A Virus, defined

Ever since the Hot Zone by Richard Preston, Ebola Zaire has always had a strange fascination. Let’s examine the origin of the modern computer virus, the biological virus.

From Wikipedia’s entry on Virus.

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 called a capsid, 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 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.

Discovery

Viral diseases such as rabies have affected humans for many centuries, but it wasn’t until relatively recently that the cause of these diseases was discovered. In the early 18th century, the wife of an English ambassador to Turkey observed the native women innoculating their children against smallpox, who subsequently became immune to the disease. In the late 18th century, Edward Jenner observed and studied a milkmaid who had caught cowpox previously and subsequently became immune to smallpox, a similar virus.

Charles Chamberland developed a porcelain filter in the late 19th century which was used to indirectly study the first documented virus, tobacco mosaic virus. Shortly afterwards, Dmitri Ivanowski published his experiments showing that crushed leaf extracts of infected tobacco plants were still infectious even after filtering any bacteria. At about the same time, several others documented filterable disease-causing agents, with several independent experiments showing that viruses were different to bacteria and caused disease in living organisms.

In the early 20th century, Frederick Twort discovered that even bacteria could be attacked by viruses. Felix d’Herelle, working independently, showed that a preparation of viruses caused areas of cellular death on thin cell cultures spread on agar. Counting these degraded areas allowed him to estimate the original number of viruses in the suspension. Finally, in 1935 Wendell Stanley crystallised the tobacco mosaic virus and found it to be mostly protein, and a short time later the virus was separated into both protein and a nucleic acid parts.

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- or 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

An artificially coloured electron micrograph of a bacteriophage


An artificially coloured electron micrograph of a bacteriophage

For more details on this topic, see Virus classification.

In taxonomy, the classification of viruses has proved to be rather difficult due to the lack of fossil record and dispute over whether 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 (ICTV) 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 determining order, taxonomists should consider the type of nucleic acid present, whether the nucleic acid is single- or double-stranded, and the presence or absence of an envelope. After these three main properties, other characteristics can be considered: the type of host, the capsid shape, immunological properties and the type of disease it causes.

In addition to this classification system, the Nobel Prize-winning biologist David Baltimore devised the Baltimore classification system. This places a virus into one of seven Groups, which separate viruses based on their mode of replication and genome type. The ICTV classification system is used in conjunction with the Baltimore classification system in modern virus classification.

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


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 dependent 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


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[2], 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


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 bacteriophage


Diagram of a bacteriophage

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. 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 approximately 1.2 megabases in length. Their large genome also contains many genes which are conserved in both prokaryotic and eukaryotic genes. The discovery of the virus has led 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 generally a species will have either one or the other—not both. One exception is 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. Also, the nucleic acids can be either linear or a closed loop.

An electron micrograph of multiple polyomavirus virions


An electron micrograph of multiple polyomavirus virions

Genome size in terms of the weight of nucleotides varies quite substantially between species. The smallest genomes code for only four proteins and weigh 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 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 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 they 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, because they are acellular; instead, they use utilize the machinery and metabolism of a host cell to produce multiple copies of themselves. They may have a lytic or a lysogenic cycle, with some viruses are capable of carrying out both. A virus can still cause degenerative effects within a cell without causing its death; collectively these are termed cytopathic effects. Released virions can be passed between hosts through either direct contact, often via body fluids, or through a vector. In aqueous environments, viruses float free in the water.

In the lytic cycle, characteristic of virulent phages such as the T4 phage, host cells will be induced by the virus to begin manufacturing the proteins necessary for virus reproduction. As well as proteins, the virus must also direct the replication of new genomes, the technique used for this varies greatly between virus species but depends heavily on the genome type. The final viral product is assembled spontaneously, though it may be aided by molecular chaperones. After the genome has been replicated and the new capsid assembled, the virus causes the cell to be broken open (lysed) to release the virus particles. Some viruses do not lyse the cell but instead exit the cell via the cell membrane in a process known as exocytosis, taking a small portion of the membrane with them as a viral envelope. 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 integrates into the host DNA and replicates along with it. The virus remains dormant but after the host cell has replicated several times, or if environmental conditions permit it, the virus will become active and enter the lytic phase. The lysogenic cycle allows the host cell to continue to survive and reproduce, therefore the virus is passed on to all of the cell’s offspring.

A falsely coloured electron micrograph of multiple bacteriophages


A falsely coloured electron micrograph of multiple bacteriophages

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. 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.

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.

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 dependent upon virally encoded RNA replicase to create copies of their genomes.

A reverse transcribing virus is any virus which replicates using reverse transcription, the formation of DNA from an RNA template. Those viruses containing RNA genomes use a DNA intermediate to replicate, whereas those containing DNA genomes use an RNA intermediate during genome replication. Both types of reverse transcribing viruses use the enzyme reverse transcriptase to carry out the nucleic acid conversion.

Lifeform debate

Multiple rotavirus virions


Multiple rotavirus virions

Argument continues over whether viruses are truly alive or not. According to the United States Code, they are considered to be micro-organisms in the sense of biological weaponry and malicious use. Scientists however are more divided. They have no trouble classifying a horse as living and can see evolutionary relationships between it and other animals, but things become complicated as they look at the more simple 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, whereas all viruses simply assemble spontaneously within cells. What then prevents the comparison to be drawn that viral self-assembly is no different than the autonomous growth of non-living crystals? Virus self-assembly within host cells also has implications for the study of the origin of life, as it lends credence to the hypothesis that life could have started as self-assembling organic molecules.

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. If they 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. 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.

Viruses and disease

For more examples of diseases caused by viruses see List of infectious 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. 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 Six (HHV6) and 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. 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.

Viruses have many different mechanisms by which they produce disease in an organism, which largely depends on the 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 carry-on effects. Although many viruses result in the disruption of healthy homeostasis, resulting in disease, they may reside relatively harmlessly within an organism. An example would include the ability of the herpes simplex virus, which cause coldsores, to remain in a dormant state within the human body.

Epidemics

For more details on this topic, see List of epidemics.

The helical Ebola virus


The helical Ebola virus

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.

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. The damage done by this disease may have significantly aided European attempts to displace or conquer the native population.

The Marburg virus


The Marburg virus

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:.

A viral plaque assay


A viral plaque assay

  • 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 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

The polio virus


The polio virus

Life sciences

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.

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. 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.

Materials science and nanotechnology

In April 2006 scientists at the Massachusetts Institute of Technology (MIT) created nanoscale metallic wires using a genetically-modified virus. 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.

The reconstructed 1918 influenza virus


The reconstructed 1918 influenza virus

Weapons

For more details on this topic, see Biological warfare.

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. 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.

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1 Response to “A Virus, defined”


  1. 1 remya March 18, 2007 at 9:17 am

    more information should be provided.information is less


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