Cross-species transmission (CST), also called interspecies transmission, host jump, or spillover, is the ability for a foreign virus,
once introduced into an individual of a new host species, to infect
that individual and spread throughout a new host population.
Steps involved in the transfer of viruses to new hosts include contact
between the virus and the host, infection of an initial individual
leading to amplification and an outbreak, and the generation within the
original or new host of viral variants that have the ability to spread
efficiently between individuals in populations of the new host Often seen in emerging viruses where one species transfers to another, which in turn transfers to humans. Examples include HIV-AIDS, SARS, ebola, swine flu, rabies, and avian influenza. Bacterialpathogens can also be associated with CST.
The exact mechanism that facilitates transfer is unknown,
however, it is believed that viruses with a rapid mutation rate are able
to overcome host-specific immunological defenses.
This can occur between species that have high contact rates. It can
also occur between species with low contact rates but usually through an
intermediary species. Bats, for example, are mammals and can directly
transfer rabies to humans through bite and also through aerosolization
of bat saliva and urine which are then absorbed by human mucous
membranes in the nose, mouth and eyes. Note: the document used as a
reference does not use the words urine or saliva so this citation is
questionable. A host shifting event is defined as a strain that was previously zoonotic and now circulates exclusively among humans.
Similarity between species, for example, transfer between
mammals, is believed to be facilitated by similar immunological
defenses. Other factors include geographic area, intraspecies
behaviours, and phylogenetic relatedness. Virus emergence relies on two
factors: initial infection and sustained transmission.
Prevalence
Cross-species transmission is the most significant cause of disease emergence in humans and other species. Wildlifezoonotic diseases of microbial origin are also the most common group of human emerging diseases, and CST between wildlife and livestock has appreciable economic impacts in agriculture by reducing livestock productivity and imposing export restrictions. This makes CST of major concern for public health, agriculture, and wildlife management.
A large proportion of viral pathogens that have emerged recently
in humans are considered to have originated from various animal species.
This is shown by several recent epidemics such as, avian flu, Ebola, monkey pox, and Hanta viruses.
There is evidence to suggest that some diseases can potentially be
re-introduced to human populations through animal hosts after they have
been eradicated in humans. There is a risk of this phenomenon occurring with morbilliviruses as they can readily cross species barriers. CST can also have a significant effect on produce industries. Genotype VI-Avian paramyxovirus serotype 1 (GVI-PMV1) is a virus that arose through cross-species transmission events from Galliformes (i.e. chicken) to Columbiformes, and has become prevalent in the poultry industry. CST of rabies
virus variants between many different species populations is a major
wildlife management concern. Introduction of these variants into
non-reservoir animals increases the risk of human exposures and
threatens current advances toward rabies control.
Many pathogens are thought to have host specialization, which explains the maintenance of distinct strains in host species.
Pathogens would have to overcome their host specificity to cross to a
new host species. Some studies have argued that host specializations
may be exaggerated, and pathogens are more likely to exhibit CST than
previously thought. Original hosts usually have low death rates when infected with a pathogen, with fatality rates tending to be much higher in new hosts.
Cross-Species Transmission between Humans and Nonhuman Primates
Due to the close relation of humans and nonhuman primates
(NHP), disease transmission between NHP and humans is relatively common
and can become a major public health concern. Diseases, such as HIV and human adenoviruses have been associated with NHP interactions.
In places where contact between humans and NHPs is frequent, precautions are often taken to prevent disease transmission. Simian foamy viruses (SFV) is an enzooticretrovirus that has high rates of cross-species transmission and has been known to affect humans bitten by infected NHPs. It has caused health concerns in places like Indonesia where visitors at monkey temples can contract SFV from temple macaques (Macaca fascicularis). TMAdV (titi monkey adenovirus) is a highly divergent, sharing <57 a="" href="https://en.wikipedia.org/wiki/Pairwise_comparison" title="Pairwise comparison">pairwise
nucleotide identity with other adenoviruses, NHP virus that had a high
fatality rate (83%) in monkeys and is capable of spreading through human
hosts.
Predicting and Preventing Transmission between Species
Prediction
and monitoring are important for the study of CSTs and their effects.
However, factors that determine the origin and fate of cross-species
transmission events remain unclear for the majority of human pathogens. This has resulted in the use of different statistical models for the analyzation of CST. Some of these include risk-analysis models, single rate dated tip (SRDT) models, and phylogenetic diffusion models. The study of the genomes of pathogens involved in CST events is very useful in determining their origin and fate. This is because a pathogens genetic diversity and mutation
rate are key factors in determining if it is able to transmit across
multiple hosts. This makes it important for the genomes of transmission
species to be partially or completely sequenced.
A change in genomic structure could cause a pathogen that has narrow
host range to become capable of exploiting a wider host range. Genetic distance between different species, geographical range, and other interaction barriers will also influence cross-species transmission.
One approach to risk assessment analysis of CST is to develop
risk-analysis models that break the ‘‘process’’ of disease transmission
into component parts. Processes and interactions that could lead to
cross-species disease transmission are explicitly described as a
hypothetical infection chain. Data from laboratory and field experiments
is used to estimate the probability of each component, expected natural
variation, and margins of error.
Different types of CST research would require different analysis
pathways to meet their needs. A study on identification of viruses in
bats that could spread to other mammals used the workflow: sequencing
of genomic samples → “cleaning” of raw reads → elimination of host reads
and eukaryotic contaminants → de novo assembly of the remaining reads →
annotation of viral contigs → molecular detection of specific viruses →
phylogenetic analysis → interpretation of data.
Detecting CST and estimating its rate based on prevalence data is challenging. Due to these difficulties computational methods are used to analyse CST events and the pathogens associated with them. The explosive development of molecular techniques has opened new possibilities for using phylogenetic analysis of pathogen genetics to infer epidemiological parameters.
This provides some insight into the origins of these events and how
they could be addressed. Methods of CST prevention are currently using
both biological and computational data. An example of this is using both
cellularassays and phylogenetic
comparisons to support a role for TRIM5α, the product of the TRIM5
gene, in suppressing interspecies transmission and emergence of
retroviruses in nature.
Cross-Species Transmission Analyzation
Phylogeny
The comparison of genomic data is very important for the study of cross-species transmission. Phylogenetic analysis
is used to compare genetic variation in both pathogens associated with
CST and the host species that they infect. Taken together, it is
possible to infer what allowed a pathogen to crossover to a new host
(i.e. mutation in a pathogen, change in host susceptibility) and how
this can be prevented in the future. If the mechanisms a pathogens uses
to initially enter a new species are well characterized and understood a
certain level of risk control and prevention can be obtained. In
contact, a poor understanding of pathogens, and their associated
diseases, makes it harder for preventive measures to be taken.
Alternative hosts can also potentially have a critical role in the evolution and diffusion of a pathogen. When a pathogen crosses species it often acquires new characteristics that allow it to breach host barriers. Different pathogen variants can have very different effects on host species.
Thus it can be beneficial to CST analysis to compare the same pathogens
occurring in different host species. Phylogenetic analysis can be used
to track a pathogens history through different species populations. Even
if a pathogen is new and highly divergent, phylogenetic comparison can
be very insightful. A useful strategy for investigating the history of epidemics caused by pathogen transmission combines molecular clock analysis, to estimate the timescale of the epidemic, and coalescent theory, to infer the demographic history of the pathogen.
When constructing phylogenies, computer databases and tools are often used. Programs, such as BLAST, are used to annotate pathogen sequences, while databases like GenBank
provide information about functions based on the pathogens genomic
structure. Trees are constructed using computational methods such as MPR
or Bayesian Inference, and models are created depending on the needs of
the study. Single rate dated tip (SRDT) models, for example, allows for estimates of timescale under a phylogenetic tree. Models for CST prediction will vary depending on what parameters need to be accounted for when constructing the model.
Most Parsimonious Reconstruction (MPR)
Parsimony
is the principle in which one chooses the simplest scientific
explanation that fits the evidence. In terms of building phylogenetic
trees, the best hypothesis
is the one that requires the fewest evolutionary changes. Using
parsimony to reconstruct ancestral character states on a phylogenetic
tree is a method for testing ecological and evolutionary hypotheses.
This method can be used in CST studies to estimate the number of
character changes that exist between pathogens in relation to their
host.
This makes MPR useful for tracking a CST pathogen to its origins. MPR
can also be used to the compare traits of host species populations.
Traits and behaviours within a population could make them more
susceptible to CST. For example, species which migrate regionally are important for spreading viruses through population networks.
Despite the success of parsimony reconstructions, research
suggests they are often sensitive and can sometimes be prone to bias in
complex models.
This can cause problems for CST models that have to consider many
variables. Alternatives methods, such as maximum likelihood, have been
developed as an alternative to parsimony reconstruction.
Using Genetic Markers
Two methods of measuring genetic variation, variable number tandem repeats (VNTRs) and single nucleotide polymorphisms (SNPs), have been very beneficial to the study of bacterial transmission. VNTRs, due to the low cost and high mutation rates, make them particularly useful to detect genetic differences in recent outbreaks,
and while SNPs have a lower mutation rate per locus than VNTRs, they
deliver more stable and reliable genetic relationships between isolates.
Both methods are used to construct phylogenies for genetic analysis,
however, SNPs are more suitable for studies on phylogenies contraction.
However, it can be difficult for these methods accurately simulate CSTs everts. Estimates of CST based on phylogenys
made using VNTR marker can be biased towards detecting CST events
across a wide range of the parameters. SNPs tend to be less biased and
variable in estimates of CST when estimations of CST rates are low and
low number of SNPs is used. In general, CST rate estimates using these
methods are most reliable in systems with more mutations, more markers,
and high genetic differences between introduced strains.
CST is very complex and models need to account for a lot of parameters
to accurately represent the phenomena. Models that oversimplify reality
can result in biased data. Multiple parameters such as number of
mutations accumulated since introduction, stochasticity,
the genetic difference of strains introduced, and the sampling effort
can make unbiased estimates of CST difficult even with whole-genome
sequences, especially if sampling is limited, mutation rates are low, or
if pathogens were recently introduced.
More information on the factors that influence CST rates is needed for
the contraction of more appropriate models to study these events.
The process of using genetic markers to estimate CST rates should
take into account several important factors to reduce bias. One, is
that the phylogenetic tree constructed in the analysis needs to capture
the underlying epidemiological process generating the tree.
The models need to account for how the genetic variability of a
pathogen influences a disease in a species, not just general differences
in genomic structure. Two, the strength of the analysis will depend on
the amount of mutation accumulated since the pathogen was introduced in
the system.
This is due to many models using amount of mutations as an indicator of
CST frequency. Therefore, efforts are focused on estimating either time
since introduction or the substitution rate of the marker (from
laboratory experiments or genomic comparative analysis). This is
important not only when using the MPR method but also for Likelihood approaches that require an estimation of the mutation rate.
Three, CST will also affect disease prevalence in the potential host,
so combining both epidemiological time series data with genetic data may
be an excellent approach to CST study
Bayesian Analysis
Bayesian
frameworks are a form of maximum likelihood-based analyses and can be
very effective in cross-species transmission studies. Bayesian inference
of character evolution methods can account for phylogenetic tree
uncertainty and more complex scenarios, with models such as the
character diffusion model currently being developed for the study of CST
in RNA viruses.
A Bayesian statistical approach presents advantages over other analyses
for tracking CST origins. Computational techniques allow integration
over an unknown phylogeny, which cannot be directly observed, and
unknown migration process, which is usually poorly understood.
The Bayesian frameworks are also wellsuited to bring together
different kinds of information. The BEAST software, which has a strong
focus on calibrated phylogenies and genealogies, illustrates this by
offering a large number of complementary evolutionary models including
substitution models, demographic and relaxed clock models that can be
combined into a full probabilistic model. By adding spatial
reconstruction, these models create the probability of biogeographical history reconstruction from genetic data. This could be useful for determining origins of cross-species transmissions.
The high effectiveness of Bayesian statistical methods has made them instrumental in evolutionary studies.
Bayesian ancestral host reconstruction under discrete diffusion models
can be used to infer the origin and effects of pathogens associated with
CST. One study on Human adenoviruses using Bayesian supported a gorilla and chimpanzee origin for the viral species, aiding prevention efforts.
Despite presumably rare direct contact between sympatric populations of
the two species, CST events can occur between them. The study also
determined that two independent HAdV-B transmission events to humans
occurred and that the HAdV-Bs circulating in humans are of zoonotic
origin and have probably affected global health for most of our species
lifetime.
Phylogenetic diffusion models are frequently used for
phylogeographic analyses, with the inference of host jumping becoming of
increasing interest.
The Bayesian inference approach enables model averaging over a number
of potential diffusion predictors and estimates the support and
contribution of each predictor while marginalizing over phylogenetic
history.
For studying viral CST, the flexibility of the Bayesian statistical
framework allows for the reconstruction of virus transmission between
different host species while simultaneously testing and quantifying the
contribution of multiple ecological and evolutionary influences of both
CST spillover and host shifting. One study on rabies in bats showed geographical range overlap is a modest predictor for CST, but not for host shifts.[3] This highlights how Bayesian inferences in models can be used for CST analysis.
Virome refers to the collection of nucleic acids, both RNA and
DNA, that make up the viral community associated with a particular
ecosystem or holobiont. The word is derived from virus and genome and first used by Forest Rohwer and colleagues to describe viral shotgun metagenomes. All macro-organisms have viromes that include bacteriophage and viruses. Viromes are important in the nutrient and energy cycling, development of immunity, and a major source of genes through lysogenic conversion.
History
Viromes were the first examples of shotgun community sequence, which is now known as metagenomics. In the 2000s, the Rohwer lab sequenced viromes from seawater, marine sediments, adult human stool, infant human stool, soil, and blood. This group also performed the first RNA virome with collaborators from the Genomic Institute of Singapore.
From these early works, it was concluded that most of the genomic
diversity is contained in the global virome and that most of this
diversity remains uncharacterized. This view was supported by individual genomic sequencing project, particularly the mycobacterium phage.
Methods of study
In
order to study the virome, virus-like particles are separated from
cellular components, usually using a combination of filtration, density
centrifugation, and enzymatic treatments to get rid of free nucleic
acids. The nucleic acids are then sequenced and analyzed using metagenomic
methods. Alternatively, there are recent computational methods that use
directly metagenomic assembled sequences to discover viruses.
The Global Ocean Viromes (GOV) is a dataset consisting of deep sequencing from over 150 samples collected across the world's oceans in two survey periods by an international team.
Virus hosts
We can determine the metagenome host from prophage identity sequence.
Viruses are the most abundant biological entities on Earth, but
challenges in detecting, isolating, and classifying unknown viruses have
prevented exhaustive surveys of the global virome. Over 5 Tb of metagenomic
sequence data were used from 3,042 geographically diverse samples to
assess the global distribution, phylogenetic diversity, and host
specificity of viruses.
Proportion of 18,470 viral connected with predicted hosts at various taxonomic levels.
In August 2016, over 125,000 partial DNA viral genomes, including the
largest phage yet identified, increased the number of known viral genes
by 16-fold. A suite of computational methods was used to identify putative host virus connections. The isolate viral host information was projected onto a group, resulting in host assignments for 2.4% of viral groups.
Then the CRISPR–Cas
prokaryotic immune system which holds a "library" of genome fragments
from phages (proto-spacers) that have previously infected the host. Spacers from isolate microbial genomes with matches to metagenomic viral contigs (mVCs) were identified for 4.4% of the viral groups and 1.7% of singletons. The hypothesis was explored that viral transfer RNA (tRNA) genes originate from their host.
Viral tRNAs identified in 7.6% of the mVCs were matched to isolate genomes from a single species or genus.
The specificity of tRNA-based host viral assignment was confirmed by
CRISPR–Cas spacer matches showing a 94% agreement at the genus level.
These approaches identified 9,992 putative host–virus associations
enabling host assignment to 7.7% of mVCs.
The majority of these connections were previously unknown, and include
hosts from 16 prokaryotic phyla for which no viruses have previously
been identified.
Three
proto-spacers encoded on mVCs identified in human oral metagenomic
samples that were linked to CRISPR spacers from hosts from distinct
phyla, Actinomycetes sp. oral taxon 180 (Actinobacteria) and
Streptococcus plurextorum DSM 22810 (Firmicutes).
Many viruses specialize in infecting related hosts. Viral generalists that infect hosts across taxonomic orders may exist. Most CRISPR spacer matches were from viral sequences to hosts within one species or genus.
Some mVCs were linked to multiple hosts from higher taxa. A viral
group composed of macs from human oral samples contained three distinct
photo-spacers with nearly exact matches to spacers in Actionbacteria and Firmicutes.
In January 2017, the IMG/VR system -- the largest interactive public virus database contained 265,000
metagenomic viral sequences and isolate viruses. This number scaled up
to over 760,000 in November 2018 (IMG/VR v.2.0). The IMG/VR systems serve as a starting point for the sequence analysis of viral fragments derived from metagenomic samples.
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, about 5,000 virus species have been described in detail, of the millions of types of viruses in the environment. Viruses are found in almost every ecosystem on Earth and are the most numerous type of biological entity. The study of viruses is known as virology, a sub-speciality of microbiology.
While not inside an infected cell or in the process of infecting a cell, viruses exist in the form of independent particles, or virions, consisting of: (i) the genetic material, i.e. long molecules of DNA or RNA that encode the structure of the proteins by which the virus acts; (ii) a protein coat, the capsid, which surrounds and protects the genetic material; and in some cases (iii) an outside envelope of lipids. The shapes of these virus particles range from simple helical and icosahedral forms to more complex structures. Most virus species have virions too small to be seen with an optical microscope, about one hundredth the size of most bacteria.
The origins of viruses in the evolutionary history of life are unclear: some may have evolved from plasmids—pieces
of DNA that can move between cells—while others may have evolved from
bacteria. In evolution, viruses are an important means of horizontal gene transfer, which increases genetic diversity in a way analogous to sexual reproduction. Viruses are considered by some to be a life form, because they carry genetic material, reproduce, and evolve through natural selection,
although they lack key characteristics (such as cell structure) that
are generally considered necessary to count as life. Because they
possess some but not all such qualities, viruses have been described as
"organisms at the edge of life", and as replicators.
Viruses spread in many ways. One transmission pathway is through disease-bearing organisms known as vectors: for example, viruses are often transmitted from plant to plant by insects that feed on plant sap, such as aphids; and viruses in animals can be carried by blood-sucking insects. Influenza viruses are spread by coughing and sneezing. Norovirus and rotavirus, common causes of viral gastroenteritis, are transmitted by the faecal–oral route, passed by contact and entering the body in food or water. HIV is one of several viruses transmitted through sexual contact and by exposure to infected blood. The variety of host cells that a virus can infect is called its "host range". This can be narrow, meaning a virus is capable of infecting few species, or broad, meaning it is capable of infecting many.
Viral infections in animals provoke an immune response that usually eliminates the infecting virus. Immune responses can also be produced by vaccines, which confer an artificially acquired immunity to the specific viral infection. Some viruses, including those that cause AIDS and viral hepatitis, evade these immune responses and result in chronic infections. Several antiviral drugs have been developed.
Etymology
The word is from the Latin neuter vīrus referring to poison and other noxious liquids, from the same Indo-European base as Sanskritviṣa, Avestanvīša, and ancient Greekἰός (all meaning "poison"), first attested in English in 1398 in John Trevisa's translation of Bartholomeus Anglicus'sDe Proprietatibus Rerum. Virulent, from Latin virulentus (poisonous), dates to c. 1400. A meaning of "agent that causes infectious disease" is first recorded in 1728, long before the discovery of viruses by Dmitri Ivanovsky in 1892. The English plural is viruses (sometimes also viri or vira), whereas the Latin word is a mass noun, which has no classically attested plural (vīra is used in Neo-Latin). The adjective viral dates to 1948. The term virion (plural virions), which dates from 1959,
is also used to refer to a single viral particle that is released from
the cell and is capable of infecting other cells of the same type.
Louis Pasteur was unable to find a causative agent for rabies and speculated about a pathogen too small to be detected by microscopes. In 1884, the French microbiologistCharles Chamberland invented the Chamberland filter (or Pasteur-Chamberland filter) with pores small enough to remove all bacteria from a solution passed through it. In 1892, the Russian biologist Dmitri Ivanovsky used this filter to study what is now known as the tobacco mosaic virus:
crushed leaf extracts from infected tobacco plants remained infectious
even after filtration to remove bacteria. Ivanovsky suggested the
infection might be caused by a toxin produced by bacteria, but did not pursue the idea.
At the time it was thought that all infectious agents could be retained
by filters and grown on a nutrient medium—this was part of the germ theory of disease. In 1898, the Dutch microbiologist Martinus Beijerinck repeated the experiments and became convinced that the filtered solution contained a new form of infectious agent.
He observed that the agent multiplied only in cells that were dividing,
but as his experiments did not show that it was made of particles, he
called it a contagium vivum fluidum (soluble living germ) and re-introduced the word virus. Beijerinck maintained that viruses were liquid in nature, a theory later discredited by Wendell Stanley, who proved they were particulate. In the same year Friedrich Loeffler and Paul Frosch passed the first animal virus through a similar filter: aphthovirus, the agent of foot-and-mouth disease.
In the early 20th century, the English bacteriologist Frederick Twort discovered a group of viruses that infect bacteria, now called bacteriophages (or commonly 'phages'), and the French-Canadian microbiologist Félix d'Herelle described viruses that, when added to bacteria on an agar plate,
would produce areas of dead bacteria. 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. Phages were heralded as a potential treatment for diseases such as typhoid and cholera, but their promise was forgotten with the development of penicillin. The development of bacterial resistance to antibiotics has renewed interest in the therapeutic use of bacteriophages.
By the end of the 19th century, viruses were defined in terms of their infectivity,
their ability to pass filters, and their requirement for living hosts.
Viruses had been grown only in plants and animals. In 1906, Ross Granville Harrison invented a method for growing tissue in lymph, and, in 1913, E. Steinhardt, C. Israeli, and R. A. Lambert used this method to grow vaccinia virus in fragments of guinea pig corneal tissue.
In 1928, H. B. Maitland and M. C. Maitland grew vaccinia virus in
suspensions of minced hens' kidneys. Their method was not widely adopted
until the 1950s when poliovirus was grown on a large scale for vaccine production.
The first images of viruses were obtained upon the invention of electron microscopy in 1931 by the German engineers Ernst Ruska and Max Knoll. In 1935, American biochemist and virologist Wendell Meredith Stanley examined the tobacco mosaic virus and found it was mostly made of protein. A short time later, this virus was separated into protein and RNA parts.
The tobacco mosaic virus was the first to be crystallised and its structure could, therefore, be elucidated 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 structure of the virus in 1955. In the same year, Heinz Fraenkel-Conrat and Robley Williams
showed that purified tobacco mosaic virus RNA and its protein coat 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.
Viruses are found wherever there is life and have probably existed since living cells first evolved. The origin of viruses is unclear because they do not form fossils, so molecular techniques are used to investigate how they arose. In addition, viral genetic material occasionally integrates into the germline of the host organisms, by which they can be passed on vertically to the offspring of the host for many generations. This provides an invaluable source of information for paleovirologists
to trace back ancient viruses that have existed up to millions of years
ago. There are three main hypotheses that aim to explain the origins of
viruses:
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', or 'reduction hypothesis'.
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). 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. This is sometimes called the 'vagrancy hypothesis', or the 'escape hypothesis'.
Co-evolution hypothesis
This is also called the 'virus-first hypothesis' 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. They have characteristics that are common to
several viruses and are often called subviral agents. Viroids are important pathogens of plants. They do not code for proteins but interact with the host cell and use the host machinery for their replication. 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. Although hepatitis delta virus genome may replicate independently
once inside a host cell, it requires the help of hepatitis B virus to
provide a protein coat so that it can be transmitted to new cells. In similar manner, the sputnik virophage is dependent on mimivirus, which infects the protozoan Acanthamoeba castellanii. These viruses, which 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.
In the past, there were problems with all of these hypotheses: the
regressive hypothesis did not explain why even the smallest of cellular
parasites do not resemble viruses in any way. The escape hypothesis did
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. Viruses are now recognised as ancient and as having origins that pre-date the divergence of life into the three domains. This discovery has led modern virologists to reconsider and re-evaluate these three classical hypotheses.
The evidence for an ancestral world of RNA cells
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.
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.
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", since they resemble organisms in that they possess genes, evolve by natural selection,
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—although bacterial species such as rickettsia and chlamydia are considered living organisms despite the same limitation. 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.
Structure
Diagram of how a virus capsid can be constructed using multiple copies of just two protein molecules
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. Most viruses cannot be seen with an optical microscope, so scanning and transmission electron microscopes are used to visualise them. 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.
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. 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.
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. In general, there are four main morphological virus types:
Helical
These viruses are composed of a single type of capsomere stacked around a central axis to form a helical
structure, which may have a central cavity, or tube. This arrangement
results in rod-shaped or filamentous virions which can be short and
highly rigid, or long and very flexible. The genetic material (typically
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 capsomeres. The
well-studied tobacco mosaic virus is an example of a helical virus.
Icosahedral
Most animal viruses are icosahedral or near-spherical with chiral icosahedral symmetry. A regular icosahedron
is the optimum way of forming a closed shell from identical sub-units.
The minimum number of identical capsomeres required for each triangular
face is 3, which gives 60 for the icosahedron. Many viruses, such as
rotavirus, have more than 60 capsomers and appear spherical but they
retain this symmetry. To achieve this, the capsomeres at the apices are
surrounded by five other capsomeres and are called pentons. Capsomeres
on the triangular faces are surrounded by six others and are called hexons.
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 icosahedron 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.
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.
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.
The poxviruses
are large, complex viruses that have an unusual morphology. The viral
genome is associated with proteins within a central disc 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-shaped.
Giant viruses
Mimivirus
is one of the largest characterised viruses, 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.
In 2011, researchers discovered the largest then known virus in samples
of water collected from the ocean floor off the coast of Las Cruces,
Chile. Provisionally named Megavirus chilensis, it can be seen with a basic optical microscope. In 2013, the Pandoravirus genus was discovered in Chile and Australia, and has genomes about twice as large as Megavirus and Mimivirus. All giant viruses have dsDNA genomes and they are classified into several families: Mimiviridae, Pithoviridae, Pandoraviridae, Phycodnaviridae, and the Mollivirus genus.
Some viruses that infect Archaea
have complex structures 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.
Genome
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
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, although only about 5,000 types have been described in detail. As of September 2015, the NCBI Virus genome database has more than 75,000 complete genome sequences, but there are doubtlessly many more to be discovered.
A virus has either a DNA or an RNA genome and is called a DNA virus or an 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.
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. 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.
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.
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 if 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 positive-strand
viral ssDNA is identical in sequence to the viral mRNA and is thus a
coding strand, while negative-strand viral ssDNA is complementary to the
viral mRNA and is thus a template strand. 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.
Genome size
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 two kilobases; the largest—the pandoraviruses—have genome sizes of around two megabases which code for about 2500 proteins. Virus genes rarely have introns and often are arranged in the genome so that they overlap.
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.
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.
Single-strand DNA viruses are an exception to this rule, as mutation
rates for these genomes can approach the extreme of the ssRNA virus
case.
Genetic mutation
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 antigenic 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. 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. 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.
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'.
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. Recombination is common to both RNA and DNA viruses.
Replication cycle
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:
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
result 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.
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.
Bacteria, like plants, have strong cell walls that a virus must breach
to infect the cell. Given that bacterial cell walls are much thinner
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.
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.
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".
Whenever the host divides, the viral genome is also replicated. The
viral genome is mostly silent within the host. At some point, the
provirus or prophage may give rise to active virus, which may lyse the
host cells. 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.
Genome replication
The genetic material within virus particles, and the method by which
the material is replicated, varies considerably between different types
of 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. 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.
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.
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. 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.
Cytopathic effects on the host cell
The range of structural and biochemical effects that viruses have on the host cell is extensive. These are called 'cytopathic effects'.
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.
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. The distinction between cytopathic and harmless is gradual. Some viruses, such as Epstein–Barr virus, can cause cells to proliferate without causing malignancy, while others, such as papillomaviruses, are established causes of cancer.
Dormant and latent infections
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. This causes persistent infections and the virus is often dormant for many months or years. This is often the case with herpes viruses.
Host range
Viruses are by far the most abundant biological entities on Earth and they outnumber all the others put together. They infect all types of cellular life including animals, plants, bacteria and fungi. 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, 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. The viruses that infect plants are harmless to animals, and most viruses that infect other animals are harmless to humans. 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.
Classification
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. This system based 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. In 1966, the International Committee on Taxonomy of Viruses
(ICTV) was formed. The system proposed by Lwoff, Horne and Tournier was
never fully accepted by the ICTV because small genome size viruses and
their 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
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. Only a small part of the
total diversity of viruses has been studied.
The general taxonomic structure of taxon ranges actually used (as of November 2018) is as follows:
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. The ICTV classification system is used in conjunction with the Baltimore classification system in modern virus classification.
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:
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 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.
These latent viruses might sometimes be beneficial, as the presence of
the virus can increase immunity against bacterial pathogens, such as Yersinia pestis.
Some viruses can cause lifelong or chronic infections, where the viruses continue to replicate in the body despite the host's defence mechanisms.
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. In populations with a high proportion of carriers, the disease is said to be endemic.
Epidemiology
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, which means 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. Another, more rare, example is the varicella zoster virus, which, although causing relatively mild infections in children and adults, can be fatal to the foetus and newborn baby.
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), the quality of healthcare and the weather.
Epidemiology is used to break the chain of infection in populations during outbreaks of viral diseases.
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 are placed in quarantine. To control the outbreak of foot-and-mouth disease in cattle in Britain in 2001, thousands of cattle were slaughtered. Most viral infections of humans and other animals have incubation periods during which the infection causes no signs or symptoms. Incubation periods for viral diseases range from a few days to weeks, but are known for most infections.
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.
This, too, is known for many viral infections, and knowledge of the
length of both periods is important in the control of outbreaks.
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.
Native American populations were devastated by contagious diseases, in particular, 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 significantly aided European attempts to displace and conquer
the native population.
A pandemic is a worldwide epidemic. The 1918 flu pandemic, which lasted until 1919, was a category 5
influenza pandemic caused by an unusually severe and deadly influenza A
virus. The victims were often healthy young adults, in contrast to most
influenza outbreaks, which predominantly affect juvenile, elderly, or
otherwise-weakened patients. Older estimates say it killed 40–50 million people,
while more recent research suggests that it may have killed as many as
100 million people, or 5% of the world's population in 1918.
Most researchers believe that HIV originated in sub-Saharan Africa during the 20th century; it is now a pandemic, with an estimated 38.6 million people now living with the disease worldwide. 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 5 June 1981, making it one of the most
destructive epidemics in recorded history. In 2007 there were 2.7 million new HIV infections and 2 million HIV-related deaths.
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.
RNA interference is an important innate defence against viruses.
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 a dicer that cuts the RNA into smaller pieces. A biochemical pathway—the RISC complex—is
activated, which ensures cell survival by degrading the viral mRNA.
Rotaviruses have evolved to avoid this defence mechanism by not
uncoating fully inside the cell, and releasing newly produced mRNA
through pores in the particle's inner capsid. Their genomic dsRNA
remains protected inside the core of the virion.
When the adaptive immune system of a vertebrate encounters a virus, it produces specific antibodies that bind to the virus and often render it non-infectious. This is called humoral immunity. Two types of antibodies are important. The first, called IgM,
is highly effective at neutralising 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. IgG antibody is measured when tests for immunity are carried out.
Antibodies can continue to be an effective defence mechanism even
after viruses have managed to gain entry to the host cell. A protein
that is in cells, called TRIM21,
can attach to the antibodies on the surface of the virus particle. This
primes the subsequent destruction of the virus by the enzymes of the
cell's proteosome system.
Two rotaviruses: the one on the right is coated with antibodies that prevent its attachment 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. 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.
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. This is
known as "escape mutation" as the viral epitopes escape recognition by
the host immune response. 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. Other viruses, called 'neurotropic viruses', are disseminated by neural spread where the immune system may be unable to reach them.
Prevention and treatment
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.
Vaccines
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. Smallpox infections have been eradicated. Vaccines are available to prevent over thirteen viral infections of humans, and more are used to prevent viral infections of animals. Vaccines can consist of live-attenuated or killed viruses, or viral proteins (antigens). 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.
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. Subunit vaccines are safe for immunocompromised patients because they cannot cause the disease. The yellow fever virus vaccine, a live-attenuated strain called 17D, is probably the safest and most effective vaccine ever generated.
Antiviral drugs
The structure of the DNA base guanosine and the antiviral drug acyclovir
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. 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.
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.
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. There is now an effective treatment that uses the nucleoside analogue drug ribavirin combined with interferon. The treatment of chronic carriers of the hepatitis B virus by using a similar strategy using lamivudine has been developed.
Infection in other species
Viruses infect all cellular life and, although viruses occur
universally, each cellular species has its own specific range that often
infect only that species. Some viruses, called satellites, can replicate only within cells that have already been infected by another virus.
Animal viruses
Viruses are important pathogens of livestock. Diseases such as foot-and-mouth disease and bluetongue are caused by viruses. 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. Like all invertebrates, the honey bee is susceptible to many viral infections. Most viruses co-exist harmlessly in their host and cause no signs or symptoms of disease.
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 usually 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. Plant viruses cannot infect humans and other animals because they can reproduce only in living plant cells.
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. RNA interference is also an effective defence in plants. When they are infected, plants often produce natural disinfectants that kill viruses, such as salicylic acid, nitric oxide, and reactive oxygen molecules.
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.
Bacterial 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 biological entity in aquatic environments—there are up to
ten times more of these viruses in the oceans than there are bacteria, reaching levels of 250,000,000 bacteriophages per millilitre of seawater. 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.
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. 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. This genetic system provides bacteria with acquired immunity to infection.
Archaeal viruses
Some viruses replicate within archaea: these are double-stranded DNA viruses with unusual and sometimes unique shapes. These viruses have been studied in most detail in the thermophilic archaea, particularly the orders Sulfolobales and Thermoproteales. Defences against these viruses involve RNA interference from repetitive DNA sequences within archaean genomes that are related to the genes of the viruses.
Most archaea have CRISPR–Cas systems as an adaptive defence against
viruses. These enable archaea to retain sections of viral DNA, which are
then used to target and eliminate subsequent infections by the virus
using a process similar to RNA interference.
Role in aquatic ecosystems
A teaspoon of seawater (~5 mL) contains about 50 million viruses, which contain enormous genetic diversity. Most of these are bacteriophages infecting heterotrophic bacteria and cyanophages
infecting cyanobacteria; these viruses are harmless to plants and
animals, and are essential to the regulation of marine and freshwater
ecosystems; they are also important mortality agents of phytoplankton, the base of the foodchain in aquatic environments. They infect and destroy bacteria in aquatic microbial communities, and are one of the most important mechanisms of recycling carbon
and nutrient cycling in marine environments. The organic molecules
released from the dead bacterial cells stimulate fresh bacterial and
algal growth, in a process known as the viral shunt. In particular, lysis of bacteria by viruses has been shown to enhance nitrogen cycling and stimulate phytoplankton growth. Viral activity may also affect the biological pump, the process whereby carbon is sequestered in the deep ocean.
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 10 to 15 times as many viruses in the
oceans as there are bacteria and archaea. Viruses are also major agents responsible for the destruction of phytoplankton including harmful algal blooms,
The number of viruses in the oceans decreases further offshore and deeper into the water, where there are fewer host organisms.
In January 2018, scientists reported that 800 million viruses, mainly of marine origin, are deposited daily from the Earth'satmosphere
onto every square meter of the planet's surface, as the result of a
global atmospheric stream of viruses, circulating above the weather
system, but below the altitude of usual airline travel, distributing
viruses around the planet.
Viruses are an important natural means of transferring genes between different species, which increases genetic diversity and drives evolution. It is thought that viruses played a central role in early evolution, before the diversification of the last universal common ancestor into bacteria, archaea and eukaryotes. Viruses are still one of the largest reservoirs of unexplored genetic diversity on Earth.
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. The study and use of viruses have provided valuable information about aspects of cell biology. 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 a 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.
The 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.
Virotherapy
Virotherapy involves the use of genetically modified viruses to treat diseases. Viruses have been modified by scientists to reproduce in cancer cells and destroy them but not infect healthy cells. Talimogene laherparepvec (T-VEC), for example, is a modified herpes simplex virus that has had a gene, which is required for viruses to replicate in healthy cells, deleted and replaced with a human gene (GM-CSF)
that stimulates immunity. When this virus infects cancer cells, it
destroys them and in doing so the presence the GM-CSF gene attracts dendritic cells
from the surrounding tissues of the body. The dendritic cells process
the dead cancer cells and present components of them to other cells of
the immune system. Having completed successful clinical trials, the virus gained approval for the treatment of melanoma in late 2015. Viruses that have been reprogrammed to kill cancer cells are called oncolytic viruses.
Materials science and nanotechnology
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.
Because of their size, shape, and well-defined chemical
structures, viruses have been used as templates for organising 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 fluorescentdyes used for signalling to prevent the formation of non-fluorescent dimers that act as quenchers. Another example is the use of CPMV as a nanoscale breadboard for molecular electronics.
Synthetic viruses
Many viruses can be synthesised de novo ("from scratch") and the first synthetic virus was created in 2002.
Although somewhat of a misconception, it is not the actual virus that
is synthesised, 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.
The ability to synthesise 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. As of November 2017,
the full-length genome sequences of 7454 different viruses, including
smallpox, are publicly available in an online database maintained by the
National Institutes of Health.
Weapons
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.
Smallpox virus devastated numerous societies throughout history
before its eradication. There are only two centres in the world
authorised by the WHO to keep stocks of smallpox virus: the State Research Center of Virology and Biotechnology VECTOR in Russia and the Centers for Disease Control and Prevention in the United States. It may be used as a weapon,
as the vaccine for smallpox sometimes had severe side-effects, it is no
longer used routinely in any country. Thus, much of the modern human
population has almost no established resistance to smallpox and would be
vulnerable to the virus.
_Virus_PHIL_1878_lores.jpg)
