Virus

From The Book of THoTH (Leaves of Wisdom)

A virus (Latin, poison) is a submicroscopic particle that can infect the cells of a biological organism. At the most basic level viruses consist of genetic material contained within a protective protein shell, which distinguishes them from other virus-like particles such as prions and viroids. The study of viruses is known as virology, and those who study viruses are called virologists.

Viruses are similar to obligate intracellular parasites as they lack the means for self-reproduction outside a host cell, but unlike parasites, which are living organisms, viruses are not truly alive. They infect a wide variety of organisms, both eukaryotes (such as animals, insects and plants) and prokaryotes (such as bacteria). A virus infecting bacteria is known as a bacteriophage, which is used mainly in its shortened form phage.

It has been argued extensively whether viruses are living organisms. They are considered non-living by the majority of virologists as they do not meet all the criteria of the generally accepted definition of life. Among other factors, viruses do not possess a cell membrane or metabolise on their own. A definitive answer is still elusive due to the fact that some organisms considered to be living exhibit characteristics of both living and non-living particles, as viruses do.

Contents 1 Origins 2 Classification 3 Structure 3.1 Size 3.2 Genetic material 4 Replication 4.1 Bacteriophage replication 4.2 DNA virus replication 4.3 RNA virus replication 5 Lifeform debate 6 Human viral diseases 6.1 Epidemics 6.2 Research 6.3 Detection, purification and diagnosis 6.4 Prevention and treatment 7 Applications 7.1 Exploring basic cellular processes 7.2 Genetic engineering 7.3 Virotherapy 7.4 Materials science and nanotechnology 7.5 Weapons 8 Etymology 9 See also 10 References 11 External links

Origins

The origins of modern viruses are not entirely clear, and there may not be a single mechanism of origin that can account for all viruses. As viruses do not fossilise well, molecular techniques have been the most useful means of hypothesising how they arose. Research in microfossil identification and molecular biology may yet discern fossil evidence dating to the Archean or Proterozoic eons. Two main hypotheses currently exist:

• Small viruses with only a few genes may be runaway stretches of nucleic acid originating from the genome of a living organism. Their genetic material could have been derived from transferable genetic elements such as plasmids or transposons, which are prone to moving around, exiting, and entering genomes.

• Viruses with larger genomes, such as poxviruses, may have once been small cells which parasitised larger host cells. Over time, genes not required by their parasitic lifestyle would have been lost in a streamlining process known as retrograde evolution – literally reverse evolution. Both the bacteria Rickettsia and Chlamydia are living cells which, like viruses, can only reproduce inside host cells. They lend credence to this hypothesis, as they are likely to have lost genes which enabled them to survive outside a host cell in favour of their parasitic lifestyle.

Other infectious particles which are even simpler in structure than viruses include viroids, satellites, and prions.

Classification

In taxonomy, the classification of viruses has proved to be rather difficult due to the lack of fossil record, and dispute over whether or not they are living or non-living. They do not fit easily into any of the domains of biological classification and therefore classification begins at the family rank. However, the domain name of Acytota has been suggested. This would place viruses on a par with the other domains of Eubacteria, Archaea, and Eukarya. It should be noted that not all families are currently classified into orders, nor all genera classified into families.

As an example of viral classification, the chicken pox virus belongs to family Herpesviridae, subfamily Alphaherpesvirinae and genus Varicellovirus. It remains unranked in terms of order. The general structure is as follows.

Order (-virales)

Family (-viridae)

Subfamily (-virinae)

Genus (-virus)

Species (-virus)

The International Committee on Taxonomy of Viruses developed the current classification system and put in place guidelines that put a greater weighting on certain virus properties in order to maintain family uniformity. In order, taxonomists should consider the type of nucleic acid present, whether the nucleic acid is single stranded or double stranded, and the presence or absence of an envelope. After these three main properties other characteristics, including the type of host, the capsid shape, immunological properties and the type of disease it causes, can be considered.

Structure

A complete virus particle, known as a virion, is little more than a gene transporter, consisting at the most basic level of nucleic acid surrounded by a protective coat of protein called a capsid. A capsid is composed of proteins encoded by the viral genome and its shape serves as the basis for morphological distinction. Virally coded protein units called protomers will self-assemble to form the capsid, requiring no input from the virus genome - however, a few viruses code for proteins which assist the construction of their capsid. Proteins associated with nucleic acid are more technically known as nucleoproteins, and the association of viral capsid proteins with viral nucleic acid is called a nucleocapsid.

In general, four main morphological virus types can be identified:

	Helical viruses
Diagram of a helical capsid	Helical capsids are composed of a single type of protomer stacked around a central circumference to form an enclosed tube resembling a spiral staircase. This arrangement results in rod-shaped virions which can be short and rigid, or long and flexible. Long helical particles must be flexible in order to prevent forces snapping the structure. The genetic material is housed on the inside of the tube, protected from the outside. Overall, the length of a helical capsid is related to the length of the nucleic acid contained within it, while the diameter is dependant on the overall length and arrangement of protomers. The well-studied tobacco mosaic virus is a helical virus.
	Icosahedral viruses
Electron micrograph of icosahedral virions	Icosahedral capsid symmetry results in a spherical appearance of viruses at low magnification but actually consists of capsomers arranged in a regular geometrical pattern, similar to a soccer ball, hence they are not truly "spherical". Capsomers are ring shaped structures constructed from five to six copies of protomers. These associate via non-covalent bonding to enclose the viral nucleic acid, though generally less intimately than helical capsids, and may involve one type of protomer or more. Icosahedral architecture was employed by R. Buckminster-Fuller in his geodesic dome, and is the most efficient way of creating an enclosed robust structure from multiple copies of a single protein. The number of proteins required to form a spherical virus capsid is denoted by the T-number, [1] where 60×t proteins are necessary. In the case of the hepatitis B virus the T-number is 4, therefore 240 proteins assemble to form the capsid.
	Enveloped viruses
Diagram of enveloped HIV	In addition to a capsid some viruses are able to hijack a modified form of the cell membrane surrounding an infected host cell, thus gaining an outer lipid layer known as a viral envelope. This extra membrane is studded with proteins coded for by the viral genome and host genome, however the lipid membrane itself and any carbohydrates present are entirely host-coded. The viral envelope can give a virion a few distinct advantages over other "naked" virions, such as protection from enzymes and chemicals. The proteins studded upon it can include glycoproteins functioning as receptor molecules, allowing healthy cells to recognise virions as "friendly" and resulting in the possible uptake of the virion into the cell. It should be noted however that some viruses are so dependent upon their viral envelope that they fail to function if it is removed.
	Complex viruses
Diagram of a complex virus	These viruses possess a capsid which is neither purely helical, nor purely icosahedral, and which may possess extra structures such as protein tails or a complex outer wall. Some bacteriophages have a complex structure consisting of an icosahedral head bound to a helical tail, the latter of which may have a hexagonal base plate with many protruding protein tail fibres. The poxviruses are large, complex viruses which possess 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. Covering the virus is an outer envelope with a thick layer of protein studded on its surface. The whole particle is slightly pleiomorphic, ranging from ovoid to brick shape.

Size

The majority of viruses which have been studied have a capsid diameter between 10 and 300 nanometres in size. To put viral size into perspective, a medium sized virion next to a flea is roughly equivalent to a human next to a mountain twice the size of Mount Everest. It should be noted that some filoviruses have a total length that can reach up to 1400 nm, however their capsid diametres are only about 80 nm. While most viruses are unable to be seen with a light microscope, some are larger than the smallest bacteria and can be seen under high magification. Both scanning and transmission electron microscopes are commonly employed to visualise virus particles.

A notable exception to the normal viral size range is the recently discovered mimivirus, with a diameter of 400 nm. They also hold the record for the largest viral genome size, possessing about 1000 genes (some bacteria only possess 400) on a genome some 1.2 megabases in length. Their large genome contains many genes which are conserved in both prokaryotic and eukaryotic genes - more than any other virus. [2] The discovery of the virus has lead many scientists to reconsider the controversial boundary between living organisms and viruses, which are currently considered as mere mobile genetic elements.

Genetic material

Both DNA and RNA are found in viral species, but as a rule of thumb a species will only have one or the other – not both. An exception to this is found in the human cytomegalovirus, which contains both a DNA core and mRNA. The nucleic acid can be either single-stranded or double-stranded, depending on the species. Therefore viruses as a group contain all four possible types of nucleic acids: double-stranded DNA, single-stranded DNA, double-stranded RNA and single-stranded RNA. Animal virus species have been observed to possess all combinations, whereas plant viruses tend to have single-stranded RNA. Bacteriophages tend to have double-stranded DNA. In addition, single- or double-stranded nucleic acid can be either linear or a closed circle.

Genome size in terms of the weight of nucleotides varies quite substantially between species. The smallest genomes code for about four proteins and weighs about 10⁶ daltons, while the largest weigh about 10⁸ daltons and code for over one hundred proteins. Some virus species possess abnormal nucleotides, such as hydroxymethylcytosine instead of cytosine, as a normal part of their genome.

For those viruses with RNA as their nucleic acid, the strands are said to be either positive-sense (also called plus-strand) or negative-sense (also called minus-strand) depending on whether or not it is complementary to viral mRNA. Positive-sense viral RNA is identical to viral mRNA and thus 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 polymerase before translation.

All double-stranded RNA genomes and some single-stranded RNA genomes are said to be segmented, or divided into separate parts. Each segment may code for one protein and are usually found together in one capsid. Not all segments are required to be in the same virion for the overall virus to be infectious, as can be seen in the brome mosaic virus.

Replication

Viral populations do not grow through cell division as they are acellular, they instead utilize the machinery and metabolism of a host cell to produce multiple copies of themselves. Released virions can be passed from host to host either through direct contact, often via body fluids, or through a vector. In aqueous environments, viruses float free in the water.

When the virus has taken over the cell, it immediately causes the host to begin manufacturing the proteins necessary for virus reproduction. Some viruses, like herpes, cause the host to produce three kinds of proteins: early proteins, enzymes used in nucleic acid replication; late proteins, proteins used to construct the virus coat; and lytic proteins, enzymes used to break open the cell for viral exit. The final viral product is assembled spontaneously, that is, the parts are made separately by the host and are joined together by chance. This self-assembly is often aided by molecular chaperones, or proteins made by the host that help the capsid parts come together.

The new viruses then leave the cell by either exocytosis or by lysis. Envelope-bound animal viruses cause the host's endoplasmic reticulum to make certain proteins, called glycoproteins, which then collect in clumps along the cell membrane. The virus is then discharged from the cell at these exit sites, referred to as exocytosis. On the other hand, bacteriophages lyse the cell to exit. To do this, the phages have a gene that codes for an enzyme called lysozyme, which breaks down the cell wall. A virus can still cause degenerative effects within a cell without causing its death, these are collectively termed cytopathic effects.

Bacteriophage replication

Bacteriophages infect specific bacteria by binding to surface receptor molecules and entering the cell. Within a short amount of time, sometimes 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. Lysis involves the breakage of the cell membrane to release the contents of the cell, which in this case also involves the newly assembled bacteriophages. 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 will be released.

Bacteriophages may have a lytic cycle, as described above, or a lysogenic cycle. Some viruses are capable of carrying out both. In the lytic cycle, characteristic of virulent phages such as the T4 phage, host cells will be broken open and suffer death after immediate replication of the virion. As soon as the cell is destroyed the viruses will have to find new host. In contrast, the lysogenic cycle does not result in immediate lysing of the host cell. Instead the viral genome will integrate with host DNA and replicate along with it. The virus remains dormant but after the host cell has replicated many times the virus will become active and enter the lytic phase, or if environmental conditions permit it. Interestingly, as the lysogenic cycle allows the host cell to continue to survive and reproduce the virus is reproduced in all of the cell’s offspring.

DNA virus replication

Animal DNA viruses, such as herpesviruses, enter the host via endocytosis, the process by which cells take in material from the external environment. This frequently occurs after chance collision with an appropriate surface receptor on a cell. After penetrating the cell, the viral genome is released from the capsid and host polymerases begin transcribing viral mRNA. New virions are assembled and released either by cell lysis or by budding off the cell membrane.

RNA virus replication

Animal RNA viruses can be placed into about four different groups depending on their mode of replication. The polarity of the RNA largely determines the replicative mechanism, as well as whether the genetic material is single-stranded or double-stranded. Some RNA viruses are actually DNA based but use a RNA-intermediate to replicate. RNA viruses are heavily dependant upon virally encoded RNA replicase to create copies of their genomes.

Lifeform debate

Argument continues over whether viruses are truly alive or not. While scientists have no trouble classifying a horse as living and can see evolutionary relationships between it and other animals, things become complicated as they look at more simple beings such as viruses, viroids and prions. In the case of viruses, they resemble life in that they possess nucleic acid and can respond to their environment in a limited fashion. They can also reproduce by creating multiple copies of themselves through simple self-assembly.

However, unlike all other forms of established lifeforms, they do not possess a cell structure, regarded as the basic unit of life. Viruses are also absent in the fossil record, making phylogenic relationships difficult to infer. Additionally, although they reproduce they do not metabolise on their own and therefore require a host cell to replicate and synthesise new products. However, confounding this previous statement is the fact that bacterial species such as Rickettsia and Chlamydia, while living organisms, are also unable to reproduce outside of a host cell. A powerful argument can be made that all accepted forms of life divide at the cell level via cell division to reproduce, wheras all viruses simply assemble spontaneously within cells. What stops the comparison being drawn that viral self-assembly is no different to the autonomous growth of non-living crystals?

Virus self-assembly within host cells also has implications for the study of the origin of life, and if the viral requirement for a host cell was abandoned it could be argued that viruses are indeed alive. If viruses are considered living then the prospect of creating artificial life is enhanced or at least the standards required to call something artificially alive are reduced.

Other questions involve the classification of viruses within the Tree of Life and its implications – if viruses are considered alive, then the criteria specifying life will have been permanently changed, leading scientists to question what the basic prerequisite of life is. Whether or not other infectious particles, such as viroids and prions, would next be considered forms of life could follow if viruses are said to be alive.

Human viral diseases

Examples of common human diseases caused by viruses include the common cold, the flu, chickenpox and cold sores. Serious diseases such as Ebola, AIDS, bird flu and SARS are all also caused by viruses. The relative ability of viruses to cause disease is described in terms of virulence.

Epidemics

A number of 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 hemorrhagic fever. [3]

Native American populations were devastated by contagious diseases, particularly smallpox, brought to the Americas by European colonists. It is unclear how many Native Americans were killed by foreign diseases after the arrival of Columbus in the Americas, but the numbers have been estimated to be close to 70% of the indigenous population. [4] The damage done by this disease may have significantly aided European attempts to displace or conquer the native population.

Jared Diamond argued in his book Guns, Germs, and Steel that highly contagious diseases develop in agricultural societies and regularly aid those societies when they expand into the territories of non-agricultural peoples.

Research

Possible connections between certain diseases and certain viruses are currently being studied, such as the connection of Human Herpesvirus Six (HHV6) to neurological diseases such as multiple sclerosis and chronic fatigue syndrome. Recently it was also shown that cervical cancer is partially caused by papillomavirus, representing evidence in humans of a link existing between cancer and an infective agent. [5] There is current controversy over whether the borna virus, previously thought of as causing neurological disease in horses, could be responsible for psychiatric illness in humans. [6]

In 2003 a new virus was discovered and named mimivirus, for the term "mimic virus", as it resembles bacteria in some respects. The giant virus is over tenfold larger than common viruses and is being examined as a possible link between viruses and "traditional" lifeforms.

Detection, purification and diagnosis

In the laboratory, several techniques for growing and detecting viruses exist. Purification of viral particles can be achieved using differential centrifugation, isopycnic centrifugation, precipitation with ammonium sulphate or ethylene glycol, and removal of cell components from a homogenised cell mixture using organic solvents or enzymes to leave the virus particles in solution.

Assays to detect and quantify viruses include:.

• Hemagglutination assays, which quantitatively measure how many virus particles are in a solution of red blood cells by the amount of agglutination the viruses cause between them. This occurs as many viruses are able to bind to the surface of one or more red blood cells.
• Direct counts using an electron microscope. A dilute mixture of virus particles and beads of known size are sprayed onto a special sheet and examined under high magnification. The virions are counted and the number extrapolated to estimate the number of virions in the undiluted mixture.
• Plaque assays involve growing a thin layer of bacterial cells onto a culture dish and adding a dilute mixture of virions onto it. The virions will infect and kill the cells they land on, producing holes in the cell layer known as plaques. The number of plaques can be counted and the number of virions estimated from it.

Detection and subsequent isolation of new viruses from patients is a specialised laboratory subject. Normally it requires the use of large facilities, expensive equipment, and trained specialists such as technicians, molecular biologists, and virologists. Often, this effort is undertaken by state and national governments and shared internationally through organizations like the World Health Organization.

Prevention and treatment

Because viruses use the machinery of a host cell to reproduce and also reside within them, they are difficult to eliminate without killing the host cell. The most effective medical approaches to viral diseases so far are vaccinations to provide resistance to infection, and drugs which treat the symptoms of viral infections. Patients often ask for, and physicians often prescribe, antibiotics. These are are useless against viruses, and their misuse against viral infections is one of the causes of antibiotic resistance in bacteria. However, in life-threatening situations the prudent course of action is to begin a course of antibiotic treatment while waiting for test results to determine whether the patient's symptoms are caused by a virus or a bacterial infection.

Applications

Exploring basic cellular processes

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

Genetic engineering

Geneticists regularly 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.

Virotherapy

Virotherapy uses viruses as treatment against various diseases, most commonly as a vector used to specifically target cells and DNA in particular. It shows promising use in the treatment of cancer and in gene therapy.

Materials science and nanotechnology

In April 2006 scientists at the Massachusetts Institute of Technology (MIT) created nanoscale metallic wires using a genetically-modified virus. [7] The MIT team was able to use the virus to create a working battery with an energy density up to three times more than current materials. The potential exists for this technology to be used in liquid crystals, solar cells, fuel cells, and other electronics in the future.

Weapons

The ability of viruses to cause devastating epidemics in human societies has led to the concern that viruses could be weaponized for biological warfare. Further concern was raised by the successful recreation of the infamous 1918 influenza virus in a laboratory. [8] The smallpox virus devastated numerous societies throughout history before its eradication. It currently exists in several secure laboratories in the world and fears that it may be stolen and used as a weapon are not totally unfounded. The modern global human population has almost no established resistance to smallpox; if it were to be released, a massive loss of life could be sustained before the virus was brought under control.

Etymology

The word is from the Latin virus referring to poison and other noxious things, first used in English in 1392. Virulent, from Latin virulentus "poisonous" dates to 1400. A meaning of "agent that causes infectious disease" is first recorded in 1728, before the discovery of viruses by the Russian-Ukrainian biologist Dmitry Ivanovsky in 1892. The adjective viral dates to 1948. Today, Virus is used to describe the biological viruses discussed above and also as a metaphor for other parasitically-reproducing things, such as memes or computer viruses (since 1972). The neologism virion or viron is used to refer to a single infective viral particle.

The Latin word is from a Proto-Indo-European root *weis- "to melt away, to flow," used of foul or malodorous fluids. It is a cognate of Sanskrit {{{3|IAST}}} "poison,", Avestan viš- "poison," Greek ios "poison," Old Church Slavonic višnja "cherry," Old Irish fi "poison," Welsh gwy "fluid"; Latin viscum (see viscous) "sticky substance" is also from the same root.

The English plural form of virus is viruses. No reputable dictionary gives any other form, including such "reconstructed" Latin plural forms as viri (which actually means men), and no plural form appears in the Latin corpus (See plural of virus). The word does not have a traditional Latin plural because its original sense, poison is a mass noun like the English word furniture, and, as pointed out above, English use of virus to denote the agent of a disease predates the discovery that these agents are microscopic parasites and thus in principle countable. Naturally this point can, and will, be extensively argued.

See also

• List of viruses
• Nanobes
• Nanobacteria
• Prion
• Provirus
• Transduction
• Viral plaque
• Viroids
• Virus classification
• WikiProject Viruses

References

• All the Virology on the WWW
• University of Leicester online notes - Virus Structure
• Chronic Active Human Herpesvirus-6 (HHV-6) Infection: A New Disease Paradigm
• Gelderblom, Hans R. (1996). 41. Structure and Classification of Viruses in Medical Microbiology 4th ed. Samuel Baron ed. The University of Texas Medical Branch at Galveston. ISBN 0963117211
• Radetsky, Peter (1994). The Invisible Invaders: Viruses and the Scientists Who Pursue Them. Backbay Books, ISBNs 0316732168 (hc), 0316732176 (pb).
• Theiler, Max and Downs, W. G. (1973). The Arthropod-Borne Viruses of Vertebrates: An Account of the Rockefeller Foundation Virus Program 1951-1970. Yale University Press.
• Prescott, L. (1993). Microbiology, Wm. C. Brown Publishers, ISBN 0697013723
• This article contains material from the Science Primer published by the NCBI, which, as a US government publication, is in the public domain at http://www.ncbi.nlm.nih.gov/About/disclaimer.html.

External links

• Chart of viral pathogens which contribute to indoor air pollution
• Viruses: The new cancer hunters - An IsraCast article on virotherapy
• The Big Picture Book of Viruses - Pictures and general information on many viruses