VIRUS

an infectious agent of small size and simple composition that can multiply only in living cells of animals, plants, or bacteria. The name is from a Latin word meaning slimy liquid or poison. The earliest indications of the biological nature of viruses came from studies in 1892 by the Russian scientist Dmitry I. Ivanovsky and in 1898 by the Dutch scientist Martinus W. Beijerinck. Beijerinck first surmised that the virus under study was a new kind of infectious agent, which he designated contagium vivum fluidum, meaning that it was a live, reproducing organism that, nevertheless, differed from other organisms. Both of these investigators found that a disease of tobacco plants could be transmitted by an agent, later called tobacco mosaic virus, passing through a minute filter that would not allow the passage of bacteria. This virus and those subsequently isolated would not grow on an artificial medium and were not visible under the light microscope. In independent studies in 1915 by the British investigator Frederick W. Twort and in 1917 by the French-Canadian scientist Flix H. d'Hrelle, lesions in cultures of bacteria were discovered and attributed to an agent called bacteriophage (eater of bacteria), now known to be viruses that specifically infect bacteria. The unique nature of these organisms meant that new methods and alternative models had to be developed to study and classify them. The study of viruses confined exclusively or largely to humans, however, posed the formidable problem of finding a susceptible animal host. In 1933 the British investigators Wilson Smith, Christopher H. Andrewes, and Patrick P. Laidlaw were able to transmit influenza to ferrets, and the influenza virus was subsequently adapted to mice. In 1941 the American scientist George K. Hirst found that influenza virus grown in tissues of the chicken embryo could be detected by its capacity to agglutinate (draw together) red blood cells. A significant advance was made by the American scientists John Enders, Thomas Weller, and Frederick Robbins, who in 1949 developed the technique of culturing cells on glass surfaces; cells could then be infected with the viruses that cause poliomyelitis (poliovirus) and other diseases. (Until this time the poliovirus could be grown only in the brains of chimpanzees or the spinal cords of monkeys.) Culturing cells on glass surfaces opened the way for the diagnosis of diseases caused by viruses identified by their effects on cells (cytopathogenic effect) and by the presence of antibodies to them in the blood. Cell culture then led to the development and production of vaccines (preparations used to elicit immunity against a disease), such as the poliovirus vaccine. Scientists were soon able to detect the number of bacterial viruses in a culture vessel by measuring their ability to break apart (lyse) adjoining bacteria, which resulted in a clearing, or plaque, in an area of bacteria (lawn) overlaid with an inert gelatinous substance, called agar. The American scientist Renato Dulbecco in 1952 applied this technique to measuring the number of animal viruses that could produce plaques in layers of adjoining animal cells overlaid with agar. In the 1940s the development of the electron microscope permitted individual virus particles to be seen for the first time, leading to the classification of viruses and giving insight into their structure. Advancements that were made in chemistry, physics, and molecular biology since the 1960s have revolutionized the study of viruses. For example, electrophoresis on gel substrates gave a deeper understanding of the protein and nucleic acid composition of viruses. More sophisticated immunologic procedures, including the use of monoclonal antibodies directed to specific antigenic sites on proteins, gave a better insight into the structure and function of viral proteins. The progress made in the physics of crystals that could be studied by X-ray diffraction provided the high resolution required to discover the basic structure of minute viruses. Applications of new knowledge about cell biology and biochemistry helped to determine how viruses use their host cells for synthesizing viral nucleic acids and proteins. The revolution that took place in the field of molecular biology allowed the genetic information encoded in nucleic acids of viruseswhich enables viruses to reproduce, synthesize unique proteins, and alter cellular functionsto be studied. In fact, the chemical and physical simplicity of viruses has made them an incisive experimental tool for probing the molecular events involved in certain life processes. This article discusses the fundamental nature of viruses: what they are, how they cause infection, and how they may ultimately cause disease or bring about the death of their host cells. For more detailed treatment of specific viral diseases, see the article infection. an infectious agent of small size and simple composition that can multiply only in living cells of animals, plants, or bacteria. Viruses are microscopic; they range in size from about 20 to 400 nanometres in diameter (1 nanometre = 10-9 metre). By contrast, the smallest bacteria are about 400 nanometres in size. A virus consists of a single- or double-stranded nucleic acid and at least one protein surrounded by a protein shell, called a capsid; some viruses also have an outer envelope composed of fatty materials (lipids) and proteins. The nucleic acid carries the virus's genomeits collection of genesand may consist of either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). The protein capsid provides protection for the nucleic acid and may contain enzymes that enable the virus to enter its appropriate host cell. Some viruses are rod-shaped, others are icosahedral (a roughly spherical shape that is actually a 20-sided polygon), and still others have complex shapes consisting of a multisided head and a cylindrical tail. Viruses are classified on the basis of their nucleic acid content, their size, the shape of the capsid, and the presence of a lipoprotein envelope. Thus, the primary division is into two classes: RNA viruses and DNA viruses. Outside of a living cell, a virus is a dormant particle; but within an appropriate host cell, it becomes an active entity capable of subverting the cell's metabolic machinery for the production of new virus particles. The virus's developmental cycle begins with the entrance of the particle's nucleic acid, and in some cases its proteins, into a susceptible host cell. Bacterial viruses adsorb and firmly attach to the surface of the bacterium and then penetrate the rigid cell wall, transmitting the viral nucleic acid into the host. Animal viruses enter host cells by a process called endocytosis. Plant viruses, by contrast, enter through wounds in the cell's outer coverings e.g., through abrasions made by wind or through punctures made by insects. Once inside the host cell, the viral genome usually directs the production of new viral componentsnew viral protein is synthesized and new viral nucleic acid is produced. These components are then assembled into complete virions (entire virus particles containing nucleic acid enclosed within a protein capsule), which are discharged from the host cell. Among bacterial viruses, called bacteriophages, or phages, the release of the new virions is accomplished by lysing (bursting) the host cell. This pattern is called a lytic type of infection. Bacteriophages sometimes, however, show a different pattern of infection, called the lysogenic, or temperate, type. In a lysogenic infection, the viral genome is integrated into the chromosome of the host cell and becomes known as a prophage, which replicates in concert with that chromosome prior to cell division. In such cases, no progeny virions are produced and the host cell remains intact. The viral genome, however, is being passed on to each new generation of cells that stem from the original host. At some point, the prophage can be excised from the host cell's genome, usually owing to an environmental trigger such as ultraviolet radiation. The viral genome is then able to replicate, with the subsequent bursting of the host cell and the release of new virions. Occasionally during the prophage's exit, some of the host cell's genetic material will be removed as well. If this phage subsequently infects another host bacterium, the piece of DNA from the previous host may become part of the new host's genome. This exchange of genetic information is called transduction, and the phage capable of carrying out the process is called a transducing phage. Viral infections of plant and animal cells resemble those of bacterial cells in many ways. The release of new virions from plant and animal cells does not, however, always involve the lysing of the host cell as it does in bacteria. Particularly among animal viruses, the new virions may be released by budding off from the cell membrane, a process that is not necessarily lethal to the host cell. In general, a viral infection produces one of four effects in a plant or animal cell: inapparent effect, in which the virus lives dormantly in the host cell; cytopathic effect, in which the cell dies; hyperplastic effect, in which the cell is stimulated to divide prior to its death; and cell transformation, in which the cell is stimulated to divide, take on abnormal growth patterns, and become cancerous. Viral infections in animals can be either localized or disseminated to many distant locations in the body. Some animal viruses produce latent infections; in these the virus persists in a quiescent state, becoming periodically active in acute episodes, as in the case of the herpes simplex viruses. There are a number of different ways an animal can respond to a viral infection. Fever is a general response; many viruses are inactivated at temperatures just slightly above the host's normal body temperature. The secretion of interferon by infected animal cells is another general response. Interferon stimulates infected cells and those close by to produce proteins that interfere with virus replication. Humans and other vertebrates also can mount an immunological attack against a specific virus. The immune system produces antibodies and sensitized cells that are tailor-made to neutralize the infecting virus. These immune defenders circulate through the body long after the virus has been neutralized, thereby providing long-term protection against reinfection by this virus. This long-term immunity is the basis for active immunization against viral diseases. In active immunization, a weakened or inactivated strain of an infectious virus is introduced into the body. This virus does not provoke an active disease state, but it does stimulate the production of immune cells and antibodies, which then protect against subsequent infection by the virulent form of the virus. Active immunizations are now routine for such viral diseases as measles, mumps, poliomyelitis, and rubella. In contrast, passive immunization is the injection of antibodies from the serum of an individual who has already been exposed to the virus. Passive immunization is used to give short-term protection to individuals who have been exposed to such viral diseases as measles and hepatitis. It is useful only if provided soon after exposure, before the virus has become widely disseminated in the body. The treatment of an established viral infection usually is restricted to palliation of the specific symptoms; for example, fluid therapy may be used to control dehydration, or aspirin may be given to relieve aches and reduce fever. There are few drugs that can be used to directly combat an infecting virus. This is because viruses use the machinery of living cells for replication; drugs that inhibit viral development also inhibit the functions of the host cell. Nonetheless, a small number of antiviral drugs are available for specific infections. The most successful controls over viral diseases are epidemiological. Large-scale active immunization programs, for example, can break the chain of transmission of a viral disease. Worldwide immunization is credited with the eradication of smallpox, once one of the most feared viral diseases. Because many viruses are carried from host to host by insects or contaminated food, insect control and hygienic food handling can help eliminate a virus from specific populations. Historical descriptions of viral diseases date as far back as the 10th century BC. The concept of the virus, however, was not established until the last decade of the 19th century, when several researchers obtained evidence that agents far smaller than bacteria were capable of causing infectious diseases. The existence of viruses was proved when bacteriophages were independently discovered by researchers in 1915 and 1917. Because their genomes are small and because large quantities can be prepared in the laboratory, bacteriophages are a favourite research tool of molecular biologists. Studies of bacteriophages have helped to illuminate such basic biological processes as genetic recombination, nucleic acid replication, and protein synthesis. Distinguishing taxonomic features Viruses are classified on the basis of their nucleic acid content, their size, the shape of their protein capsid, and the presence of a surrounding lipoprotein envelope. The primary taxonomic division is into two classes based on nucleic acid content: DNA viruses or RNA viruses. The DNA viruses are subdivided into those that contain either double-stranded or single-stranded DNA. The RNA viruses also are divided into those that contain double-stranded or single-stranded RNA. Further subdivision of the RNA viruses is based on whether the RNA genome is segmented or not. If the viruses contain single-stranded RNA as their genetic information, they are divided into positive-strand viruses if the RNA is of messenger sense (directly translatable into proteins) or negative-strand viruses if the RNA must be transcribed by a polymerase into mRNA. All viruses falling into one of these nucleic acid classifications are further subdivided on the basis of whether the nucleocapsid (protein coat and enclosed nucleic acid) assumes a rodlike or a polygonal (usually icosahedral) shape. The icosahedral viruses are further subdivided into families based on the number of capsomers making up the capsids. Finally, all viruses fall into two classes depending on whether the nucleocapsid is surrounded by a lipoprotein envelope. Some virologists adhere to a division of viruses into those that infect bacteria, plants, or animals; these classifications have some validity, particularly for the unique bacterial viruses with tails, but there is otherwise so much overlap that taxonomy based on hosts seems unworkable. Classification based on diseases caused by viruses also is not tenable, because closely related viruses frequently do not cause the same disease. Eventually, it is likely that the classification of viruses will be based on the nucleotide sequences of their nucleic acids rather than on structural components, as is now the case. The basic taxonomic group is called a family, designated by the suffix -viridae. The major taxonomic disagreement among virologists is whether to segregate viruses within a family into a specific genus and further subdivide them into species names. Most virologists believe that a binomial nomenclature, as used for bacteria, into italicized and Latinized genera and species is unwarranted. For this reason, no Latin names are used in the classification of viruses presented here. Moreover, only the well-characterized viruses of animals are presented. Annotated classification DNA viruses RNA viruses Additional reading Descriptions of the diseases and their epidemiology are included in Bernard N. Fields and David M. Knipe (eds.), Fields Virology, 2nd ed., 2 vol. (1990), a text on the structure, biological properties, replication, and immunology of virtually all human viruses of medical importance. David O. White and Frank J. Fenner, Medical Virology, 4th ed. (1994), is intended for medical students and other health professionals. The Viruses, 24 vol. (198294), a monographic series, critically analyzes in detail the biology, chemistry, and physical properties of each family of virusese.g., Bernard Roizman and Carlos Lopez (eds.), The Herpesviruses, 4 vol. (198285); and Jay A. Levy (ed.), The Retroviridae, 3 vol. (199294). C.H. Andrewes, The Natural History of Viruses (1967), offers a personal account by one of the pioneers in the field. Arnold J. Levine, Viruses (1992), a beautifully illustrated and well-written history and description of virology, provides insight into its scientific development. Sherwood Casjens (ed.), Virus Structure and Assembly (1985), contains an illustrated series of essays by some of the major contributors to the understanding of the physical principles that determine the structure and assembly of viruses. Abner Louis Notkins and Michael B.A. Oldstone (eds.), Concepts in Viral Pathogenesis (1984), Concepts in Viral Pathogenesis II (1986), and Concepts in Viral Pathogenesis III (1989), contain a detailed series of chapters by leading investigators on the disease-causing properties of many pathogenetic viruses. The international classification of the families, genera, species, and strains of all viruses discovered by 1991 may be found in R.I.B. Francki et al. (eds.), Classification and Nomenclature of Viruses (1991). Robert G. Webster and Allan Granoff (eds.), Encyclopedia of Virology, 3 vol. (1994), contains extremely well-annotated descriptions of every known virus in alphabetical order by common names with detailed indexes and tables. Robert R. Wagner