Medical Microbiology
University of Edinburgh
Medical School
Teviot Place tel: 0131 650 1000
Edinburgh EH8 9AG fax: 0131 650 6531
Dr Sarah Rowland Jones
Molecular Immunology Group
Institute of Molecular Medicine
John Radcliffe Hospital
Headington tel: 01865
222336
Oxford OX3 9DU fax: 01865 222502
The Head of the Molecular Immunology Group is Professor Andrew
McMichael.
Some helpful contacts
National AIDS Directory and HIV/AIDS Treatments Directory available in some libraries or by subscription from:
NAM Publications
52 The Eurolink Centre
49 Effra Road tel: 0171 737 1846
London SW2 1BZ fax: 0171 737 6190
The National AIDS Directory includes information on health services, local
authority services, Body Positive and self-help groups, local and national
organizations, drug agencies, needle exchanges and all other agencies providing
services in the fight against AIDS. The HIV/AIDS Treatments Directory includes
detailed information on the immune system and HIV, opportunistic infections and
symptoms, drugs and therapies, medical care and medical procedures, clinical
trials and a guide to understanding the treatment choices available to
people with HIV and AIDS.
On basic molecular biology and new drugs
Drs Jonathan Karn and Michael Gait
MRC Laboratory for Molecular Biology
Hills Road
Cambridge tel: 01223 248011
CB3 2QH
fax: 01223 213556
On gene therapy and AIDS
Dr Andrew Lever
Department of Medicine
University of Cambridge
The Old Schools
Trinity Lane tel: 01223 337733
Cambridge CB2 1TN fax: 01223 336846
On HIV and infection of macrophages
Dr Siamon Gordon
William Dunn School of Pathology
South Parks Road
Oxford
tel: 01865 275534
OX1 3RE
fax: 01865 275501
On the crystallographic structure of CD4 receptors
Dr Neil Barclay
William Dunn School of Pathology
South Parks Road
Oxford
tel: 01865 275534
OX1 3RE
fax: 01865 275501
On mathematical modelling of the epidemic and processes taking place
in the body
Professors Roy Anderson and Bob May F.R.S. and Dr Martin Mowak
Department of Zoology
University of Oxford
South Parks Road
Oxford
tel: 01865 271170
OX1 3PS
fax: 01865 310447
On the epidemiology of haemophilia
National Haemophilia Study collated by
Dr Sarah Darby
ICRF Cancer Epidemiology Unit
The Gibson Building
The Radcliffe Infirmary tel: 01865 311933
Oxford OX2 6HE fax: 01865 310545
Clinicians dealing with HIV patients
Professor Jonathan Wever
St Mary's Hospital Medical School
Norfolk Place
London
tel: 0171 723 1252
W2
1PG
fax: 0171 725 6645
Professor Tony Pinching
St Bartholemew's Hospital
West Smithfield
London
tel: 0171 601 8888
EC1A 6BE fax:
0171 600 3839
Professor Ian Weller
University College Hospital
Mortimer Market Centre
Mortimer Market
London
tel: 0171 387 9300
WC1E 6AU fax:
0171 380 9669
Professor Richard Tedder
The Middlesex Hospital
Mortimer Street
London
tel: 0171 380 9490
W1N 8AA
fax: 0171 580 5896
Especially on diagnostic virology, virus load and drug resistance.
Dr Brian Gazzard
Chelsea and Westminster Hospital
369 Fulham Road
London
tel: 0181 746 5612
SW10 fax: 0181 746
5611
Dr Anne Johnson
University College London Medical School
Mortimer Market Centre
Mortimer Market
London
tel: 0171 388 8880
WC1E 6AU fax:
0171 380 9669
Epidemiologist who co-ordinated a national study on sexual habits.
National statistics on AIDS
Dr Noel Gill
Communicable Disease Surveillance Centre
Public Health Laboratory
61 Collindale Avenue
London
tel: 0181 200 1295
NW9 5HT
fax: 0181 200 7868
On immunity
Professor Gus Dalgliesh
St George's Hospital Medical School
Cranmer Terrace
Tooting
London
tel: 0181 672 9944
SW17 0RE fax:
0181 725 2992
Ref: PR 12 (95) INFORMATION NOTE
Enquiries to:
Miss Anna Link
Science Promotion Section
The Royal Society
6 Carlton House Terrace
London SW1Y 5AG
Tel: 0171 839 5561 ext 315 22 March 1995
AIDS RESEARCH - CRISIS WHAT CRISIS?
On 18 January 1995 a press briefing on AIDS, organized jointly by the Royal Society and the Association of British Science Writers, was held at the Royal Society as part of a programme to further the public understanding of science. The enclosed document was prepared after the briefing to summarize key issues raised by the speakers at the time and also to provide a list of relevant contacts for future reference. This document does not necessarily constitute the views of the Royal Society, and views expressed in it should not be attributed to the Society.
The document is free of copyright and may be used without reference to source.