User:Graham Beards/viruses

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Scanning electron micrograph of HIV-1 viruses, coloured green, budding from a lymphocyte

Sir Peter Medawar (1915–1987) described a virus as "a piece of bad news wrapped in a protein coat".[1] With the exception of the bacteriophages, viruses had a well-deserved reputation for being nothing but the cause of diseases and death. The discovery of the abundance of viruses and their overwhelming presence in many ecosystems has led modern virologists to consider them in a new light.[2] They are everywhere. It is estimated that there are 1031 viruses on Earth, most of them are bacteriophages, and most of them are in the oceans.[3] They are the most abundant species on Earth,[4] and they infect all types of organisms, from animals and plants to bacteria and archaea.[5] Since Dmitri Ivanovsky's 1892 article describing a non-bacterial pathogen infecting tobacco plants, and the discovery of the tobacco mosaic virus by Martinus Beijerinck in 1898,[6] about 5,000 viruses have been described in detail,[7] although there are millions of different types.[8] Viruses have existed since since life first appeared on Earth although their origins are unclear.

Viruses are small infectious agents that can replicate only inside living cells. A single virus particle (known as a virion) consists of two or three parts: the genetic material made from either DNA or RNA, long molecules that carry genetic information; a protein coat that protects these genes; and in some cases an envelope of lipids that surrounds the protein coat when they are outside a cell. The average virus is about one one-hundredth the size of the average bacterium. Most viruses are too small to be seen directly with an optical microscope and they are, to all intents and purposes, invisible. It would take 30,000 to 750,000 viruses, side by side, to stretch to 1 centimetre (0.39 in).

Despite their size, the ability of viruses to cause disease and death has changed the course of human history. Their existence has only been known of for about 100 years, but much is now known about them. Although often feared, most viruses exist in peaceful coexistence with their hosts, and they play a key role in maintaining life on Earth.


Etymology[edit]

The word is from the Latin virus referring to poison and other noxious substances, first used in English in 1392.[9] Virulent, from Latin virulentus (poisonous), dates to 1400.[10] A meaning of "agent that causes infectious disease" is first recorded in 1728,[9] before the discovery of viruses by Dmitri Ivanovsky in 1892. The plural is viruses. The adjective viral dates to 1948.[11] The term virion (plural virions), which dates from 1959,[12] is also used to refer to a single, stable infective viral particle that is released from the cell and is fully capable of infecting other cells of the same type.[13]

Origins and evolution[edit]

Viruses are ancient. Studies at the molecular level have revealed relationships between viruses infecting organisms from each of the three domains of life, and viral proteins that pre-date the divergence of life and thus the last universal common ancestor.[14] This indicates that viruses emerged early in the evolution of life and existed before modern cells.[15] Viruses are found wherever there is life, [16] but they do not form fossils because they are much smaller than the grains of sedimentary rocks that fossilise plants and animals. The evolution of viruses has had to be traced by other methods. DNA sequencing has been the most powerful, and has provided unexpected insights.[17] Computers are used to measure viral relationships by comparing their DNA or RNA sequences. As would be expected, viruses of the same genus have much of their sequences in common and more distantly related viruses less in common, which is used to draw phylogenetic trees. The mutation rates for many viruses have been measured, allowing estimates to be made of when species of viruses diverged from common ancestors.[18]

There are three main hypotheses that try to explain the origins of viruses:[19][20]

Regressive hypothesis 
Viruses may have once been small cells that parasitised larger cells. Over time, genes not required by their parasitism were lost. The bacteria rickettsia and chlamydia are living cells that, like viruses, can reproduce only inside host cells. They lend support to this hypothesis, as their dependence on parasitism is likely to have caused the loss of genes that enabled them to survive outside a cell. This is also called the degeneracy hypothesis,[21][22] or reduction hypothesis.[23]
Cellular origin hypothesis 
Some viruses may have evolved from bits of DNA or RNA that "escaped" from the genes of a larger organism. The escaped DNA could have come from plasmids (pieces of naked DNA that can move between cells) or transposons (molecules of DNA that replicate and move around to different positions within the genes of the cell).[24] Once called "jumping genes", transposons are examples of mobile genetic elements and could be the origin of some viruses. They were discovered in maize by Barbara McClintock in 1950.[25] This is sometimes called the vagrancy hypothesis,[21][26] or the escape hypothesis.[23]
Coevolution hypothesis 
This is also called the virus-first hypothesis[23] and proposes that viruses may have evolved from complex molecules of protein and nucleic acid at the same time as cells first appeared on Earth and would have been dependent on cellular life for billions of years. Viroids are molecules of RNA that are not classified as viruses because they lack a protein coat. However, they have characteristics that are common to several viruses and are often called subviral agents.[27] Viroids are important pathogens of plants.[28] They do not code for proteins but interact with the host cell and use the host machinery for their replication.[29] The hepatitis delta virus of humans has an RNA genome similar to viroids but has a protein coat derived from hepatitis B virus and cannot produce one of its own. It is, therefore, a defective virus and cannot replicate without the help of hepatitis B virus.[30] In similar manner, the sputnik virophage is dependent on mimivirus, which infects the protozoan Acanthamoeba castellanii.[31] These viruses that are dependent on the presence of other virus species in the host cell are called satellites and may represent evolutionary intermediates of viroids and viruses.[32][33]

There are problems with all of these hypotheses: the regressive hypothesis does not explain why even the smallest of cellular parasites do not resemble viruses in any way. The escape hypothesis does not explain the complex capsids and other structures on virus particles. The virus-first hypothesis contravened the definition of viruses in that they require host cells.[23] Viruses are now recognised as ancient and to have origins that pre-date the divergence of life into the three domains.[34] This discovery has led modern virologists to reconsider and re-evaluate these three classical hypotheses.[34]

The evidence for an ancestral world of RNA cells[35] and computer analysis of viral and host DNA sequences are giving a better understanding of the evolutionary relationships between different viruses and may help identify the ancestors of modern viruses. To date, such analyses have not proved which of these hypotheses is correct.[35] However, it seems unlikely that all currently known viruses have a common ancestor, and viruses have probably arisen numerous times in the past by one or more mechanisms.[36]

Time-line of paleoviruses in the human lineage[37]

The human genome contains traces of ancient and extinct viruses that once infected hominids and primates, leaving copies of their DNA in the DNA of modern humans; about 31 different families of viruses, called human endogenous retroviruses, have been discovered.[37] Although retroviruses are RNA viruses (which have genes made from RNA not DNA), their reproduction involves a stage where their genes are translated into DNA and inserted into the host cell's DNA.[38] Most of these DNA copies stay in the host cell's genome permanently. A few enter the DNA of the reproductive cells and are passed down through generations of the host's offspring.[39] The last addition to the human genome is estimated to have occurred between 100,000 and 1,000,000 years ago.[37] The discovery of this ancient, once viral, DNA in the human genome has given birth to the science of paleovirology, which although still in its infancy has already provided insights into the co-evolution of humans and viruses and the development of human resistance to them. The study of these "virtual fossils" has become a valuable tool in the study of virus evolution.[37]

Viruses evolve following changes in their DNA (or RNA), some quite rapidly, and the best adapted mutants quickly outnumber their less fit counterparts. In this sense their evolution is Darwinian, just like that of their host organisms.[40] The way viruses reproduce in their host cells makes them particularly susceptible to the genetic changes that help to drive their evolution.[41] The RNA viruses are especially prone to mutations.[42] In host cells there are mechanisms for correcting mistakes when DNA replicates and these kick in whenever cells divide.[42] These important mechanisms prevent potentially lethal mutations from being passed on to offspring. But these mechanisms do not work for RNA and when an RNA virus replicates in its host cell, changes in their genes are occasionally introduced in error, some of which are lethal. One virus particle can produce millions of progeny viruses in just one cycle of replication, therefore the production of a few "dud" viruses is not a problem. Most mutations are "silent" and do not result in any obvious changes to the progeny viruses, but others confer advantages that increase the fitness of the viruses in the environment. These could be changes to the virus particles that disguise them so they are not identified by the cells of the immune system or changes that make antiviral drugs less effective. Both of these changes occur frequently with HIV.[43]

Phylogenetic tree showing the relationships of morbilliviruses of different species[44]

Many viruses (for example, influenza A virus) can "shuffle" their genes with other viruses when two similar strains infect the same cell. This phenomenon is called genetic shift, and is often the cause of new and more virulent strains appearing. Other viruses change more slowly as mutations in their genes gradually accumulate over time, a process known as genetic drift.[45]

Through these mechanisms new viruses are constantly emerging and present a continuing challenge to attempts to control the diseases they cause.[46][47] Most species of viruses are now known to have common ancestors, and although the "virus first" hypothesis has yet to gain full acceptance, there is little doubt that the thousands of species of modern viruses have evolved from less numerous ancient ones.[48] The morbilliviruses, for example, are a group of closely related, but distinct viruses that infect a broad range of animals. The group includes measles virus, which infects humans and primates; canine distemper virus, which infects many animals including dogs, cats, bears, weasels and hyaenas; rinderpest, which infects cattle and buffalo; and other viruses of seals, porpoises and dolphins.[49] Although it not possible to prove which of these rapidly evolving viruses is the earliest, for such a closely related group of viruses to be found in such diverse hosts suggests a possible ancient common ancestor.[50]

Organisms at the edge of life[edit]

Opinions differ on whether viruses are a form of life, or organic structures that interact with living organisms. They have been described as "organisms at the edge of life",[51] since they resemble organisms in that they possess genes and evolve by natural selection,[52] and reproduce by creating multiple copies of themselves through self-assembly. Although they have genes, they do not have a cellular structure, which is often seen as the basic unit of life. Viruses do not have their own metabolism, and require a host cell to make new products. They therefore cannot naturally reproduce outside a host cell[53] – although bacterial species such as rickettsia and chlamydia are considered living organisms despite the same limitation.[54][55] Accepted forms of life use cell division to reproduce, whereas viruses spontaneously assemble within cells. They differ from autonomous growth of crystals as they inherit genetic mutations while being subject to natural selection. Virus self-assembly within host cells has implications for the study of the origin of life, as it lends further credence to the hypothesis that life could have started as self-assembling organic molecules.[5]

Morphology[edit]

A cartoon showing several identical molecules of protein forming a hexigon
Diagram of how a virus capsid can be constructed using multiple copies of just two protein molecules
Structure of icosahedral Cowpea Mosaic Virus

Viruses display a wide diversity of shapes and sizes, called morphologies. In general, viruses are much smaller than bacteria. Most viruses that have been studied have a diameter between 20 and 300 nanometres. Some filoviruses have a total length of up to 1400 nm; their diameters are only about 80 nm.[56] Most viruses cannot be seen with an optical microscope so scanning and transmission electron microscopes are used to visualise virions.[57] To increase the contrast between viruses and the background, electron-dense "stains" are used. These are solutions of salts of heavy metals, such as tungsten, that scatter the electrons from regions covered with the stain. When virions are coated with stain (positive staining), fine detail is obscured. Negative staining overcomes this problem by staining the background only.[58]

A simplified diagram of the structure of a virus

A complete virus particle, known as a virion, consists of nucleic acid surrounded by a protective coat of protein called a capsid. These are formed from identical protein subunits called capsomeres.[59] Viruses can have a lipid "envelope" derived from the host cell membrane. The capsid is made from proteins encoded by the viral genome and its shape serves as the basis for morphological distinction.[60][61] Virally coded protein subunits will self-assemble to form a capsid, in general requiring the presence of the virus genome. Complex viruses code for proteins that assist in the construction of their capsid. Proteins associated with nucleic acid are known as nucleoproteins, and the association of viral capsid proteins with viral nucleic acid is called a nucleocapsid. The capsid and entire virus structure can be mechanically (physically) probed through atomic force microscopy.[62][63] In general, there are four main morphological virus types:

Structure of tobacco mosaic virus: RNA coiled in a helix of repeating protein sub-units
Electron micrograph of icosahedral adenovirus
Herpes viruses have a lipid envelope that surrounds the virus particle.
Helical
These viruses are composed of a single type of capsomer stacked around a central axis to form a helical structure, which may have a central cavity, or hollow tube. This arrangement results in rod-shaped or filamentous virions: These can be short and highly rigid, or long and very flexible. The genetic material, in general, single-stranded RNA, but ssDNA in some cases, is bound into the protein helix by interactions between the negatively charged nucleic acid and positive charges on the protein. Overall, the length of a helical capsid is related to the length of the nucleic acid contained within it and the diameter is dependent on the size and arrangement of capsomers. The well-studied tobacco mosaic virus is an example of a helical virus.[64]
Icosahedral
Most animal viruses are icosahedral or near-spherical with icosahedral symmetry. A regular icosahedron is the optimum way of forming a closed shell from identical sub-units. The minimum number of identical capsomers required is twelve, each composed of five identical sub-units. Many viruses, such as rotavirus, have more than twelve capsomers and appear spherical but they retain this symmetry. Capsomers at the apices are surrounded by five other capsomers and are called pentons. Capsomers on the triangular faces are surrounded by six others and are called hexons.[65] Hexons are in essence flat and pentons, which form the 12 vertices, are curved. The same protein may act as the subunit of both the pentamers and hexamers or they may be composed of different proteins.
Prolate
This is an isosahedron elongated along the fivefold axis and is a common arrangement of the heads of bacteriophages. This structure is composed of a cylinder with a cap at either end.[66]
Envelope
Some species of virus envelop themselves in a modified form of one of the cell membranes, either the outer membrane surrounding an infected host cell or internal membranes such as nuclear membrane or endoplasmic reticulum, thus gaining an outer lipid bilayer known as a viral envelope. This membrane is studded with proteins coded for by the viral genome and host genome; the lipid membrane itself and any carbohydrates present originate entirely from the host. The influenza virus and HIV use this strategy. Most enveloped viruses are dependent on the envelope for their infectivity.[67]
Complex
These viruses possess a capsid that is neither purely helical nor purely icosahedral, and that may possess extra structures such as protein tails or a complex outer wall. Some bacteriophages, such as Enterobacteria phage T4, have a complex structure consisting of an icosahedral head bound to a helical tail, which may have a hexagonal base plate with protruding protein tail fibres. This tail structure acts like a molecular syringe, attaching to the bacterial host and then injecting the viral genome into the cell.[68]
The structure of icosahedral viruses is defined by a triangulation number

Icosahedral viruses are assigned a triangulation number (T-number) to describe the relationship between the number of protein molecules that form pentagons or hexagons. The T-number idea was originally developed to explain the quasi-symmetry by Caspar and Klug in 1962.[69]

A truncated icosahedron with a triangulation number of 3

The poxviruses are large, complex viruses that have an unusual morphology. The viral genome is associated with proteins within a central disk structure known as a nucleoid. The nucleoid is surrounded by a membrane and two lateral bodies of unknown function. The virus has an outer envelope with a thick layer of protein studded over its surface. The whole virion is slightly pleiomorphic, ranging from ovoid to brick shape.[70] Mimivirus is the largest characterised virus, with a capsid diameter of 400 nm. Protein filaments measuring 100 nm project from the surface. The capsid appears hexagonal under an electron microscope, therefore the capsid is probably icosahedral.[71] In 2011, researchers discovered a larger virus on ocean floor of the coast of Las Cruces, Chile. Provisionally named Megavirus chilensis, it can be seen with a basic optical microscope. [72]

Some viruses that infect Archaea have complex structures that are unrelated to any other form of virus, with a wide variety of unusual shapes, ranging from spindle-shaped structures, to viruses that resemble hooked rods, teardrops or even bottles. Other archaeal viruses resemble the tailed bacteriophages, and can have multiple tail structures.[73]

Genomes[edit]

Genomic diversity among viruses
Property Parameters
Nucleic acid
  • DNA
  • RNA
  • Both DNA and RNA (at different stages in the life cycle)
Shape
  • Linear
  • Circular
  • Segmented
Strandedness
  • Single-stranded
  • Double-stranded
  • Double-stranded with regions of single-strandedness
Sense
  • Positive sense (+)
  • Negative sense (−)
  • Ambisense (+/−)

An enormous variety of genomic structures can be seen among viral species; as a group, they contain more structural genomic diversity than plants, animals, archaea, or bacteria. There are millions of different types of viruses,[8] although only about 5,000 of them have been described in detail.[74] A virus has either DNA or RNA genes and is called a DNA virus or a RNA virus, respectively. The vast majority of viruses have RNA genomes. Plant viruses tend to have single-stranded RNA genomes and bacteriophages tend to have double-stranded DNA genomes.[75]

Viral genomes are circular, as in the polyomaviruses, or linear, as in the adenoviruses. The type of nucleic acid is irrelevant to the shape of the genome. Among RNA viruses and certain DNA viruses, the genome is often divided up into separate parts, in which case it is called segmented. For RNA viruses, each segment often codes for only one protein and they are usually found together in one capsid. However, all segments are not required to be in the same virion for the virus to be infectious, as demonstrated by brome mosaic virus and several other plant viruses.[56]

A viral genome, irrespective of nucleic acid type, is almost always either single-stranded or double-stranded. Single-stranded genomes consist of an unpaired nucleic acid, analogous to one-half of a ladder split down the middle. Double-stranded genomes consist of two complementary paired nucleic acids, analogous to a ladder. The virus particles of some virus families, such as those belonging to the Hepadnaviridae, contain a genome that is partially double-stranded and partially single-stranded.[75]

For most viruses with RNA genomes and some with single-stranded DNA genomes, the single strands are said to be either positive-sense (called the plus-strand) or negative-sense (called the minus-strand), depending on whether or not they are complementary to the viral messenger RNA (mRNA). Positive-sense viral RNA is in the same sense as viral mRNA and thus at least a part of it can be immediately translated by the host cell. Negative-sense viral RNA is complementary to mRNA and thus must be converted to positive-sense RNA by an RNA-dependent RNA polymerase before translation. DNA nomenclature for viruses with single-sense genomic ssDNA is similar to RNA nomenclature, in that the coding strand for the viral mRNA is complementary to it (−), and the non-coding strand is a copy of it (+).[75] However, several types of ssDNA and ssRNA viruses have genomes that are ambisense in that transcription can occur off both strands in a double-stranded replicative intermediate. Examples include geminiviruses, which are ssDNA plant viruses and arenaviruses, which are ssRNA viruses of animals.[76]

Genome size varies greatly between species. The smallest viral genomes – the ssDNA circoviruses, family Circoviridae – code for only two proteins and have a genome size of only 2 kilobases; the largest – mimiviruses – have genome sizes of over 1.2 megabases and code for over one thousand proteins.[77] In general, RNA viruses have smaller genome sizes than DNA viruses because of a higher error-rate when replicating, and have a maximum upper size limit.[78] Beyond this limit, errors in the genome when replicating render the virus useless or uncompetitive. To compensate for this, RNA viruses often have segmented genomes – the genome is split into smaller molecules – thus reducing the chance that an error in a single-component genome will incapacitate the entire genome. In contrast, DNA viruses generally have larger genomes because of the high fidelity of their replication enzymes.[79] Single-strand DNA viruses are an exception to this rule, however, as mutation rates for these genomes can approach the extreme of the ssRNA virus case.[80]

A cartoon showing how viral genes can be shuffled to form new viruses
How antigenic shift, or reassortment, can result in novel and highly pathogenic strains of human flu

Viruses undergo genetic change by several mechanisms. These include a process called genetic drift where individual bases in the DNA or RNA mutate to other bases. Most of these point mutations are "silent" – they do not change the protein that the gene encodes – but others can confer evolutionary advantages such as resistance to antiviral drugs.[81] Antigenic shift occurs when there is a major change in the genome of the virus. This can be a result of recombination or reassortment. When this happens with influenza viruses, pandemics might result.[82] RNA viruses often exist as quasispecies or swarms of viruses of the same species but with slightly different genome nucleoside sequences. Such quasispecies are a prime target for natural selection.[83]

Segmented genomes confer evolutionary advantages; different strains of a virus with a segmented genome can shuffle and combine genes and produce progeny viruses or (offspring) that have unique characteristics. This is called reassortment or viral sex.[84]

Genetic recombination is the process by which a strand of DNA is broken and then joined to the end of a different DNA molecule. This can occur when viruses infect cells simultaneously and studies of viral evolution have shown that recombination has been rampant in the species studied.[85] Recombination is common to both RNA and DNA viruses.[86][87]

Replication cycle[edit]

Diagram of a typical eukaryotic cell, showing subcellular components. Organelles: (1) nucleolus (2) nucleus (3) ribosome (4) vesicle (5) rough endoplasmic reticulum (ER) (6) Golgi apparatus (7) Cytoskeleton (8) smooth ER (9) mitochondria (10) vacuole (11) cytoplasm (12) lysosome (13) centrioles within centrosome (14) virus particle shown to approximate scale

Proteins are essential to life. Cells produce new protein molecules from amino acid building blocks based on information coded in DNA. Each type of protein is a specialist that only performs one function, so if a cell needs to do something new, it must make a new protein. Viruses force the cell to make new proteins that the cell does not need, but are needed for the virus to reproduce. Protein synthesis basically consists of two major steps: transcription and translation.

Transcription is the process where information in DNA, called the genetic code, is used to produce RNA copies called messenger RNA (mRNA). These migrate through the cell and carry the code to ribosomes where it is used to make proteins. This is called translation because the protein's amino acid structure is determined by the mRNA's code. Information is hence translated from the language of nucleic acids to the language of amino acids. Some RNA genes of viruses function directly as mRNA without further modification. For this reason, these viruses are called positive-sense RNA viruses.[88] In other RNA viruses, the RNA is a complementary copy of mRNA and these viruses rely on the cell's or their own enzyme to make mRNA. These are called negative-sense RNA viruses. In viruses made from DNA, the method of mRNA production is similar to that of the cell. The species of viruses called retroviruses behave completely differently: they have RNA, but inside the host cell a DNA copy of their RNA is made with the help of the enzyme reverse transcriptase. This DNA is then incorporated into the host's, and copied into mRNA by the cell's normal pathways.[89] Viral populations do not grow through cell division, because they are acellular. Instead, they use the machinery and metabolism of a host cell to produce multiple copies of themselves, and they assemble in the cell.

A typical virus replication cycle
Some bacteriophages inject their genomes into bacterial cells (not to scale)

The life cycle of viruses differs greatly between species but there are six basic stages in the life cycle of viruses:[90]

  • Attachment is a specific binding between viral capsid proteins and specific receptors on the host cellular surface. This specificity determines the host range of a virus. For example, HIV infects a limited range of human leucocytes. This is because its surface protein, gp120, specifically interacts with the CD4 molecule – a chemokine receptor – which is most commonly found on the surface of CD4+ T-Cells. This mechanism has evolved to favour those viruses that infect only cells in which they are capable of replication. Attachment to the receptor can induce the viral envelope protein to undergo changes that results in the fusion of viral and cellular membranes, or changes of non-enveloped virus surface proteins that allow the virus to enter.
  • Penetration follows attachment: Virions enter the host cell through receptor-mediated endocytosis or membrane fusion. This is often called viral entry. The infection of plant and fungal cells is different from that of animal cells. Plants have a rigid cell wall made of cellulose, and fungi one of chitin, so most viruses can get inside these cells only after trauma to the cell wall.[91] However, nearly all plant viruses (such as tobacco mosaic virus) can also move directly from cell to cell, in the form of single-stranded nucleoprotein complexes, through pores called plasmodesmata.[92] Bacteria, like plants, have strong cell walls that a virus must breach to infect the cell. However, given that bacterial cell walls are much less thick than plant cell walls due to their much smaller size, some viruses have evolved mechanisms that inject their genome into the bacterial cell across the cell wall, while the viral capsid remains outside.[93]
  • Uncoating is a process in which the viral capsid is removed: This may be by degradation by viral enzymes or host enzymes or by simple dissociation; the end-result is the releasing of the viral genomic nucleic acid.
  • Replication of viruses involves primarily multiplication of the genome. Replication involves synthesis of viral messenger RNA (mRNA) from "early" genes (with exceptions for positive sense RNA viruses), viral protein synthesis, possible assembly of viral proteins, then viral genome replication mediated by early or regulatory protein expression. This may be followed, for complex viruses with larger genomes, by one or more further rounds of mRNA synthesis: "late" gene expression is, in general, of structural or virion proteins.
  • Assembly - Following the structure-mediated self-assembly of the virus particles, some modification of the proteins often occurs. In viruses such as HIV, this modification (sometimes called maturation) occurs after the virus has been released from the host cell.[94]
  • Release- Viruses can be released from the host cell by lysis, a process that kills the cell by bursting its membrane and cell wall if present: This is a feature of many bacterial and some animal viruses. Some viruses undergo a lysogenic cycle where the viral genome is incorporated by genetic recombination into a specific place in the host's chromosome. The viral genome is then known as a "provirus" or, in the case of bacteriophages a "prophage".[95] Whenever the host divides, the viral genome is also replicated. The viral genome is mostly silent within the host; however, at some point, the provirus or prophage may give rise to active virus, which may lyse the host cells.[96] Enveloped viruses (e.g., HIV) typically are released from the host cell by budding. During this process the virus acquires its envelope, which is a modified piece of the host's plasma or other, internal membrane.[97]

The genetic material within virus particles, and the method by which the material is replicated, varies considerably between different types of viruses.

DNA viruses 
The genome replication of most DNA viruses takes place in the cell's nucleus. If the cell has the appropriate receptor on its surface, these viruses enter the cell sometimes by direct fusion with the cell membrane (e.g., herpesviruses) or – more usually – by receptor-mediated endocytosis. Most DNA viruses are entirely dependent on the host cell's DNA and RNA synthesising machinery, and RNA processing machinery; however, viruses with larger genomes may encode much of this machinery themselves. In eukaryotes the viral genome must cross the cell's nuclear membrane to access this machinery, while in bacteria it need only enter the cell.[98]
RNA viruses
Replication usually takes place in the cytoplasm. RNA viruses can be placed into four different groups depending on their modes of replication. The polarity (whether or not it can be used directly by ribosomes to make proteins) of single-stranded RNA viruses largely determines the replicative mechanism; the other major criterion is whether the genetic material is single-stranded or double-stranded. All RNA viruses use their own RNA replicase enzymes to create copies of their genomes.[99]
Reverse transcribing viruses
These have ssRNA (Retroviridae, Metaviridae, Pseudoviridae) or dsDNA (Caulimoviridae, and Hepadnaviridae) in their particles. Reverse transcribing viruses with RNA genomes (retroviruses), use a DNA intermediate to replicate, whereas those with DNA genomes (pararetroviruses) use an RNA intermediate during genome replication. Both types use a reverse transcriptase, or RNA-dependent DNA polymerase enzyme, to carry out the nucleic acid conversion. Retroviruses integrate the DNA produced by reverse transcription into the host genome as a provirus as a part of the replication process; pararetroviruses do not, although integrated genome copies of especially plant pararetroviruses can give rise to infectious virus.[100] They are susceptible to antiviral drugs that inhibit the reverse transcriptase enzyme, e.g. zidovudine and lamivudine. An example of the first type is HIV, which is a retrovirus. Examples of the second type are the Hepadnaviridae, which includes Hepatitis B virus.[101]

Effects on the host cell[edit]

The range of structural and biochemical effects that viruses have on the host cell is extensive.[102] These are called cytopathic effects.[103] Most virus infections eventually result in the death of the host cell. The causes of death include cell lysis, alterations to the cell's surface membrane and apoptosis.[104] Often cell death is caused by cessation of its normal activities because of suppression by virus-specific proteins, not all of which are components of the virus particle.[105]

Some viruses cause no apparent changes to the infected cell. Cells in which the virus is latent and inactive show few signs of infection and often function normally.[106] This causes persistent infections and the virus is often dormant for many months or years. This is often the case with herpes viruses.[107][108] Some viruses, such as Epstein-Barr virus, can cause cells to proliferate without causing malignancy,[109] while others, such as papillomaviruses, are established causes of cancer.[110]

Host range[edit]

Viruses are by far the most abundant biological entities on Earth and they outnumber all the others put together.[111] They infect all types of cellular life including animals, plants, bacteria and fungi.[112] However, different types of viruses can infect only a limited range of hosts and many are species-specific. Some, such as smallpox virus for example, can infect only one species – in this case humans,[113] and are said to have a narrow host range. Other viruses, such as rabies virus, can infect different species of mammals and are said to have a broad range.[114] The viruses that infect plants are harmless to animals, and most viruses that infect other animals are harmless to humans.[115] The host range of some bacteriophages is limited to a single strain of bacteria and they can be used to trace the source of outbreaks of infections by a method called phage typing.[116]

Classification[edit]

Classification seeks to describe the diversity of viruses by naming and grouping them on the basis of similarities. In 1962, André Lwoff, Robert Horne, and Paul Tournier were the first to develop a means of virus classification, based on the Linnaean hierarchical system.[117] This system bases classification on phylum, class, order, family, genus, and species. Viruses were grouped according to their shared properties (not those of their hosts) and the type of nucleic acid forming their genomes.[118] Later the International Committee on Taxonomy of Viruses was formed. However, viruses are not classified on the basis of phylum or class, as their small genome size and high rate of mutation makes it difficult to determine their ancestry beyond Order. As such, the Baltimore Classification is used to supplement the more traditional hierarchy.

ICTV classification[edit]

The International Committee on Taxonomy of Viruses (ICTV) developed the current classification system and wrote guidelines that put a greater weight on certain virus properties to maintain family uniformity. A unified taxonomy (a universal system for classifying viruses) has been established. The 7th lCTV Report formalised for the first time the concept of the virus species as the lowest taxon (group) in a branching hierarchy of viral taxa.[119] However, at present only a small part of the total diversity of viruses has been studied, with analyses of samples from humans finding that about 20% of the virus sequences recovered have not been seen before, and samples from the environment, such as from seawater and ocean sediments, finding that the large majority of sequences are completely novel.[120]

The general taxonomic structure is as follows:

Order (-virales)
Family (-viridae)
Subfamily (-virinae)
Genus (-virus)
Species (-virus)

In the current (2011) ICTV taxonomy, six orders have been established, the Caudovirales, Herpesvirales, Mononegavirales, Nidovirales, Picornavirales and Tymovirales. A seventh order Ligamenvirales has also been proposed. The committee does not formally distinguish between subspecies, strains, and isolates. In total there are 6 orders, 87 families, 19 subfamilies, 349 genera, about 2,284 species and over 3,000 types yet unclassified.[121][122][123]

Baltimore classification[edit]

A diagram showing how the Baltimore Classification is based on a virus's DNA or RNA and method of mRNA synthesis
The Baltimore Classification of viruses is based on the method of viral mRNA synthesis.

The Nobel Prize-winning biologist David Baltimore devised the Baltimore classification system.[124][125] The ICTV classification system is used in conjunction with the Baltimore classification system in modern virus classification.[126][127][128]

The Baltimore classification of viruses is based on the mechanism of mRNA production. Viruses must generate mRNAs from their genomes to produce proteins and replicate themselves, but different mechanisms are used to achieve this in each virus family. Viral genomes may be single-stranded (ss) or double-stranded (ds), RNA or DNA, and may or may not use reverse transcriptase (RT). In addition, ssRNA viruses may be either sense (+) or antisense (−). This classification places viruses into seven groups:

As an example of viral classification, the chicken pox virus, varicella zoster (VZV), belongs to the order Herpesvirales, family Herpesviridae, subfamily Alphaherpesvirinae, and genus Varicellovirus. VZV is in Group I of the Baltimore Classification because it is a dsDNA virus that does not use reverse transcriptase.

Roles in human diseases[edit]

A photograph of the upper body of a man labelled with the names of viruses that infect the different parts
Overview of the main types of viral infection and the most notable species involved[129][130]

Examples of common human diseases caused by viruses include the common cold, influenza, chickenpox and cold sores. Many serious diseases such as ebola, AIDS, avian influenza and SARS are caused by viruses. The relative ability of viruses to cause disease is described in terms of virulence. Other diseases are under investigation as to whether they too have a virus as the causative agent, such as the possible connection between human herpesvirus 6 (HHV6) and neurological diseases such as multiple sclerosis and chronic fatigue syndrome.[131] Viruses have different mechanisms by which they produce disease in an organism, which depends largely on the viral species. Mechanisms at the cellular level primarily include cell lysis, the breaking open and subsequent death of the cell. In multicellular organisms, if enough cells die, the whole organism will start to suffer the effects. Although viruses cause disruption of healthy homeostasis, resulting in disease, they may exist relatively harmlessly within an organism. An example would include the ability of the herpes simplex virus, which causes cold sores, to remain in a dormant state within the human body. This is called latency[132] and is a characteristic of the herpes viruses including Epstein-Barr virus, which causes glandular fever, and varicella zoster virus, which causes chickenpox and shingles. Most people have been infected with at least one of these types of herpes virus.[133] However, these latent viruses might sometimes be beneficial, as the presence of the virus can increase immunity against bacterial pathogens, such as Yersinia pestis.[134] Some viruses can cause lifelong or chronic infections, where the viruses continue to replicate in the body despite the host's defence mechanisms.[135] This is common in hepatitis B virus and hepatitis C virus infections. People chronically infected are known as carriers, as they serve as reservoirs of infectious virus.[136] In populations with a high proportion of carriers, the disease is said to be endemic.[137]

Viruses are an established cause of cancer in humans and other species. Viral cancers occur only in a minority of infected persons (or animals). Cancer viruses come from a range of virus families, including both RNA and DNA viruses, and so there is no single type of "oncovirus" (an obsolete term originally used for acutely transforming retroviruses). The development of cancer is determined by a variety of factors such as host immunity[138] and mutations in the host.[139] Viruses accepted to cause human cancers include some genotypes of human papillomavirus, hepatitis B virus, hepatitis C virus, Epstein-Barr virus, Kaposi's sarcoma-associated herpesvirus and human T-lymphotropic virus. The most recently discovered human cancer virus is a polyomavirus (Merkel cell polyomavirus) that causes most cases of a rare form of skin cancer called Merkel cell carcinoma.[140] Hepatitis viruses can develop into a chronic viral infection that leads to liver cancer.[141][142] Infection by human T-lymphotropic virus can lead to tropical spastic paraparesis and adult T-cell leukemia.[143] Human papillomaviruses are an established cause of cancers of cervix, skin, anus, and penis.[144] Within the Herpesviridae, Kaposi's sarcoma-associated herpesvirus causes Kaposi's sarcoma and body cavity lymphoma, and Epstein–Barr virus causes Burkitt's lymphoma, Hodgkin’s lymphoma, B lymphoproliferative disorder, and nasopharyngeal carcinoma.[145] Merkel cell polyomavirus, which is closely related to the simian SV40 virus, and mouse polyomaviruses have been used as animal models for cancer viruses for over 50 years.[146]

Diagnosis[edit]

Koplik spots a sign of the onset of measles. These appear on the mucosa of the cheeks and tongue, and are irregularly-shaped, bright red spots often with a bluish-white central dot.

For many virus infections, diagnosis can be made from the signs and symptoms alone. Some infections are more difficult to diagnose and laboratory tests are required. In humans and other animals, blood tests are often used because when the adaptive immune system of a vertebrate encounters a virus, it produces specific antibodies which bind to the virus and render it non-infectious. Two types of antibodies are important. The first called IgM is highly effective at combating viruses but is only produced by the cells of the immune system for a few weeks. The second, called, IgG is produced indefinitely. The presence of IgM in the blood of the host is used to test for acute infection, whereas IgG indicates an infection sometime in the past.[147] Both types of antibodies are measured when tests for immunity are carried out.[148] Other tests include those that allow the detection of the virus's DNA (or RNA) in samples of blood and other bodily fluids, and those that can react with with parts of the viruses called antigens that can be found in infected fluids and cells.[149]

Epidemiology[edit]

Viral epidemiology is the branch of medical science that deals with the transmission and control of virus infections in humans. Transmission of viruses can be vertical, that is from mother to child, or horizontal, which means from person to person. Examples of vertical transmission include hepatitis B virus and HIV where the baby is born already infected with the virus.[150] Another, rarer, example is the varicella zoster virus, which, although causing relatively mild infections in humans, can be fatal to the foetus and new-born baby.[151]

Horizontal transmission is the most common mechanism of spread of viruses in populations. Transmission can occur when: body fluids are exchanged during sexual activity, e.g., HIV; blood is exchanged by contaminated transfusion or needle sharing, e.g., hepatitis C; exchange of saliva by mouth, e.g., Epstein-Barr virus; contaminated food or water is ingested, e.g., norovirus; aerosols containing virions are inhaled, e.g., influenza virus; and insect vectors such as mosquitoes penetrate the skin of a host, e.g., dengue. The rate or speed of transmission of viral infections depends on factors that include population density, the number of susceptible individuals, (i.e., those not immune),[152] the quality of healthcare and the weather.[153]

Epidemiology is used to break the chain of infection in populations during outbreaks of viral diseases.[154] Control measures are used that are based on knowledge of how the virus is transmitted. It is important to find the source, or sources, of the outbreak and to identify the virus. Once the virus has been identified, the chain of transmission can sometimes be broken by vaccines. When vaccines are not available sanitation and disinfection can be effective. Often infected people are isolated from the rest of the community and those that have been exposed to the virus placed in quarantine.[155] To control the outbreak of foot-and-mouth disease in cattle in Britain in 2001, thousands of cattle were slaughtered.[156] Most viral infections of humans and other animals have incubation periods during which the infection causes no signs or symptoms.[157] Incubation periods for viral diseases range from a few days to weeks but are known for most infections.[158] Somewhat overlapping, but mainly following the incubation period, there is a period of communicability; a time when an infected individual or animal is contagious and can infect another person or animal.[158] This too is known for many viral infections and knowledge the length of both periods is important in the control of outbreaks.[159] When outbreaks cause an unusually high proportion of cases in a population, community or region they are called epidemics. If outbreaks spread worldwide they are called pandemics.[160]

Host defence mechanisms[edit]

The body's first line of defence against viruses is the innate immune system. This comprises cells and other mechanisms that defend the host from infection in a non-specific manner. This means that the cells of the innate system recognise, and respond to, pathogens in a generic way, but, unlike the adaptive immune system, it does not confer long-lasting or protective immunity to the host.[161]

RNA interference is an important innate defence against viruses.[162] Many viruses have a replication strategy that involves double-stranded RNA (dsRNA). When such a virus infects a cell, it releases its RNA molecule or molecules, which immediately bind to a protein complex called dicer that cuts the RNA into smaller pieces. A biochemical pathway called the RISC complex is activated, which degrades the viral mRNA and the cell survives the infection. Rotaviruses avoid this mechanism by not uncoating fully inside the cell and by releasing newly produced mRNA through pores in the particle's inner capsid. The genomic dsRNA remains protected inside the core of the virion.[163][164]

When the adaptive immune system of a vertebrate encounters a virus, it produces specific antibodies that bind to the virus and render it non-infectious. This is called humoral immunity. Two types of antibodies are important. The first, called IgM, is highly effective at neutralizing viruses but is produced by the cells of the immune system only for a few weeks. The second, called IgG, is produced indefinitely. The presence of IgM in the blood of the host is used to test for acute infection, whereas IgG indicates an infection sometime in the past.[165] IgG antibody is measured when tests for immunity are carried out.[166]

Two spherical rotavirus particles, one is coated with antibody which looks like many small birds, regularly spaced on the surface of the virus
Two rotaviruses: the one on the right is coated with antibodies that stop its attaching to cells and infecting them

A second defence of vertebrates against viruses is called cell-mediated immunity and involves immune cells known as T cells. The body's cells constantly display short fragments of their proteins on the cell's surface, and, if a T cell recognises a suspicious viral fragment there, the host cell is destroyed by killer T cells and the virus-specific T-cells proliferate. Cells such as the macrophage are specialists at this antigen presentation.[167] The production of interferon is an important host defence mechanism. This is a hormone produced by the body when viruses are present. Its role in immunity is complex; it eventually stops the viruses from reproducing by killing the infected cell and its close neighbours.[168]

Not all virus infections produce a protective immune response in this way. HIV evades the immune system by constantly changing the amino acid sequence of the proteins on the surface of the virion. These persistent viruses evade immune control by sequestration, blockade of antigen presentation, cytokine resistance, evasion of natural killer cell activities, escape from apoptosis, and antigenic shift.[169] Other viruses, called neurotropic viruses, are disseminated by neural spread where the immune system may be unable to reach them.

Many virus infections are spread from person to person and immunity in a proportion of the population can protect susceptible individuals because the chain of transmission is broken. This is known as herd immunity. The reproductive rate – the number of further cases caused by an infected person - is known for many virus infections. If this rate is reduced to less than one, the infection will stop spreading. And if humans are the only host for the virus, the disease can be eradicated.[170]

Estimated Herd Immunity thresholds for some vaccine preventable viral infections[171]
Disease Transmission R0 Herd immunity threshold
Measles Airborne 12–18 83–94%
Mumps Airborne droplet 4–7 75–86%
Polio Fecal-oral route 5–7 80–86%
Rubella Airborne droplet 5–7 80–85%
Smallpox Social contact 6–7 83–85%
^ - R0 is the basic reproduction number, or the average number of secondary infectious cases that are produced by a single index case in completely susceptible population.

Prevention and treatment[edit]

Because viruses use vital metabolic pathways within host cells to replicate, they are difficult to eliminate without using drugs that cause toxic effects to host cells in general. The most effective medical approaches to viral diseases are vaccinations to provide immunity to infection, and antiviral drugs that selectively interfere with viral replication.[172][173]

Vaccines[edit]

Vaccination is a cheap and effective way of preventing infections by viruses. Vaccines were used to prevent viral infections long before the discovery of the actual viruses. Their use has resulted in a dramatic decline in morbidity (illness) and mortality (death) associated with viral infections such as polio, measles, mumps and rubella.[174] Smallpox infections have been eradicated.[175] Vaccines are available to prevent over thirteen viral infections of humans,[176] and more are used to prevent viral infections of animals.[177] Vaccines can consist of live-attenuated or killed viruses, or viral proteins (antigens).[178] Live vaccines contain weakened forms of the virus, which do not cause the disease but, nonetheless, confer immunity. Such viruses are called attenuated. Live vaccines can be dangerous when given to people with a weak immunity, (who are described as immunocompromised), because in these people, the weakened virus can cause the original disease.[179] Biotechnology and genetic engineering techniques are used to produce subunit vaccines. These vaccines use only the capsid proteins of the virus. Hepatitis B vaccine is an example of this type of vaccine.[180] Subunit vaccines are safe for immunocompromised patients because they cannot cause the disease.[181] The yellow fever virus vaccine, a live-attenuated strain called 17D, is probably the safest and most effective vaccine ever generated.[182]

The structure of DNA showing the position of the nucleosides and the phosphorus atoms that form the "backbone" of the molecule

Antiviral drugs[edit]

The guanosine analogue Aciclovir

Antiviral drugs are often nucleoside analogues, (fake DNA building-blocks), which viruses mistakenly incorporate into their genomes during replication. The life-cycle of the virus is then halted because the newly synthesised DNA is inactive. This is because these analogues lack the hydroxyl groups, which, along with phosphorus atoms, link together to form the strong "backbone" of the DNA molecule. This is called DNA chain termination.[183] Examples of nucleoside analogues are aciclovir for Herpes simplex virus infections and lamivudine for HIV and Hepatitis B virus infections. Aciclovir is one of the oldest and most frequently prescribed antiviral drugs.[184] Other antiviral drugs in use target different stages of the viral life cycle. HIV is dependent on a proteolytic enzyme called the HIV-1 protease for it to become fully infectious. There is a large class of drugs called protease inhibitors that inactivate this enzyme.[185]

Hepatitis C is caused by an RNA virus. In 80% of people infected, the disease is chronic, and without treatment, they are infected for the remainder of their lives. However, there is now an effective treatment that uses the nucleoside analogue drug ribavirin combined with interferon.[186] The treatment of chronic carriers of the hepatitis B virus by using a similar strategy using lamivudine has been developed.[187]

Infection in other species[edit]

Viruses infect all cellular life and, although viruses occur universally, each cellular species has its own specific range that often infect only that species.[188] Some viruses, called satellites, can replicate only within cells that have already been infected by another virus.[31] Viruses are important pathogens of livestock. Diseases such as foot-and-mouth disease and bluetongue are caused by viruses.[189] Companion animals such as cats, dogs, and horses, if not vaccinated, are susceptible to serious viral infections. Canine parvovirus is caused by a small DNA virus and infections are often fatal in pups.[190] Like all invertebrates, the honey bee is susceptible to many viral infections.[191] However, most viruses co-exist harmlessly in their host and cause no signs or symptoms of disease.[192]

Plants[edit]

Peppers infected by mild mottle virus

There are many types of plant virus, but often they cause only a loss of yield, and it is not economically viable to try to control them. Plant viruses are often spread from plant to plant by organisms, known as vectors. These are normally insects, but some fungi, nematode worms, and single-celled organisms have been shown to be vectors. When control of plant virus infections is considered economical, for perennial fruits, for example, efforts are concentrated on killing the vectors and removing alternate hosts such as weeds.[193] Plant viruses cannot infect humans and other animals because they can reproduce only in living plant cells.[194]

Plants have elaborate and effective defence mechanisms against viruses. One of the most effective is the presence of so-called resistance (R) genes. Each R gene confers resistance to a particular virus by triggering localised areas of cell death around the infected cell, which can often be seen with the unaided eye as large spots. This stops the infection from spreading.[195] RNA interference is also an effective defence in plants.[196] When they are infected, plants often produce natural disinfectants that kill viruses, such as salicylic acid, nitric oxide, and reactive oxygen molecules.[197]

Plant virus particles or virus-like particles (VLPs) have applications in both biotechnology and nanotechnology. The capsids of most plant viruses are simple and robust structures and can be produced in large quantities either by the infection of plants or by expression in a variety of heterologous systems. Plant virus particles can be modified genetically and chemically to encapsulate foreign material and can be incorporated into supramolecular structures for use in biotechnology.[198]

Bacteria[edit]

An electron micrograph showing a portion of a bacterium covered with viruses
Transmission electron micrograph of multiple bacteriophages attached to a bacterial cell wall

Bacteriophages are a common and diverse group of viruses and are the most abundant form of biological entity in aquatic environments – there are up to ten times more of these viruses in the oceans than there are bacteria,[199] reaching levels of 250,000,000 bacteriophages per millilitre of seawater.[200] These viruses infect specific bacteria by binding to surface receptor molecules and then entering the cell. Within a short amount of time, in some cases just minutes, bacterial polymerase starts translating viral mRNA into protein. These proteins go on to become either new virions within the cell, helper proteins, which help assembly of new virions, or proteins involved in cell lysis. Viral enzymes aid in the breakdown of the cell membrane, and, in the case of the T4 phage, in just over twenty minutes after injection over three hundred phages could be released.[201]

The major way bacteria defend themselves from bacteriophages is by producing enzymes that destroy foreign DNA. These enzymes, called restriction endonucleases, cut up the viral DNA that bacteriophages inject into bacterial cells.[202] Bacteria also contain a system that uses CRISPR sequences to retain fragments of the genomes of viruses that the bacteria have come into contact with in the past, which allows them to block the virus's replication through a form of RNA interference.[203][204] This genetic system provides bacteria with acquired immunity to infection.

Archaea[edit]

Some viruses replicate within archaea: these are double-stranded DNA viruses with unusual and sometimes unique shapes.[205][73] These viruses have been studied in most detail in the thermophilic archaea, particularly the orders Sulfolobales and Thermoproteales.[206] Defences against these viruses may involve RNA interference from repetitive DNA sequences within archaean genomes that are related to the genes of the viruses.[207][208]

Role in aquatic ecosystems[edit]

Phytoplankton bloom in the Bay of Biscay. Viruses help to destroy harmful algal blooms

A teaspoon of seawater contains about one million viruses.[209] They are essential to the regulation of saltwater and freshwater ecosystems.[210] Most of these viruses are bacteriophages, which are harmless to plants and animals. They infect and destroy the bacteria in aquatic microbial communities, comprising the most important mechanism of recycling carbon in the marine environment. The organic molecules released from the bacterial cells by the viruses stimulate fresh bacterial and algal growth.[211]

Microorganisms constitute more than 90% of the biomass in the sea. It is estimated that viruses kill approximately 20% of this biomass each day and that there are 15 times as many viruses in the oceans as there are bacteria and archaea. Viruses are the main agents responsible for the rapid destruction of harmful algal blooms,[212] which often kill other marine life.[213] The number of viruses in the oceans decreases further offshore and deeper into the water, where there are fewer host organisms.[214] The effects of marine viruses are far-reaching; by increasing the amount of photosynthesis in the oceans, viruses are indirectly responsible for reducing the amount of carbon dioxide in the atmosphere by approximately 3 gigatonnes of carbon per year.[214] Viruses are efficient gene donators and it has been estimated that 10 percent of the world's photosynthesis is driven by genes that originated in marine bacteriophges.[215] The oceans are a vast untapped reservoir viral diversity and the important role that viruses play in marine ecology has become a subject of fruitful research.[216]

Like any organism, marine mammals are susceptible to viral infections. In 1988 and 2002, thousands of harbor seals were killed in Europe by phocine distemper virus.[217] Many other viruses, including caliciviruses, herpesviruses, adenoviruses and parvoviruses, circulate in marine mammal populations.[214]

Role in evolution[edit]

Viruses are an important natural means of transferring genes between different species, which increases genetic diversity and drives evolution.[218] It is thought that viruses played a central role in the early evolution, before the diversification of bacteria, archaea and eukaryotes and at the time of the last universal common ancestor of life on Earth.[219] Viruses are still one of the largest reservoirs of unexplored genetic diversity on Earth.[214][220]

Extraterrestrials[edit]

The crew of Apollo 11 in quarantine after returning to Earth, visited by Richard Nixon.

In 1979, the famous physicist Sir Fred Hoyle and N.C Wickramasinghe, first proposed their theory of microbial panspermia in that virus pandemics originate in outer space.[221] Although some hospital consultants in charge of infection control might secretly think this is true, the theory was soon discredited by virologists who used more proven epidemiology.[222] But for life, to exist – "as we know it"[223] – it needs water, energy and a rich source of carbon and some trace elements.[224] So, given the size of the universe, there seems little doubt that life as we know it exists elsewhere.[225] When, in 1969, astronauts Armstrong, Aldrin and Collins returned from the moon, they were quarantined for 21 days in case they had been infected with lunar microbes. But these fears were unjustified and subsequent lunar explorers were not subjected to the indignity.[226] The possibility of the existence of viruses on other worlds cannot be dismissed but it is unlikely that these would pose a threat to life on earth because of their co-evolution with their hosts and subsequent host specificity. Given that the earth-bound tomato bushy stunt virus has such a narrow host range, it is hard to conceive that extraterrestrial viruses might have a specificity broad enough to enable them to infect life on Earth.[227]

Viruses in history[edit]

Prehistory[edit]

Electron micrograph of smallpox viruses; the “dumbbell-shaped” structure inside the smallpox virus particle is the viral core, which contains the viral DNA.

Over the past 50,000–100,000 years as modern humans dispersed throughout the world new infectious diseases, including those caused by viruses, emerged.[228] Smallpox, which was one of the most lethal and devastating viral infections, might have emerged first among agricultural communities in Africa in about 10,000 BC.[229] The virus, which only infected humans, probably descended from the poxviruses of rodents.[230] Humans probably came into contact with these rodents, and some people became infected by the viruses they carried.

When viruses cross this so called "species barrier" their effects can be severe,[231] and humans may have had little natural resistance. Contemporary humans lived in small communities, and those who succumbed to infection either died or developed immunity. In humans, this acquired immunity is only passed down to offspring temporarily through breast milk and the antibodies, which cross the placenta from the mother's blood to the unborn child's. Therefore, sporadic outbreaks probably occurred in each generation. In about 9000 BC, when many people began to settle on the fertile flood plains of the River Nile, the population became dense enough for the virus to maintain a constant presence thanks to the high concentration of susceptible people.[232]

The Neolithic age, which began in the Middle East in about 9500 BC, was a time when humans became farmers. This agricultural revolution embraced the development of monoculture and presented an opportunity for the rapid spread of several species of plant viruses.[233] The divergence and spread of sobemoviruses – southern bean mosaic virus – date from this time[234] and the spread of the potyviruses of potatoes, and other fruits and vegetables, began about 6,600 years ago.[233]

About 10,000 years ago the humans who inhabited the lands around the Mediterranean basin began to domesticate wild animals. Pigs, cattle, goats, sheep, horses, camels, cats and dogs were all kept and bred in captivity.[235] These animals would have brought their viruses with them. The transmission of viruses from animals to humans can occur, but such zoonotic infections are rare and subsequent human-to-human transmission is even rarer, although there are notable exceptions such as influenza. Most viruses are species specific and would have posed no threat to humans. But as humans became more dependent on domesticated animals, any outbreaks of disease among their livestock – in animals these are called epizootics – could have devastating consequences.

Other, more ancient, viruses are less of a threat. Humans have lived with herpes virus infections since humans first came into being. The virus passed to us from other mammals more than 80 million years ago.[236] Humans have developed a tolerance to these viruses, and most are infected with at least one species of them without being aware of it. Records of these milder virus infections are understandably rare. But there is no reason to doubt that early hominids suffered from colds, 'flu and diarrhoea caused by viruses just as humans do today. It is the younger viruses that cause epidemics and pandemics – and it is those that history records.[236]

Antiquity[edit]

An Egyptian stele thought to depict a poliovirus victim, 18th Dynasty (1580–1350 BC)

Among the earliest records of a viral infection is an Egyptian stele thought to depict an Egyptian priest from the 18th Dynasty (1580–1350 BC) with a foot drop deformity characteristic of a poliovirus infection.[237] The mummy of Siptah – a ruler during the 19th Dynasty – shows signs of poliomyelitis, and that of Ramesses V and some other Egyptian mummies buried over 3000 years ago show evidence of smallpox.[238] There was an epidemic of smallpox in Athens in 430 BC. A quarter of the Athenian army died from the infection along with many of the city's civilians.[239]

A Japanese print from the 19th century depicting the burning of cattle infected with rinderpest

Measles is an old disease, but it was not until the 10th century that the Persian physician Muhammad ibn Zakariya al-Razi (865–925) (known as "Rhazes") first identified it.[240] Rhazes used the Arabic name "hasbah" for measles, but it has had many other names including "rubeola" from the Latin word rubeus, which means red, and "morbilli", which means "small plague".[241] The close similarities between measles virus, canine distemper virus, and rinderpest virus have given rise to speculation that measles was first transmitted to humans from domesticated dogs or cattle.[242] The measles virus appears to have fully diverged from the then-widespread rinderpest virus by the 11th and 12th centuries.[243] The earliest likely origin is within the seventh century: for this earlier origin there is some linguistic evidence.[244][245]

One measles infection confers lifelong immunity, therefore the virus requires a high population density to become endemic and probably did not occur in the Neolithic.[240] (In more recent times, measles has become extinct on remote islands with populations of less than 500,000 people.[242]) Following the emergence of the virus in the Middle East it reached India by 2500 BC.[246] Measles was so common in children at the time it was not recognised as a disease. In Egyptian hieroglyphs it was described as a normal stage of human development.[247] The Americas and Australia remained free of measles and smallpox until the arrival of European colonists between the 15th and 18th centuries.[228]

One of the earliest descriptions of a virus-infected plant can be found in a poem written by the Japanese Empress Kōken (718–770), in which she describes a plant in summer with yellowing leaves. The plant, later identified as Eupatorium lindleyanum, is often infected with Tomato yellow leaf curl virus.[248]

Middle Ages[edit]

A woodcut from the Middle Ages showing a rabid dog

The Middle Ages witnessed many plagues and pestilences. The rapidly growing population of Europe and the rising concentrations of people in its towns and cities became a fertile ground for many infectious and contagious diseases, of which the Black Death – a bacterial infection – is probably the most notorious.[249] Except for smallpox and influenza, documented outbreaks of infections now known to be caused by viruses are rare. Rabies, a disease that had been recognised for over 4000 years,[250] was rife in Europe, and continued to be until the development of a vaccine by Louis Pasteur in 1886.[251] The average life expectancy during the Middle Ages was 35 years and 60% of children died before the age of 16, many of them during their first 6 years of life. Among the plethora of diseases common at the time were influenza, measles, and smallpox.[252]

Measles was endemic throughout the highly populated countries of Europe, North Africa, and the Middle East. In England the disease, then called "mezils", was first described in the 13th century, and was probably one of the 49 plagues that occurred between 526 and 1087.[246] Rinderpest has been recognised since Roman times.[253] The disease, which originated in Asia, was first brought to Europe by the invading Huns in 370. Later invasions of Mongols, led by Genghis Khan and his army, started pandemics in Europe in 1222, 1233 and 1238. The infection subsequently reached England following the importation of cattle from Europe.[254] At the time rinderpest was a devastating disease with a mortality rate of 80–90%. The resulting loss of cattle cased famine and starvation.[254]

Early modern period[edit]

Ambrosius Bosschaert (1573–1620) "Still Life"

Many paintings can be found in the museums of Europe depicting tulips with attractive coloured stripes. Most, such as the still life studies of Johannes Bosschaert, were painted during the 17th century. These flowers were particularly popular and became sought after by those who could afford them. It was not known at the time that these attractive – and very expensive – stripes were caused by a virus accidentally transferred by humans to tulips from jasmine.[255]

Until the Irish Great Famine of 1845–1852, the commonest cause of disease in potatoes was not the mould that causes blight but a virus. The disease, called "curl", is caused by Potato leafroll virus, and it was widespread in England in the 1770s, where it destroyed 75% of the potato crop. At the time, the Irish potato crop remained relatively unscathed.[256]

Girolamo Fracastoro thought measles was caused by "seeds".

In 1546 Girolamo Fracastoro (1478–1553) wrote a classic description of measles. He thought the disease was caused by "seeds" (seminaria) that were spread from person to person. An epidemic hit London in 1670, recorded by Thomas Sydenham (1624–1689), who thought it was caused by toxic vapours emanating from the earth.[246] Sydenham had been a soldier and fought for the Parliamentarians during the English Civil War. As a physician, he was a skilled observer and kept meticulous records.[257]

A short time after Henry Tudor's victory at the Battle of Bosworth on 22 August 1485, his army suddenly went down with "the English sweat", which contemporary observers described as something new.[258] It was probably influenza, although we cannot be sure,[259] because records from the time when medicine was not a science can be unreliable.[260] The language used to describe diseases in these sources is often vague and colloquial. We read of "plagues of mice", "changes in the direction of the wind" and the "influence of comets". This makes retrospective diagnosis difficult. As medicine became a science, the descriptions of disease became less vague and records became more reliable.

References to influenza infections date from the late 15th and early 16th centuries,[261] but infections almost certainly occurred long before then.[262] The first that was reliably recorded began in Malta in July 1580, and swept across Europe, Africa, and Asia.[263] More than a century passed before the three pandemics of the 18th century; the one that took place during 1781–2 was probably the most devastating in history.[264] The pandemic began in November 1781 in the East Indies and reached Moscow in December. In February 1782 it hit St. Petersburg and by May it had reached Denmark.[265] Within six weeks, three-quarters of the British population were infected and the pandemic soon spread to the Americas.[266]

Sixteenth-century Aztec drawing of a smallpox victim

Along with measles and influenza, smallpox was taken to the Americas by the Spanish.[267] Smallpox was endemic in Spain, having been introduced by the Moors from Africa.[268] In 1519, an epidemic of smallpox broke out in the Aztec capital Tenochtitlan, which was started by the army of Pánfilo de Narváez (1478–1528), who followed Hernán Cortés (1495–1587) from Cuba, and had an African slave suffering from smallpox aboard his ship.[268] When the Spanish finally entered the capital in the summer of 1521, they saw it strewn with the bodies of smallpox victims.[269] The epidemic, and those that followed during 1545–1548 and 1576–1581, eventually killed more than half of the native population.[270] Most of the Spanish were immune and with his army of fewer than 900 men, it would not have been possible for Cortés to defeat the Aztecs and conquer Mexico without the help of smallpox.[271]

History repeated itself, and many Native American populations were devastated by the spread of smallpox, measles, and influenza.[228] There were, on average, fourteen epidemics of smallpox in the 18th century and by 1733, the disease had affected all Six Nations. In 1738, half the population of Cherokee died from the disease. In Pennsylvania, in 1763, Europeans intentionally exposed Native Americans to smallpox.[272] It is not known exactly how many Native Americans were killed, but the damage done by this disease significantly aided European attempts to displace and conquer the native population.[273]

16th century Aztec drawing of a measles victim

By the 18th century, smallpox was endemic in Europe. There were five epidemics in London between 1719 and 1746, and large outbreaks occurred in other major European cities. By the end of the century about 400,000 Europeans were dying from the disease each year.[274] It reached South Africa in 1713, having been carried by ships from India, and decimated the population of Hottentots in 1713 and 1755.[275] In 1789 the disease struck Australia,[274] and in the 19th century, smallpox became the single major cause of death of the Australian Aborigines.[276]

Yellow fever is an often lethal disease caused by a flavivirus. The virus is transmitted to humans by mosquitoes (Aedes aeypti) and first appeared over 3,000 years ago.[277] In 1647, the first recorded epidemic occurred on Barbados and was called "Barbados distemper" by John Winthrop (1588–1649), who was the governor of the island at the time. He passed quarantine laws to protect the people – the first ever such laws in North America.[278] Further epidemics of the disease occurred in the North Americas in the 17th, 18th, and 19th centuries.[279]

The first known cases of dengue fever occurred in Indonesia and Egypt in 1779 and trade ships brought the disease to the US, where an epidemic occurred in Philadelphia in 1780.[280] In the 19th century there were frequent dengue epidemics throughout the Americas, and by 1897 almost the whole of the southern US was affected.[280]

Discovery of vaccination[edit]

Edward Jenner

Lady Mary Wortley Montagu (1689–1762) was an aristocrat, a writer and the wife of a Member of Parliament. In 1716, her husband, Edward Wortley Montagu was appointed British Ambassador in Istanbul. She followed him there and two weeks after her arrival discovered the local practice of protection against smallpox by variolation – the injection of pus from smallpox victims into the skin.[232] Her younger brother had died of smallpox, and she too had had the disease but survived. Determined to spare her five-year-old son Edward from similar suffering, she ordered the embassy surgeon, Charles Maitland to variolate him. On her return to London, she asked Maitland to variolate her four-year-old daughter in the presence of the king's physicians.[281] Later, Montagu persuaded the Prince and Princess of Wales to sponsor a public demonstration of the procedure. Six prisoners who had been condemned to death and were awaiting execution at Newgate Prison were offered a full pardon for serving as the subjects of the public experiment. They accepted, and in 1721 were variolated. All the prisoners recovered from the procedure and to test its protective effect one of them, a nineteen-year-old woman, was ordered to sleep in the same bed as a ten-year-old smallpox victim for six weeks. She did not contract the disease.[282] The experiment was repeated on six orphan children who survived the ordeal and by 1722, even King George I's grandchildren had been inoculated. But the practice was not entirely safe and two percent died as a result.[283] Although the number of lives saved far outweighed those lost, the practice was not widely adopted.[284]

A cartoon from 1802 depicting Jenner vaccinating – the recipients are shown with cows emerging from their bodies.

At the time nothing was known about viruses or immunity and no one knew how variolation worked.[285]

Edward Jenner (1749–1823), a British rural physician, was variolated as a boy. He had suffered greatly from the ordeal but survived fully protected from smallpox. Jenner knew of a local belief that dairy workers who had contracted a relatively mild infection called cowpox were immune to smallpox. He decided to test the "theory" (though he was probably not the first to do). On 14 May 1796 he selected "a healthy boy, about eight years old for the purpose of inoculation for the Cow Pox".[286] The boy was James Phipps (1788–1853) who survived the experiment and suffered only a mild fever. On 1 July 1796, Jenner took some "smallpox matter" (probably infected pus) and repeatedly inoculated Phipp's arms with it. Phipps survived, and was subsequently inoculated with smallpox more than 20 times without succumbing to the disease. Vaccination – the word is derived from the Latin vacca meaning "cow" – had been invented.[287]

Louis Pasteur and rabies[edit]

Louis Pasteur

Rabies is an often fatal disease caused by the infection of mammals with rabies virus. Today it is mainly a disease that affects wild mammals such as foxes and bats, but it is one of the oldest known virus diseases: rabies is a Sanskrit word (rabhas) that dates from 3000 BC,[251] which means "madness" or "rage"[247] and the disease has been known for over 4000 years.[250] The ancient Greeks called it "lyssa" or "lytta" also meaning madness.[250] Although not a cause of epidemics the infection was greatly feared because of its horrendous symptoms, which include insanity, hydrophobia, and death.[250] The disease had been known since antiquity, and references to rabies can be found in the Laws of Eshnunna, which date from 2300 BC. Aristotle (384–322 BC) wrote one of earliest undisputed descriptions of the disease and how it was passed to humans. Celsus in the first century AD first recorded the symptom called hydrophobia and suggested the saliva of infected animals and humans contained a slime or poison – to describe this he used the word "virus".[250] In France during the time of Louis Pasteur there were only a few hundred infections in humans each year, but cures were desperately sought. Aware of the extreme danger, Pasteur worked on what he knew would be a challenge, and began to look for the "microbe" in the saliva of mad dogs.[288]

A member of Pasteur's team, Emile Roux (1853–1933), studied how long the spinal cords of dogs that had died from the disease remained infectious. Roux invented an ingenious glass bottle in which he hung the spinal cords to dry them. Pasteur was impressed with Roux's invention and ordered more bottles to be made. Pasteur never credited Roux for his invention and Roux considered his idea stolen; Roux never worked on rabies again. After 14 days of drying, Pasteur showed that when the dried spinal cords were crushed and injected into healthy dogs they did not become infected. He repeated the experiment several times on the same dog with tissue that had been dried for fewer and fewer days, until the dog survived after injections of fresh rabies infected spinal tissue. Pasteur had immunised the dog against rabies as he later did with 50 more.[289]

A cartoon from 1826 depicting a rabid dog on a London street

Although he had little idea how his method worked, he went on to test it on a boy. Joseph Meister (1876–1940) was brought to Pasteur by his mother on 6 July 1885. He was covered in bites, having been set upon by a mad dog. A bricklayer had defended the boy from the dog with an iron bar, but only after the salivating dog had bitten the boy 14 times. Meister's mother begged Pasteur to help her son. Pasteur was a scientist, not a physician, and he was well aware of the consequences for him if things were to go wrong. Pasteur decided to help the boy and injected him with increasingly virulent rabid rabbit spinal cord over the following 10 days.[290] Later Pasteur wrote, "as the death of this child appeared inevitable, I decided, not without deep and severe unease ... to try out on Joseph Meister the procedure, which had consistently worked on dogs".[291]

The date set for the final inoculation using undried tissue was 16 July. Pasteur's assistant, Grancher, was given the task, but accidentally jabbed himself with the infected needle, and thus became the second guinea pig to receive Pasteur's new treatment. Later, in an argument about the ethics of what they had done, Pasteur's whole team, including Pasteur himself, clandestinely inoculated one another. Although still angry with Pasteur, Roux discovered what was going on and, as he was the only qualified physician on the team, took charge of the dangerous situation.

It was too late for the men to stop. Fortunately, they all lived to tell the tale and Meister returned home with his mother on 27 July. But the full truth was kept a secret for many years.[292] Pasteur successfully treated a second boy in October that same year; Jean-Baptiste Jupille (1869–1923) was a 15-year-old shepherd boy who had been severely bitten as he tried to protect other children from a rabid dog.[293] Pasteur's method of treatment subsequently remained in use for over 50 years.[294]

Not much was known about the cause of the disease until in 1903 when Adelchi Negri (1876–1912) first saw microscopic lesions in the brains of rabid animals now called Negri bodies.[295] He wrongly thought they were protozoan parasites. However Paul Remlinger (1871–1964) soon showed by filtration experiments that they were much smaller than protozoa and even smaller than bacteria. Thirty years later, Negri bodies were shown to be accumulations of particles 100–150 nanometres long, now known to be the size of rhabdovirus particles – the virus that causes rabies.[250]

Modern period[edit]

Smallpox eradication[edit]

Rahima Banu, the last known case of naturally-occurring smallpox in the world, which occurred in 1975.[296]

Smallpox virus was one of the biggest killers of the 20th century; it had managed to kill 300 million people since 1900.[297] In 1966 an agreement was reached by the World Health Assembly (the decision-making body of World Health Organisation) to start an "intensified smallpox eradication programme" and attempt to eradicate the disease within ten years.[298] At the time, smallpox was still endemic in thirty-one countries[299] including in Brazil, the whole of the Indian sub-continent, Indonesia and sub-Saharan Africa.[298] This ambitious goal was considered achievable for several reasons: The vaccine afforded exceptional protection; there was only one type of the virus; there were no animals that naturally carried it; the incubation period of the infection was known and rarely varied from 12 days; and infections always gave rise to symptoms, so it was clear who had the disease and who did not.[300][301]

Following mass vaccinations, disease detection and containment were central to the eradication campaign. As soon as cases were detected, the victims were isolated as were their close contacts who were also vaccinated.[302] Successes came quickly, by 1970 smallpox was no longer endemic in western Africa, and by 1971 in Brazil.[303] By 1973, smallpox remained endemic only in the Indian sub-continent, Botswana and Ethiopia.[299] Finally, after thirteen years of coordinated disease surveillance and vaccination campaigns throughout the world, the World Health Organisation declared smallpox eradicated in 1979.[304] Although the main weapon used was vaccinia virus, which was used as the vaccine, no one seems to know exactly where vaccinia virus came from; it is not the strain of cowpox that Edward Jenner had used, and it is not a weakened form of smallpox.[305]

The eradication campaign was not without casualties. Most notable was the death of Janet Parker (c. 1938–1978) and the subsequent suicide of virologist Henry Bedson (1930–1978).[306] Before the September 11 attacks on America in 2001, it was planned to destroy all the remaining stocks of smallpox virus that were kept in laboratories in US and Russia. Had this plan gone ahead, smallpox virus would have been the first to be made extinct by human intervention.[307]

Measles[edit]

Measles is highly contagious. Before the introduction of vaccination in the US in the 1960s there were more than 500,000 cases a year resulting in about 400 deaths. In developed countries children were mainly infected between the ages of three and five years old, but in developing countries half the children were infected before the age of two.[308] In the US and the UK, there were regular annual or bi-annual epidemics of the disease, which depended on the number of children born each year.[309] The current epidemic strain evolved at the beginning of the 20th century – probably between 1908 and 1943.[310]

Reported cases of measles in England and Wales from 1940–2007. The graph shows the bi-annual cycle of epidemics that followed the war.

In London between 1950 and 1968 there were epidemics every two years, but in Liverpool, which had a higher birth rate, there was an annual cycle of epidemics. During the Great Depression in the US before the Second World War the birth rate was low, and epidemics of measles were sporadic. After the war the birth rate increased, and epidemics occurred regularly every two years. In developing countries with very high birth rates, epidemics occurred every year.[309] Measles is still a major problem in densely populated, less-developed countries, with high birth rates but lacking effective vaccination campaigns.[311]

In the US, by the mid-1970s the incidence of measles had fallen by 90%.[312] This reduction was achieved by a mass vaccination programme that was known as "make measles a memory" and similar vaccination campaigns in other countries have reduced the levels of infection by 99% over the past 50 years.[313] Susceptible individuals remain a source of infection and include those who have migrated from countries with ineffective vaccination schedules, or who refuse the vaccine or choose not to have their children vaccinated.[314]

Humans are the only natural host of measles virus.[312] Immunity to the disease following an infection is lifelong; that afforded by vaccination is long term but eventually wanes.[315] The use of the vaccine is not without risk, and its use has been controversial.[316] But despite these controversies measles has been eliminated from Finland, Sweden and Cuba.[317] Japan abolished mandatory vaccination in 1992, and in 1995–1997 more than 200,000 cases were reported in the country.[318] Measles remains a public health problem in Japan, where it is now endemic and a National Measles Elimination Plan was established in December 2007, with a view to eliminating the disease from the country by 2012.[319] The possibility of global elimination of measles has been debated in the medical literature since the introduction of the vaccine in the 1960s. Should the current campaign to eradicate poliomyelitis be successful, it is likely that the debate will be renewed.[320]

Poliomyelitis[edit]

The prevalence of poliomyelitis in 2005. The countries where polio was endemic are shown in red, those with imported cases are in green.
This 1963 poster featured CDC’s national symbol of public health, the "Wellbee", who was depicted here encouraging the public to receive an oral polio vaccine.
Young polio victims receiving physiotherapy in the 1950s

During the summers of the mid-20th century parents dreaded the annual appearance of poliomyelitis, which was commonly known as "infantile paralysis".[321] The disease was rarer at the beginning of the century and worldwide there were only a few thousand cases a year, but by the 1950s there were 60,000 cases each year in the US alone.[322] During 1916 and 1917 there had been a major epidemic in the US; 27,000 cases and 6,000 deaths were recorded, with 9,000 cases in New York City alone.[323] At the time nobody knew how the virus was spreading.[324] Many of the city's inhabitants, including scientists, thought that impoverished slum-dwelling immigrants were to blame even though the prevalence of the disease was higher in the more prosperous districts such as Staten Island – a pattern that had been seen in other cities such as Philadelphia.[325] The disease was not confined to the US, many other industrialised countries were affected at the same time. Before the outbreaks in the US, large epidemics occurred in Sweden.[326]

The reason for the rise of poliomyelitis in industrialised countries in the 20th century has never been fully explained. Why a disease that is caused by a virus that is passed from person to person by the faecal-oral route,[327] and only naturally infects humans,[328] became a problem during times of improved sanitation and increasing affluence is a paradox.[327] Although the virus was discovered at the beginning of the 20th century, just how ubiquitous it became was unrecognised until the 1950s. It is now known that only 1–2% of individuals who are infected develop the disease, and most infections are mild.[329] During epidemics the virus was everywhere, which explains the failed attempts by public health officials to isolate a source.[328]

Following the development of vaccines in the mid-1950s, mass vaccination campaigns took place in many countries. In the US,following a campaign promoted by the March of Dimes, the annual number of polio cases fell dramatically; from 76,000 in 1955 to less than 1,000 in 1967.[330] The last US outbreak was in 1979.[331] In 1988 the World Health Organisation along with others launched the Global Polio Eradication Initiative, and by 1994 the Americas were declared to be free of disease, followed by the Pacific region in 2000 and Europe in 2003.[332] By 2007 poliomyelitis had been eradicated from all countries except, India, Pakistan, Bangladesh, and Nigeria.[333] As of 2010, outbreaks of infection are still being reported in other countries following importation of polio virus from those regions.[334]

Origin and emergence of HIV[edit]

right to right: the African green monkey source of SIV, the sooty mangabey source of HIV-2 and the chimpanzee source of HIV-1

Most researchers believe that HIV originated in sub-Saharan Africa during the 20th century;[335] it is now a pandemic, with an estimated 38.6 million people now living with the disease worldwide.[336] The Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) estimate that AIDS has killed more than 25 million people since it was first recognised on June 5, 1981, making it one of the most destructive epidemics in recorded history.[337] In 2007 there were 2.7 million new HIV infections and 2 million HIV-related deaths.[338] HIV-1 is one of the most significant viruses to have emerged in the last quarter of the 20th century.[339] As of 2010, over 40 million people have been infected and more than 25 million of them have died from AIDS-related diseases.[340] When, in 1981 a scientific article was published that reported the deaths of five young gay men, no one knew the full scale of the epidemic, or that the virus had been silently emerging over several decades.[341] The viruses – there are two of them – HIV-1 and HIV-2, originated in non-human primates and first infected humans in western equatorial Africa,[342] but HIV-1 rapidly spread across the world.[343] Shortly after HIV-1 was discovered in 1983 it was shown to be closely related to SIV, a retrovirus of monkeys and chimpanzees.[344] There are different strains of HIV-1 and HIV-2 and each evolved independently from primates. How these viruses entered the human population is not fully understood, but during the 1960s and 1970s there were large population shifts from rural to urban areas in Africa.[345] Analysis of the RNA from several strains of HIV-1 and HIV-2 has shown that these viruses evolved from SIV-related viruses during the first half of the 20th century.[346] This happened more the once and three groups of HIV-1 (called M, N and O) and two groups of HIV-2 (called A and B) emerged independently. This occurred around 1920 (O), 1930 (M) and N more recently. All of these groups of HIV had appeared by the 1960s and were circulating in central Africa.[347] The spread of HIV to the western world probably began in the 1960s when Haitians returned to their homeland from the Congo.[348] Apart from Africa, Haiti has the longest established HIV/AIDS epidemic and tourism during the 1960s probably aided the spread of the virus to the US, where in quietly circulated for over a decade before it was discovered.[349] Similarly, HIV-2 group A emerged in about 1940 and HIV-2 B in about 1945. But it is impossible to be precise, because the method of estimation used is statistical. Those dates represent the most likely years within a range of about ten years either side.[350]

Haemorrhagic fevers[edit]

Several highly lethal viral pathogens are members of the Filoviridae. Filoviruses are filament-like viruses that cause viral hemorrhagic fever, and include the Ebola and Marburg viruses. The Marburg virus attracted widespread press attention in April 2005 for an outbreak in Angola. Beginning in October 2004 and continuing into 2005, the outbreak was the world's worst epidemic of any kind of viral haemorrhagic fever.[351]

Influenza[edit]

When influenza virus undergoes a genetic shift many humans have no immunity to the new strain, and if the population of susceptible individuals is high enough to maintain the chain of infection then pandemics occur. The genetic changes usually happen when different strains of the virus co-infect animals, particularly birds and swine. Although many viruses of vertebrates are restricted to one species, influenza virus is an exception.[352] The last pandemic of the 19th century occurred in 1899 and resulted in the deaths of 250,000 people in Europe alone. The virus, which originated in Russia or Asia, was the first to be rapidly spread by people on trains and steamships.[353]

A new strain of the virus emerged in 1918, and the subsequent pandemic of Spanish flu was one of the worst natural disasters in history.[353] The death toll was enormous; there were 550,000 reported deaths caused by the disease in the US, ten times the country's losses during the First World War. Throughout the world more than 20 million people died from the infection.[354] Although cases of influenza occurred every winter, there were only two other pandemics in the 20th century.

In 1957 another new strain of the virus emerged and caused a pandemic of Asian flu; although the virus was not as virulent as the 1918 strain, over one million died worldwide.[355] The next pandemic occurred when Hong Kong flu emerged in 1968, a new strain of the virus that completely replaced the 1957 strain.[356] Affecting mainly the elderly, the 1968 pandemic was the least severe, but 33,800 were killed in the US.[357] It might be no coincidence that new strains of influenza virus often originate in the far east; in rural China the concentration of ducks, pigs, and humans in close proximity is the highest in the world.[358] More than 30 years passed until the next pandemic in 2009, but none of the last three has caused anything near the devastation seen in 1918. Exactly why the strain of influenza that emerged in 1918 was so devastating is a question that still remains unanswered.[353]

Yellow fever, dengue and other arboviruses[edit]

Aedes aegypti feeding on human blood

The arboviruses are viruses that are transmitted to humans and other vertebrates by blood-sucking insects. These viruses are diverse; the term "arbovirus" – which was derived from "arthropod borne virus" – is no longer used in formal taxonomy because many different species of virus are known to be spread in this way.[359] There are more than 500 species of arboviruses, but in the 1930s only three were known to cause disease in humans, yellow fever, dengue and Pappataci fever.[360] More than 100 of these viruses are now known to cause human diseases.[361]

Yellow fever is the most notorious disease caused by a flavivirus.[362] In 1905, the last major epidemic occurred in the US.[279] During the building of the Panama Canal thousands of workers succumbed and died from the disease.[363] Yellow fever originated in Africa and the virus was brought to the Americas on cargo ships, which were harbouring the Aedes aegypti that carries the virus. The first recorded epidemic in Africa occurred in Ghana, West Africa, in 1926.[364] In the 1930s the disease re-emerged in Brazil. Fred Soper, an American epidemiologist (1893–1977), discovered the importance of the sylvatic cycle of infection in non-human hosts, and that humans were a "dead end" that broke this cycle.[365]

Although the yellow fever vaccine is one of the most successful ever developed,[366] epidemics continue to occur. In 1986–91 epidemics occurred in West Africa and over 20,000 people were infected, 4,000 of whom died.[367]

In the 1930s, St. Louis encephalitis, eastern equine encephalitis and western equine encephalitis emerged in the US. The virus that causes La Crosse encephalitis was discovered in the 1960s,[368] and West Nile virus arrived in New York in 1999.[369] As of 2010, dengue is the most prevalent arbovirus and increasingly virulent strains of the virus have spread across Asia and the Americas.[370]

Hepatitis viruses[edit]

Hepatitis is a disease of the liver that has been recognised since antiquity.[371] Symptoms include jaundice, a yellowing of the skin, eyes and body fluids.[372] There are numerous causes, including viruses – particularly hepatitis A virus, hepatitis B virus and hepatitis C virus.[373] Throughout history epidemics of jaundice have been reported mainly affecting soldiers at war. This "campaign jaundice" was common in the Middle Ages. It occurred among Napoleon's armies and during most of the major conflicts of 19th and 20th centuries, including the American Civil War, where over 40,000 cases were reported including around 150 deaths.[374] But the viruses that cause epidemic jaundice were not discovered until the middle of the 20th century.[375] The diseases caused by hepatitis viruses were all recognised before the viruses were discovered. The name for epidemic jaundice, hepatitis A, and for blood-borne infectious jaundice, hepatitis B, were first used in 1947,[376] following a publication in 1946 giving evidence that the two disease were distinct.[377] The first virus discovered that could cause hepatitis was hepatitis B in the 1960s.[378] Hepatitis A virus was not discovered until 1974.[379]

Gastroenteritis viruses[edit]

There are many types of viruses that infect the gut but most of them, such as the enterovirues, do not cause gastroenteritis. These viruses use the cells of the gut as a gateway to other organs where the infections become overt.[380] However, two types of viruses, rotavirus and norovirus, are a frequent cause of gastroenteritis.

Rotavirus[edit]

In 1943, Jacob Light and Horace Hodes proved that a filterable agent in the faeces of children with infectious diarrhoea also caused scours (livestock diarrhoea) in cattle.[381] Three decades later, preserved samples of the agent were shown to be rotavirus.[382] In the intervening years, a virus in mice[383] was shown to be related to the virus causing scours.[384] In 1973, Ruth Bishop and colleagues described related viruses found in children with gastroenteritis.[385]

In 1974, Thomas Henry Flewett suggested the name rotavirus after observing that, when viewed through an electron microscope, a rotavirus particle looks like a wheel (rota in Latin);[386][387] the name was officially recognised by the International Committee on Taxonomy of Viruses four years later.[388] In 1976, related viruses were described in several other species of animals.[384] These viruses, all causing acute gastroenteritis, were recognised as a collective pathogen affecting humans and animals worldwide.[386] Rotavirus serotypes were first described in 1980,[389] and in the following year, rotavirus from humans was first grown in cell cultures derived from monkey kidneys, by adding trypsin (an enzyme found in the duodenum of mammals and now known to be essential for rotavirus to replicate) to the culture medium.[390] The ability to grow rotavirus in culture accelerated the pace of research, and by the mid-1980s the first candidate vaccines were being evaluated.[391]

In 1998, a rotavirus vaccine was licensed for use in the United States. Clinical trials in the United States, Finland, and Venezuela had found it to be 80 to 100% effective at preventing severe diarrhoea caused by rotavirus A, and researchers had detected no statistically significant serious adverse effects.[392][393] The manufacturer, however, withdrew it from the market in 1999, after it was discovered that the vaccine may have contributed to an increased risk for intussusception, a type of bowel obstruction, in one of every 12,000 vaccinated infants.[394] The experience provoked intense debate about the relative risks and benefits of a rotavirus vaccine.[395] In 2006, two new vaccines against rotavirus A infection were shown to be safe and effective in children,[396] and in June 2009 the World Health Organization recommended that rotavirus vaccination be included in all national immunisation programmes to provide protection against this virus.[397]

Norovirus[edit]

Noroviruses are a frequent cause of gastroenteritis in adults and children.[398] Discovered in 1972 when virologists started to use electron microscopes to examine samples of faeces, they were the first viruses shown to cause gastroenteritis.[399] They frequently cause outbreaks of disease in hospitals and other places were people congregate in semi-closed settings.[400] The viruses are small (about 27nM in diameter), non-enveloped, single-stranded RNA viruses. As of 2012, there is no vaccine to prevent norovirus infections and general infection control measures are used to combat outbreaks, but often these are inadequate, which leads to disruption in hospitals and ruined holidays on cruise ships.[401]

Warts and all[edit]

Transmission electron micrograph of a papillomavirus

The human papillomviruses – there are more than 100 types – are the cause of benign papillomas or warts, which occur mainly on the hands, feet and genitals.[402] They are non-enveloped icosahedral viruses, about 55nM in diameter with a circular dsDNA genome.[403] Some strains, particularly types HPV16 and HPV18 can cause cervical cancer,[404] and the viral DNA is found in almost all of the cancerous cells. [405]

The viruses were is discovered in cells from cases of cervical cancer 1983, but earlier, in 1972, the association of the human papilloma viruses with skin cancer in epidermodysplasia verruciformis was proposed by Stefania Jabłońska in Poland. In 1978, Jabłońska and Gerard Orth at the Pasteur Institute discovered HPV-5 in skin cancer.[406]

These viruses cause cancer by integrating their DNA into a host cell chromosome.[407] The viruses have eight or nine genes, two of which, E6 and E7 cause cells to divide and grow. In cells where integration has not occurred, this causes warts, but when integration has occurred these genes are much more active and the cells become cancerous.[408] Pap smears and PCR are used to detect the early stages of infection and a vaccine to prevent infection is available, which greatly reduce the incidence of cervical cancer.[409]

The cells from the HeLa line contain extra DNA in their genomes that originated from human papillomaviruses.[410]

Epizootics[edit]

Female sheep with bluetongue disease

During the 20th century significant outbreaks of viral diseases in animals, particularly livestock, occurred worldwide. The many diseases caused by viruses included foot and mouth disease, rinderpest of cattle, avian and swine influenza, swine fever and bluetongue of sheep. Viral disease of livestock can be devastating both to farmers and the wider community as the outbreaks of foot and mouth disease in the UK in 2001 has shown.[411]

In the early years of the 20th century rinderpest disease of cattle was common in Asia and parts of Europe.[412] The prevalence of the disease was steadily reduced during the course of the century by control measures that included vaccination.[413] By 1908 Europe was free from the disease although outbreaks did occur following the Second World War, but these were quickly controlled. But the prevalence of the disease increased in Asia, and in 1957 Thailand had to appeal for aid because so many buffaloes had died that the paddy fields could not be prepared for rice growing.[414] Russia west of the Urals, remained free from the disease – Vladimir Lenin passed several laws on the control of the disease – but cattle in the east of Russia were constantly infected with rinderpest that originated in Mongolia and China where the prevalence remained high.[415] India controlled the spread of the disease, which had retained a foothold in the southern states of Tamil Nadu and Kerala, throughout the 20th century,[416] but eradicated the disease by 1995.[417] Africa suffered two major panzootics in the 1920s and 1980s.[418] There was a severe outbreak in Somalia in 1928 and the disease was widespread in the country until 1953. In the 1980s, outbreaks in Tanzania and Kenya were controlled by the use of 26 million doses of vaccine, and a recurrence of the disease in 1997 was suppressed by an intensive vaccination campaign.[419] By the end of the century rinderpest had been eradicated from most countries. A few pockets of infection remained in Ethiopia and Sudan,[420] and in 1994 of the Global Rinderpest Eradication Programme was launched by the Food and Agriculture Organization with the aim of global eradication by 2010.[421]

Foot-and-mouth disease is a highly contagious infection caused by an aphthovirus, and is classified in the same family as poliovirus. The virus has infected animals, mainly ungulates, in Africa since ancient times and was probably brought to the Americas in the 19th century by imported livestock.[422] Foot-and-mouth disease is rarely fatal, but the economic losses incurred by outbreaks in sheep and cattle herds can be high.[423] The last occurrence of the disease in the US was in 1929, but as recently as 2001, several large outbreaks occurred throughout the UK and thousands of animals were killed and burnt.[424]

Influenza is mainly a disease of pigs and birds, but not humans, although it has probably infected us since antiquity.[425] The virus can cause mild to severe epizootics in wild and domesticated animals.[426] Many species of wild birds migrate and this has spread influenza across the continents throughout the ages. The virus has evolved into numerous strains and continues to do so, posing an ever-present threat.[427]

In the early years of the 21st century epizootics in livestock caused by viruses continued to have serious consequences. Bluetongue disease, a disease caused by an orbivirus broke out in sheep in France in 2007.[428] Until then the disease had been mainly confined to the Americas, Africa, southern Asia and northern Australia, but it is now an emerging disease around the Mediterranean.[429]

Like any organism, marine mammals are susceptible to viral infections. In 1988 and 2002, thousands of harbor seals were killed in Europe by phocine distemper virus.[430] Many other viruses, including caliciviruses, herpesviruses, adenoviruses and parvoviruses, circulate in marine mammal populations.[214]

Agriculture[edit]

Electron micrograph of the rod-shaped particles of tobacco mosaic virus that are too small to be seen using a light microscope

In 1882, Adolf Mayer (1843–1942) described a condition of tobacco plants, which he called "mosaic disease" ("mozaïkziekte"). The diseased plants had variegated leaves that were mottled.[431] He excluded the possibility of a fungal infection and could not detect any bacterium and speculated that a "soluble, enzyme-like infectious principle was involved".[432] He did not pursue his idea any further, and it was the filtration experiments of Ivanovsky and Beijerinck that suggested the cause was a previously unrecognised infectious agent. After tobacco mosaic was recognized as a virus disease, virus infections of many other plants were discovered.[432]

The importance of tobacco mosaic virus in the history of viruses cannot be overstated. It was the first virus to be discovered, and the first to be crystallised and its structure shown in detail. The first X-ray diffraction pictures of the crystallised virus were obtained by Bernal and Fankuchen in 1941. On the basis of her pictures, Rosalind Franklin discovered the full DNA structure of the virus in 1955.[433] In the same year, Heinz Fraenkel-Conrat and Robley Williams showed that purified tobacco mosaic virus RNA and its coat protein can assemble by themselves to form functional viruses, suggesting that this simple mechanism was probably the means through which viruses were created within their host cells.[434]

Drawing of geminiviruses

By 1935 many plant diseases were thought to be caused by viruses. In 1922, John Kunkel Small (1869–1938) discovered that insects could act as vectors and transmit virus to plants. In the following decade many diseases of plants were shown to be caused by viruses that were carried by insects and in 1939, Francis Holmes, a pioneer in plant virology,[435] described 129 viruses that caused disease of plants.[436] Modern, intensive agriculture provides a rich environment for many plant viruses. In 1948, in Kansas, US, 7% of the wheat crop was destroyed by wheat streak mosaic virus. The virus was spread by mites called Aceria tulipae.[437]

In 1970, the Russian plant virologist Joseph Atabekov discovered that many plant viruses only infect a single species of host plant.[435] The International Committee on Taxonomy of Viruses now recognises over 900 plant viruses.[438]

Whiteflies (Trialeurodes vaporariorum) are the vector of cassava mosaic virus

During the 20th century, many "old" disease of plants were discovered to be caused by viruses. These included, maize streak and cassava mosaic disease.[439] As with humans, when plants thrive in close proximity, so do their viruses. This can cause huge economic losses and human tragedies. In Jordan during the 1970s, where tomatoes and cucurbits (cucumbers, melons and gourds) were extensively grown, entire fields were infected with viruses.[440] Similarly, in the Ivory Coast, thirty different viruses infected crops such as legumes and vegetables. And in Kenya cassava mosaic virus, maize streak virus and groundnut viral diseases caused the loss of up to 70% of the crop.[440] Cassava is the most abundant crop that is grown in eastern Africa and it is a staple crop for more than 200 million people. It was introduced to Africa from South America and grows well in soils with poor fertility. The most important disease of cassava is caused by cassava mosaic virus, which is a geminivirus, which is transmitted to the plants by whiteflies. The disease was first recorded in 1894 and outbreaks of the disease occurred in eastern Africa throughout the century, which often resulted in famine.[441]

The sweet potato whitefly transmits geminiviruses to crops and can cause damage that costs millions of US dollars. In the 1920s the sugarbeet growers in the western United states were subjected to huge economic loss caused by damage done to their crops by the leafhopper-transmitted beet curly top geminivirus. In 1956, 25–50 percent of the rice crop in Cuba and Venezuala was destroyed by rice hoja blanca tenivirus and caused the loss of many rice fields in Columbia in 1958. Outbreaks recurred in 1981, which caused losses of up to 100 percent.[442] In Ghana by 1977, the mealybug transmitted cacao swollen root badnavirus caused the loss of 162 million cacao trees, and further trees were lost at the rate of 15 million each year. [443]

Such disasters occurred when human intervention caused ecological changes by introducing crops to new vectors and viruses. Cacao is native to South America and was introduced to West Africa in the late 19th century. In 1936, swollen root disease had been transmitted to plantations by mealybugs from indigenous trees.[444] New habits can trigger outbreaks of plant virus diseases. Before 1970, the rice yellow sobemoviurs was only found in the Kisumu district of Kenya, but following the irrigation of large areas of East Africa and extensive rice cultivation, the virus spread throughout East Africa.[445] Human activity also introduced plant viruses to naive crops. The citrus tristeza closterovirus (CTV) was introduced to South America from Africa between 1926 and 1930. At the same time to highly efficient aphid vector Toxoptera citricidus was carried form Asia to South America and this accelerated the transmission of the virus. By 1950, more than 6 million citrus trees had been destroyed in Brazil.[446] CTV and citrus trees probably coevolved for centuries in their original countries. The dispersal of CTV to other regions and its interaction with new citrus varieties resulted in devastating outbreaks of plant diseases.[447] Because of the problems caused by the introduction – by humans – of plant viruses, many countries have strict importation controls on any materials that can harbour dangerous plant viruses or their insect vectors.[448]

History of virology[edit]

The history of virology – the scientific study of viruses and the infections they cause – begins in the closing years of the 19th century. Although Louis Pasteur and Edward Jenner developed the first vaccines to protect against viral infections, they did not know that viruses existed.

The first evidence of the existence of viruses came from experiments with filters that had pores small enough to retain bacteria. In 1892, Dmitry Ivanovsky used one of these filters to show that sap from a diseased tobacco plant remained infectious to healthy tobacco plants despite having been filtered. Martinus Beijerinck called the filtered, infectious substance a "virus" and this discovery is considered to be the beginning of virology. In the 20th century many viruses were discovered.

Early virologists[edit]

Martinus Beijerinck in his laboratory in 1921

Despite his other successes, Louis Pasteur (1822–1895) was unable to find a causative agent for rabies and speculated about a pathogen too small to be detected using a microscope.[449] In 1884, the French microbiologist Charles Chamberland (1851–1931) invented a filter – known today as the Chamberland filter – that had pores smaller than bacteria. Thus, he could pass a solution containing bacteria through the filter and completely remove them from the solution.[450] In 1892, the Russian biologist Dmitry Ivanovsky (1864–1920) used this filter to study what is now known as the tobacco mosaic virus. His experiments showed that crushed leaf extracts from infected tobacco plants remain infectious after filtration. Ivanovsky suggested the infection might be caused by a toxin produced by bacteria, but did not pursue the idea.[451]

In 1898, the Dutch microbiologist Martinus Beijerinck (1851–1931) repeated the experiments and became convinced that the filtered solution contained a new form of infectious agent.[452] He observed that the agent multiplied only in cells that were dividing and he called it a contagium vivum fluidum (soluble living germ) and re- introduced the word virus.[451] Beijerinck maintained that viruses were liquid in nature, a theory later discredited by the American biochemist and virologist Wendell Meredith Stanley (1904–1971), who proved they were particles.[451] In the same year Friedrich Loeffler (1852–1915) and Paul Frosch (1860–1928) passed the first animal virus through a similar filter and discovered the cause of foot-and-mouth disease.[453]

In 1881, Carlos Finlay (1833–1915), a Cuban physician, first suggested that mosquitoes were carrying the cause of yellow fever,[454] a theory that was proved in 1900 by Walter Reed (1851–1902). During 1901 and 1902, William Crawford Gorgas (1854–1920) organised the destruction of the mosquitoes' breeding habitats in Cuba, which dramatically reduced the prevalence of the disease.[455] Gorgas later organised the elimination of the mosquitoes from Panama, which allowed the Panama Canal to be opened in 1914.[456] The virus was finally isolated by Max Theiler (1899–1972) in 1932 who went on to develop a successful vaccine.[457]

By 1928 enough was known about viruses to enable Thomas Milton Rivers (1888–1962) to write the first book about all known viruses and his Filtrable Viruses was published in 1928. Rivers, who survived typhoid fever at the age of twelve, went on to have a distinguished career in virology. He was born in Jonebro, Georgia USA, was awarded a BA degree from Emory College in 1909 and graduated in medicine at Johns Hopkins University in 1915. In 1926, he was invited to speak at a meeting organised by the Society of American Bacteriology where he said for the first time, "Viruses appear to be obligate parasites in the sense that their reproduction is dependent on living cells."[458]

That viruses were particles was not considered unnatural and fitted in nicely with the germ theory. It is assumed that Dr. J. Buist of Edinburgh was the first person to see virus particles in 1886, when he reported seeing "micrococci" in vaccine lymph. But he had probably seen clumps of vaccinia virus.[459] In the years that followed, as optical microscopes were improved "inclusion bodies" were seen in many virus-infected cells, but these aggregates of virus particles were still too small to reveal any detailed structure. It was not until the invention of the electron microscope in 1931 by the German engineers Ernst Ruska (1906–1988) and Max Knoll (1887–1969),[460] that virus particles, especially bacteriophages, were shown to have a complex structure. The sizes of viruses determined using this new microscope fitted in well with those estimated by filtration experiments. Viruses were expected to be small, but the range of sizes came as a surprise. Some were only a little smaller than the smallest known bacteria, and the smaller viruses were of similar sizes to complex organic molecules.[461]

In 1935, Wendell Stanley examined the tobacco mosaic virus and found it was mostly made of protein.[462] In 1939, Stanley and Max Lauffer (1914) separated the virus into protein and RNA parts.[463] The discovery of RNA in the particles was important because in 1928, Fred Griffith (c.1879–1941) provided the first evidence that its "cousin", DNA, formed genes.[464]

In Pasteur's day, and for many years after his death the word "virus" was used to describe any cause of infectious disease. Painstaking work, by many bacteriologists, soon discovered the cause of numerous infections. However, some infections remained, many of them horrendous, but for which no bacterial cause could be found. These agents were invisible and could only be grown in living animals. The discovery of viruses was the key that unlocked the door that withheld the secrets of the cause of these mysterious infections. And, although Koch's postulates could not be fulfilled for many of these infections, this did not stop the pioneer virologists from looking for viruses in infections for which no other cause could be found.[465]

Bacteriophages[edit]

Bacteriophage

Bacteriophages are viruses that infect bacteria. There are over 5,100 types of bacteriophages. They are important in marine ecology: as the infected bacteria burst, carbon compounds are released back into the environment, which stimulates fresh organic growth. Bacteriophages are useful in scientific research because they are harmless to humans and can be studied easily. These viruses can be a problem in industries that produce food and drugs by fermentation and depend on healthy bacteria. Some bacterial infections are becoming difficult to control with antibiotics, so there is a growing interest in the use of bacteriophages to treat infections in humans.[466]

The structure of a typical bacteriophage

Discovery[edit]

Bacteriophages were discovered in the early 20th century, by the English bacteriologist Frederick Twort (1877–1950).[467] But before this time, in 1896, the bacteriologist Ernest Hanbury Hankin (1865–1939) reported that something in the waters of the River Ganges could kill Vibrio cholera – the cause of cholera. Whatever it was in the water could be passed through filters that remove bacteria but was destroyed by boiling.[468] Twort discovered the action of bacteriophages on staphylococci bacteria. He noticed that when grown on nutrient agar some colonies of the bacteria became watery or "glassy". He collected some of these watery colonies and passed them through a Chamberland filter to remove the bacteria and discovered that when the filtrate was added to fresh cultures of bacteria, they in turn became watery.[467] He proposed that the agent might be "an amoeba, an ultramicroscopic virus, a living protoplasm, or an enzyme with the power of growth".[468]

Félix d'Herelle (1873–1949) was a mainly self-taught French-Canadian microbiologist. In 1917 he discovered that "an invisible antagonist", when added to bacteria on agar, would produce areas of dead bacteria.[467] The antagonist, now known to be a bacteriophage could pass through a Chamberland filter. He accurately diluted a suspension of these viruses and discovered that the highest dilutions (lowest virus concentrations), rather than killing all the bacteria, formed discrete areas of dead organisms. Counting these areas and multiplying by the dilution factor allowed him to calculate the number of viruses in the original suspension.[469] He realised that he had discovered a new form of virus and later coined the term "bacteriophage".[470][471] Between 1918 and 1921 d'Herelle discovered different types of bacteriophages that could infect several other species of bacteria including Vibrio cholera.[472] Bacteriophages were heralded as a potential treatment for diseases such as typhoid and cholera, but their promise was forgotten with the development of penicillin.[470] Since the early 1970s, bacteria have continued to develop resistance to antibiotics such as penicillin, and this has led to a renewed interest in the use of bacteriophages to treat serious infections.[473]

Early research[edit]

D'Herelle travelled widely to promote the use of bacteriophages in the treatment of bacterial infections. In 1928, he became professor of biology at Yale and founded several research institutes.[474] He was convinced that bacteriophages were viruses despite opposition from established bacteriologists such as the Nobel Prize winner Jules Bordet (1870–1961). Bordet argued that bacteriophages were not viruses but just enzymes released from "lysogenic" bacteria. He said "the invisible world of d'Herelle does not exist".[475] But in the 1930s, the proof that bacteriophages were viruses was provided by Christopher Andrews (1896–1988) and others. They showed that these viruses differed in size and in their chemical and serological properties.

In 1940, the first electron micrograph image of a bacteriophage was published and this silenced sceptics who had argued that bacteriophages were relatively simple enzymes and not viruses.[476] Numerous other types of bacteriophages were quickly discovered and were shown to infect bacteria wherever they are found. But this early research was interrupted by World War II. Even d'Herelle was silenced. Despite his Canadian citizenship, he was interned by the Vichy Government until the end of the war.[477] Knowledge of bacteriophages increased in the 1940s following the formation of the Phage Group by scientists throughout the US. Among the members were Max Delbrück (1906–1981) who founded a course on bacteriophages at Cold Spring Harbor Laboratory.[473] He showed that bacterial resistance to infection by bacteriophages was caused by random genetic mutations and not by adaptation.[478] Other key members of the Phage Group included Salvador Luria (1912–1991) and Alfred Hershey (1908–1997). During the 1950s, Hershey and Chase made important discoveries on the replication of DNA during their studies on a bacteriophage called T2. Together with Delbruck they were jointly awarded the 1969 Nobel Prize in Physiology or Medicine "for their discoveries concerning the replication mechanism and the genetic structure of viruses".[479] Since then, the study of bacteriophages has provided insights into the switching on and off of genes, and a useful mechanism for introducing foreign genes into bacteria and many other fundamental mechanisms of molecular biology.[480]

20th century[edit]

By the end of the 19th century, viruses were defined in terms of their infectivity, their ability to be filtered, and their requirement for living hosts. Up until this time, viruses had only been grown in plants and animals, but in 1906, Ross Granville Harrison (1870–1959) invented a method for growing tissue in lymph,[481] and, in 1913, E Steinhardt, C Israeli, and RA Lambert used this method to grow vaccinia virus in fragments of guinea pig corneal tissue.[482] In 1928, HB and MC Maitland grew vaccinia virus in suspensions of minced hens' kidneys.[483] Their method was not widely adopted until the 1950s, when poliovirus was grown on a large scale for vaccine production.[484]

At the turn of the 20th century, evidence for the existence of viruses was obtained from experiments with filters that had pores too small for bacteria to pass through; the term "filterable virus" was coined to describe them.[485] Although the modern concept of a virus was at that time slowly beginning to gain acceptance, the word is ancient. In Latin it means a "slimy liquid, poison offensive odour or taste", and it first appears in the medical literature in the 18th century to describe a poisonous fluid.[486]

A modern electron microscope

Until the 1930s most scientists believed that viruses were small bacteria, but following the invention of the electron microscope in 1938 they were shown to be completely different, to a degree that not all scientists were convinced they were anything other than accumulations of toxic proteins. The situation changed radically when it was discovered that viruses contain genetic material in the form of DNA or RNA.[487] Once they were recognised as distinct biological entities they were soon shown to be the cause of numerous infections of plants, animals, and even of bacteria.[488]

Of the many diseases of humans that were discovered to be caused by viruses in the 20th century only one, smallpox, has been eradicated. Two others – measles and poliomyelitis – could be, but the diseases caused by viruses such as HIV and influenza virus have proved to be more difficult to control.[489] Others diseases, such as those caused by arboviruses, are presenting new challenges.[490]

Late 20th century[edit]

The second half of the 20th century was the golden age of virus discovery and most of the 2,000 recognised species of animal, plant, and bacterial viruses were discovered during these years.[478][491] In 1946, Bovine virus diarrhea was discovered,[492] which is still possibly the commonest pathogen of cattle throughout the world[493] and in 1957, equine arterivirus was discovered.[494] In the 1950s, improvements in virus isolation and detection methods resulted in the discovery of several important human viruses including, Varicella zoster virus,[495] the paramyxoviruses,[496] – which include measles virus,[497] and respiratory syncytial virus[496] – and the rhinoviruses that cause the common cold.[498] In the 1960s more viruses were discovered. In 1963, the hepatitis B virus was discovered by Baruch Blumberg (b. 1925),[499] and in 1965, Howard Temin (1934–1994) described the first retrovirus.[500] Reverse transcriptase, the key enzyme that retroviruses use to translate their RNA into DNA, was first described in 1970, independently by Howard Temin and David Baltimore (b. 1938).[124] This was important to the development of antiviral drugs – a key turning-point in the history of viral infections.[501] In 1983 Luc Montagnier (b. 1932) and his team at the Pasteur Institute in France, first isolated the retrovirus now called HIV.[502] New viruses and strains of viruses were discovered in every decade of the second half of the 20th century. These discoveries have continued in the 21st century as new viral diseases such as SARS[503] and nipah virus[504] have emerged. Despite scientists' achievements over the past one hundred years, viruses continue to pose new threats and challenges.[505]

Table 1. Some of the many viruses that were discovered in the 20th century

Year Virus References
1908 poliovirus [506]
1911 Rous sarcoma virus [507]
1915 bacteriophage of staphylococci [467]
1917 bacteriophage of shigellae [467]
1918 bacteriophage of salmonellae [469]
1927 yellow fever virus [508]
1930 western equine encephalitis virus [509]
1933 eastern equine encephalitis virus [509]
1934 mumps virus [510]
1935 Japanese encephalitis virus [511]
1943 Dengue virus [370]
1949 enteroviruses [512]
1952 Varicella zoster virus [495]
1953 adenovirus [513]
1954 measles virus [497]
1956 paramyxoviruses, rhinovirus [496][498]
1958 monkeypox [514]
1962 rubella virus [515]
1963 hepatitis B virus [516]
1964 Epstein–Barr virus [517]
1965 retroviruses [518]
1966 Lassa fever virus [519]
1967 Marburg virus [520]
1972 norovirus [521]
1973 rotavirus, hepatitis A virus [522][523]
1975 parvovirus B19 [524]
1976 Ebola virus [525]
1980 human T-lymphotropic virus 1 [526]
1982 human T-lymphotropic virus 2 [526]
1983 HIV [527]
1986 human herpesvirus 6 [528]
1989 hepatitis C virus [529]
1990 hepatitis E virus, Human herpesvirus 7 [530]
1994 henipavirus [531]
1997 Anelloviridae [532]

21st century[edit]

As humans have changed their behaviour during the course of history, so have viruses. In ancient times the human population was too small for pandemics to occur and, in the case of some viruses, too small for them to survive. In the 20th and 21st century increasing population densities, revolutionary changes in agriculture and farming methods, and high speed travel have contributed to the spread of new viruses and the re-appearance of old ones.[533][534] Like smallpox, some viral diseases might be conquered, but others, such as SARS will continue to present new challenges.[535] Although vaccines are still the most powerful weapon against viruses, in recent decades antiviral drugs have been developed to specifically target viruses as they replicate in their hosts.[536] The 2009 influenza pandemic showed how rapidly new strains of viruses continue to spread around the world, despite our efforts to contain them.[537] Advances in virus discovery and control continue to be made. Human metapneumovirus, which is a cause of respiratory infections including pneumonia was discovered in 2001.[538] A vaccine for the papillomaviruses that cause cervical cancer was developed between 2002 and 2006.[539] In 2003, the largest virus by far, mimivirus was discovered to infect amoebae.[540] In 2005, human T lymphotropic viruses 3 and 4 were discovered.[541] And, in 2008 the WHO Global Polio Eradication Initiative was re-launched with a plan to eradicate poliomyelitis by 2015.[542]

Applications[edit]

Life sciences and medicine[edit]

Scientist studying the H5N1 influenza virus

Viruses are important to the study of molecular and cell biology as they provide simple systems that can be used to manipulate and investigate the functions of cells.[543] The study and use of viruses have provided valuable information about aspects of cell biology.[544] For example, viruses have been useful in the study of genetics and helped our understanding of the basic mechanisms of molecular genetics, such as DNA replication, transcription, RNA processing, translation, protein transport, and immunology.

Geneticists often use viruses as vectors to introduce genes into cells that they are studying. This is useful for making the cell produce a foreign substance, or to study the effect of introducing a new gene into the genome. In similar fashion, virotherapy uses viruses as vectors to treat various diseases, as they can specifically target cells and DNA. It shows promising use in the treatment of cancer and in gene therapy. Eastern European scientists have used phage therapy as an alternative to antibiotics for some time, and interest in this approach is increasing, because of the high level of antibiotic resistance now found in some pathogenic bacteria.[545] Expression of heterologous proteins by viruses is the basis of several manufacturing processes that are currently being used for the production of various proteins such as vaccine antigens and antibodies. Industrial processes have been recently developed using viral vectors and a number of pharmaceutical proteins are currently in pre-clinical and clinical trials.[546]

Materials science and nanotechnology[edit]

Current trends in nanotechnology promise to make much more versatile use of viruses. From the viewpoint of a materials scientist, viruses can be regarded as organic nanoparticles. Their surface carries specific tools designed to cross the barriers of their host cells. The size and shape of viruses, and the number and nature of the functional groups on their surface, is precisely defined. As such, viruses are commonly used in materials science as scaffolds for covalently linked surface modifications. A particular quality of viruses is that they can be tailored by directed evolution. The powerful techniques developed by life sciences are becoming the basis of engineering approaches towards nanomaterials, opening a wide range of applications far beyond biology and medicine.[547]

Because of their size, shape, and well-defined chemical structures, viruses have been used as templates for organizing materials on the nanoscale. Recent examples include work at the Naval Research Laboratory in Washington, D.C., using Cowpea Mosaic Virus (CPMV) particles to amplify signals in DNA microarray based sensors. In this application, the virus particles separate the fluorescent dyes used for signalling to prevent the formation of non-fluorescent dimers that act as quenchers.[548] Another example is the use of CPMV as a nanoscale breadboard for molecular electronics.[549]

Synthetic viruses[edit]

Many viruses can be synthesized de novo ("from scratch") and the first synthetic virus was created in 2002.[550] Although somewhat of a misconception, it is not the actual virus that is synthesized, but rather its DNA genome (in case of a DNA virus), or a cDNA copy of its genome (in case of RNA viruses). For many virus families the naked synthetic DNA or RNA (once enzymatically converted back from the synthetic cDNA) is infectious when introduced into a cell. That is, they contain all the necessary information to produce new viruses. This technology is now being used to investigate novel vaccine strategies.[551] The ability to synthesize viruses has far-reaching consequences, since viruses can no longer be regarded as extinct, as long as the information of their genome sequence is known and permissive cells are available. Currently, the full-length genome sequences of 2408 different viruses (including smallpox) are publicly available at an online database, maintained by the National Institutes of Health.[552]

Weapons[edit]

The ability of viruses to cause devastating epidemics in human societies has led to the concern that viruses could be weaponised for biological warfare. Further concern was raised by the successful recreation of the infamous 1918 influenza virus in a laboratory.[553]

The smallpox virus devastated numerous societies throughout history before its eradication. There are officially only two centers in the world that keep stocks of smallpox virus – the Russian Vector laboratory, and the United States Centers for Disease Control.[554] But fears that it may be used as a weapon are not totally unfounded;[554] the vaccine for smallpox has sometimes severe side-effects – during the last years before the eradication of smallpox disease more people became seriously ill as a result of vaccination than did people from smallpox[555] – and smallpox vaccination is no longer universally practiced.[556] Thus, much of the modern human population has almost no established resistance to smallpox.[554]

Friendly viruses[edit]

Once considered as only a cause of disease, viruses are now known to be essential components of the biosphere. The Human Genome Project has revealed the presence of numerous viral DNA sequences scattered throughout the human genome.[557] These sequences make up around 8% of human DNA,[37] and appear to be the remains of ancient retrovirus infections of human ancestors.[558] These pieces of DNA have firmly established themselves in human DNA.[559] Most of this DNA is no longer functional, and a few sequences might occasionally cause harm, but the remainder seem to be harmless. Some may have brought with them novel genes that are important in human development.[560][561]

The emergence of strains of bacteria that are resistant to a broad range of antibiotics has become a problem in the treatment of bacterial infections.[562] Only two new classes of antibiotics have been developed in the past 30 years,[563] and the search is on for novel ways of combating bacterial infections.[562] The use of bacteriophages to control bacteria was first described by Russian scientists in the 1950s and 1960s.[564] At the time, this work was largely ignored in the West because antibiotic-resistant bacteria were not a cause for concern, but the more recent and escalating problems caused by antibiotic-resistant bacteria has stimulated a renewed interest in the use of bacteriophages and phage therapy.[565]

The debate as to whether viruses are alive continues. In 2000, they were officially declared as non-living by the International Committee on Taxonomy of Viruses,[566] but the debate continues.[567][568]

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