Genial hosts and unwanted guests

Encyclopaedia of Virology
January 20, 1995

The emergence of the human immunodeficiency virus has cast a shadow over our hopes of controlling infectious disease. Where did it come from? Will there be other viruses like HIV? Will a vaccine be possible? Such questions focus our attention on what we have learned about viruses and immunity to viruses in the past few years. In this ambitious encyclopaedia, the editors have tried to make this knowledge accessible to a wide range of readers, from A-level students to professional virologists.

The question of where viruses come from is still unanswered. While bacteria are cells that can often survive and grow independently of a host, viruses are much smaller parasites that depend absolutely on living inside a host cell. Nothing is known with certainty of how viruses originated, although it seems increasingly likely that they first arose as breakaway bits of a cell's DNA (or RNA). They are the most successful "selfish genes".

Many viruses seem to have emerged in recent history as the cause of important diseases in humans. But we now know that these viruses have not arisen de novo in the past few years: they appear to be new because they have only recently colonised the human species. The influenza virus is a good example of this emergence. A great deal of effort has been spent analysing the genetic variability of the 'flu virus, and much of this work was done in the laboratory of one of the editors, R. G. Webster. The results show there are many more strains of the virus in birds, particularly in ducks, than in humans; and that the 'flu virus is evolving quickly in humans, but hardly changes at all in birds. The strong implication is that influenza virus was originally an avian virus, and that occasional strains can infect humans as well. This conclusion is an increasingly common one: many other viruses, such as Lassa fever virus, canine parvovirus, and several haemorrhagic fever viruses, appear to have jumped a "species barrier" and established themselves in a new host. It now seems probable that HIV also made the species jump, but when and where this happened are a matter of great controversy.

How many viruses already in existence are yet to be discovered? HIV is not the only "new" virus, and indeed many others cause significant, if less dramatic, diseases than Aids. But estimates of the proportion of human viruses discovered vary enormously between 7per cent and 90 per cent. Part of the difficulty in estimating how many more might appear is this: we are beginning to realise that the growing density and mobility of the population greatly increase the chance that a small spark of a virus infection can catch fire, and establish a new endemic infection in humans. In fact, it is probable that many viruses, such as polio and measles, became endemic in humans only when our ancestors left hunting and gathering to settle down on farms, where the concentration of people was denser. As the world population increases relentlessly, it therefore gets harder to foresee the epidemic behaviour of virus infections and the spread of new agents into humans. But it is reasonable to hope that most will be less virulent than HIV.

The intense study of the DNA sequence of viral genes has shown that viruses change their genetic make-up continuously, in a running battle with their hosts. Viruses with RNA as their genetic material, such as HIV, can change particularly fast, and this presents a great problem for the immune system, whose job it is to recognise and destroy organisms such as viruses but leave our own tissues undamaged. Just as the immune system has learned how to recognise one strain, the virus can mutate and escape recognition, keeping one step ahead of the defence.

DNA sequencing and the other molecular techniques have also turned up many unexpected surprises, such as the discovery that fossil remains of retroviruses - relatives of HIV and certain tumour viruses - are widely scattered throughout the DNA of all higher animals, including ourselves. A peculiar feature of retroviruses is that they insert themselves into the DNA of the cell that they have entered. In most cases this has little consequence for the cell, though very occasionally it can be one of the several steps in the production of a tumour. But what happens if the virus insinuates itself into the DNA of an egg or a sperm? Unless it damages the cell, the virus's DNA will be passed on to the offspring. A few examples have been described, although not in humans, where this virus DNA can be resurrected and cause disease in succeeding generations. However, this is uncommon. Usually the genes of the virus are merely passed down through the generations, and in this way we all inherit from our parents a remarkable fossil record of past infections with retroviruses. Some of these so-called "endogenous retroviruses" are identical in chimpanzees and humans, suggesting there was at least one widespread epidemic before we parted company with the apes some millions of years ago.

In an odd way it is reassuring that we carry round with us the incontrovertible evidence that the human race and its ancestors have survived so many retrovirus epidemics in the past. However, there is no telling how virulent such infections were, and it is unlikely they were as virulent as HIV.

On a casual reading of this encyclopaedia, one might not realise the vital part the study of viruses has played in biology in the past 50 years, especially in genetics, cancer biology, molecular biology and immunology. The clues are scattered throughout the book. Fundamental advances in genetics were made in the study of bacteriophages (viruses that infect bacteria) starting with the proof by Hershey and Chase in 1952 that DNA is the carrier of genetic information. The discovery of messenger RNA and the elucidation of the genetic code followed within a few years, also from experiments on viruses.

One of the most dramatic steps forward in understanding the causes of cancer, the discovery of oncogenes or "cancer genes", was made about 15 years ago by scientists examining the genetics of viruses that cause cancer. The finding, which was quite unanticipated, was that homologues of the viral oncogenes existed in normal mammalian cells. It was quickly appreciated that these "cellular oncogenes" are central to the control of normal cell growth and division, as well as helping to cause malignant disease when mutated or over-expressed.

Because viruses have only a few genes and multiply very quickly compared with animals, they have also made an excellent system to study the control of gene expression: that is, how genes are switched on and off as they are needed. Most recently, again because of their genetic simplicity, viruses have been the key to understanding precisely how our immune system recognises a microbe as foreign, and there is widespread hope that this will throw light on other diseases of unknown cause, such as multiple sclerosis, in which the immune system seems to go wrong and attack normal tissues.

This extraordinary detail has far outrun our understanding of virus infections in vivo. Why, for example, do some people die quickly of liver failure when infected with the hepatitis B virus, when others have a mild illness with a slight fever? Fifteen years ago, we hoped that the molecular dissection of viruses would explain these conundrums, and indeed there are examples in which the contribution of individual virus genes is now understood with amazing precision, such as in retroviruses. However, we now realise there are subtle factors that often directly affect the outcome of a virus infection. A much more severe infection can sometimes be caused by a virus that replicates just a little bit faster, giving it what may seem only a trivial advantage in the arms race against the immune system. But no one has yet devised a satisfactory way of measuring the highly complex dynamics of virus replication and the immune response in vivo, and this branch of virology is still at the level of natural history.

Also scattered throughout the encyclopaedia are clues to the remarkable clinical successes of virology. Anti-viral vaccines have been one of the greatest triumphs of medicine, from the earliest highly empirical trials of smallpox vaccination in Asia, to Jenner and at last to the eradication of smallpox in 1979. Very recently, the Pan-American Health Organisation also declared the Americas free of polio. Yet it is sobering to reflect upon how much of the approach to developing vaccines remains entirely empirical. Pasteur made a virus less virulent to humans by serial passage of the infectious material from one animal to another, and this - or a very similar method - is still usually the best means of producing a safe and effective vaccine. As an immunologist will always remind you, we cannot do much better than this until we know which aspects of the immune response to a virus are really essential and beneficial, and how best to evoke such a response safely. Because of some notable failures, where the vaccine worsened the disease, many scientists are reluctant to second-guess the subtleties of the immune system.

Is a vaccine possible for HIV, then? This virus is a particularly difficult problem because it itself attacks and eventually destroys the immune system, although no one can yet satisfactorily explain why it takes so long. Two years ago there was a general despondency over the prospects for an HIV vaccine, but now, because of unexpected developments, there is a real hope of advance. It seems that one of the genes of HIV, nef, whose function is still very poorly understood, is essential for rapid and efficient infection. A mutant virus with an abnormal or missing nef gene appears to be able to act as an effective vaccine in animals. Because of the capacity of HIV to change so quickly, there is a danger that these vaccine strains might revert to the fully virulent virus before good immunity is produced: as usual, outwitting the virus is not a simple matter. But there is intense interest in following this line of research, as it is certainly one of the most hopeful developments for years.

The emphasis throughout this encyclopaedia is on the science of virology, rather than on the clinical practice of infectious disease medicine, although the clinical features of infection are, of course, discussed. Each entry is divided into sections, which in the case of entries on individual viruses are to an extent stereotyped (history, taxonomy and classification, structure, transmission and host range, clinical features, and so on). This makes it an easy matter to compare rapidly what is known - and unknown - between different viruses. At the end of the entry there is a brief further reading list, which is usually well up to date. Unlike some encyclopaedias, this one also has an excellent (87-page) index, so the cross-referencing is efficient.

Virology is a large and sprawling subject that merges indistinctly into many other disciplines such as immunology, molecular biology and clinical medicine. It has therefore become more and more difficult for an undergraduate - or indeed anyone else - to grasp its extent. Darwin took several years to realise the significance of the different finches he saw in the Galapagos Islands, and yet in virology many new species have been discovered, one might almost say whole islands as well, in the past 25 years. For a long time there has been a gap in the virological literature between the unashamed lecture-notes crammer book, and the essential but somewhat indigestible treatise such as Virology by Fields et al. The Encyclopaedia of Virology aims to fill this gap, and does so admirably.

Charles Bangham is consultant virologist, John Radcliffe Hospital, Oxford.

Encyclopaedia of Virology: Volumes One, Two and Three

Editor - Robert G. Webster and Allan Granoff
ISBN - 12 226960 8 (all 3 volumes), 226961 6 (Vol.1), 226962 4 (Vol.2), 226960 (Vol.3)
Publisher - Academic Press
Price - £250.00 (3 volume set)
Pages - 1622

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