Viruses
Introduction
Viruses are everywhere, in all ecosystems, and all cellular organisms are infected by them.
Some viruses generate serious diseases in humans, including Zika fever, influenza, and AIDS.
Some viruses fill essential niches, particularly in marine ecosystems and the human gut, where they cycle nutrients and improve health.
In research, viruses serve as tools and model systems in molecular biology and genetic engineering, including vectors for gene cloning, delivery devices for gene therapy, and the CRISPR antiviral defense system for gene editing.
6.1 Viruses in Ecosystems
A virus is an acellular particle that infects a host cell and directs it to produce progeny particles (more viruses).
The virus particle, or virion, generally consists of a viral genome (DNA or RNA) contained within a protein capsid.
Virus Infect Specific Hosts
Viruses typically infect specific hosts and a range of cells within these hosts.
Bacteriophages (or phages) are viruses that infect bacteria. Their replication is observed as a plaque of lysed cells on a lawn of bacteria growing in a Petri dish.
An example of a human virus is the measles virus.
An example of a plant virus is the tobacco mosaic virus.
Are Viruses Alive?
Historically, viruses were defined as non living particles.
Ivanovsky and Beijerinck proposed the existence of viruses when they discovered infectious agents that passed through filters with pores too small for cells to pass.
Stanley earned the 1946 Nobel Prize in Chemistry for crystalizing viruses and thus reinforcing them as nonliving.
Today, we recognize that viruses must enter into and infect a host cell to create progeny virions. Although some viruses possess genes for transfer RNAs and some (but not all) ribosomal components, no virus can synthesize a protein.
Integrated Viral Genomes
Some viruses do more than replicate within a cell; they integrate their genomes into that of the host.
In effect, such viruses become a part of the host organism.
A bacteriophage that integrates its genome into its bacterial host’s genome is called a prophage.
Within a human cell, an integrated viral genome is called a provirus.
A permanently integrated provirus transmitted from one human to another via the germ line is called an endogenous virus.
Dynamic Nature of Viruses
We now know that a virus may interconvert among three very different forms:
Virion, or virus particle – An inert particle that does not carry out any metabolism or energy conversion.
Intracellular replication complex – Within a host cell, the viral gene products direct the cell’s enzymes to assemble progeny virions at “virus factories” called replication complexes.
Viral genome integrated within host DNA – Some types of viral genomes may integrate within a host chromosome as a prophage or provirus. This may be a permanent condition.
The inert nature of the virion particle, which lacks metabolism and the ability to reproduce independent of its host, argues that viruses are nonliving.
The virion assembly process argues that viruses are living organisms.
The genomes of large viruses show evidence of reductive evolution (evolutionary loss of genes) from a cellular origin, whereas genomes of small RNA viruses indicate they may have been built up from mere parts of a cell.
These claims are debated regularly by virologists.
Ecological Role of Viruses
While viruses are the tiniest of biological entities, they play starring roles in ecosystems.
The sum of viral populations in an ecosystem is called the virome.
On a global scale, viruses are critical players in carbon balance.
For example, in marine ecosystems viruses cycle organic food molecules between multiple species.
Marine bacteriophages and eukaryotic viruses infect numerous aquatic hosts. When the host organisms die, their organic matter provides both swimmers and bottom dwellers with carbon and nitrogen for growth.
A. Bacteriophages and eukaryotic viruses convert marine organisms into dissolved organic molecules and particles. The organic particles settle to the benthos (marine sediment), where they provide carbon and nitrogen for corals and other marine life.
B. Rebecca Vega Thurber studies the virome of coral reefs.
Acute viruses rapidly kill their hosts and thus act as predators or parasites to limit host population density.
Host death recycles nutrients back to the community.
Surviving hosts have undergone selection for resistance.
In a host community, the overall effect of the acute virome is to increase host diversity.
Persistent viruses remain in hosts where they may evolve traits that confer positive benefits in a virus-host mutualism
Viral Disease
The range of host species infected by a given virus is known as its host range.
Some viruses can infect only a single species; for example, HIV infects only humans.
By contrast, West Nile virus, transmitted by mosquitoes, infects many species of birds and mammals.
Chronic viral infections are more common than acute disease.
In contrast to our vast arsenal of antibiotics (effective against bacteria), the number of antiviral drugs remains small.
Viral Structure
The structure of a virion keeps the viral genome intact, and it enables infection of the appropriate host cell.
A virion possesses a genome of either DNA or RNA. The precise configuration of the genome varies with virus type.
The protein capsid packages the viral genome and delivers it into the host cell.
Different viruses make different types of capsids.
Capsid types are either symmetrical or asymmetrical.
Symmetrical Virions
Icosahedral viruses
Are polyhedral with 20 identical triangular faces
Have a structure that exhibits rotational symmetry
In some icosahedral viruses, the capsid is enclosed in an envelope that is derived from the cell membrane of the host organism.
The envelope contains glycoprotein spikes, which are encoded by the virus.
Some viruses contain tegument proteins between the envelope and the capsid.
Filamentous viruses
The capsid consists of a long tube of protein that possesses helical symmetry. The capsid protein monomers surround the genome, which usually winds helically within the tube.
Vary in length, depending on genome size
Include bacteriophages as well as animal viruses
Asymmetrical Virions
Influenza viruses are RNA viruses that lack capsid symmetry.
Instead, the RNA segments are coated with nucleocapsid proteins.
Poxviruses are large asymmetrical viruses with genomes that contain over 200 genes.
Their genome is surrounded by several layers.
A core envelope studded with spike proteins
An outer membrane
They also contain a large number of accessory proteins.
These are needed early in viral infection.
Tailed Viruses
Tailed viruses have complex multipart structures that often include elaborate delivery devices.
For example, the bacteriophage T4 has an icosahedral “head” that is attached to a helical “neck,” baseplate, and tail fibers.
Viroids and Prions
Viroids are RNA molecules that infect plants.
They have no protein capsid.
They are replicated by host RNA polymerase.
Some have catalytic ability
Prions are infectious proteins.
They have no nucleic acid component.
They have an abnormal structure that alters the conformation of other normal proteins.
6.3 Viral Genomes and Classification
Viral genomes can be:
DNA or RNA
Single- or double-stranded (ss or ds)
Linear, circular, or segmented
The form of the genome has key consequences for the mode of infection, and for the course of a viral disease.
Viral genomes are used as the basis of virus classification.
Viral Genomes: Small or Large
Small viruses commonly have a small genome, encoding fewer than ten genes.
The genes may actually overlap in sequence.
Many small viral genomes consist of RNA.
The “giant viruses” have genomes of double-stranded DNA comprising 300–2,500 genes.
The mimivirus, which infects amoebas, is as large as some bacteria.
It can actually become infected by smaller viruses called virophages.
A surprising source of giant viruses is in the frozen environments of the Arctic and Antarctic regions.
The Siberian tundra reveals even more remarkable viruses.
Pithovirus
Mollivirus sibericum
Contains parts of a ribosome
Giant viruses have genomes that specify a surprisingly large number of enzymes with housekeeping cell functions.
Such large, cell-like genomes suggest the likelihood that a virus evolved from a parasitic cell.
Baltimore Virus Classification
In 1971, David Baltimore proposed that the classes of viruses be distinguished by two main criteria.
Genome composition (RNA or DNA)
The route used to express messenger RNA (mRNA)
Baltimore shared the 1975 Nobel Prize in Physiology or Medicine for discovering how tumor viruses cause cancer.
So far, the genome composition and mechanisms of replication and mRNA expression define seven fundamental groups of viruses:
Group I: Double-stranded DNA viruses
Group II: Single-stranded DNA viruses
Group III: Double-stranded RNA viruses
Group IV: (+) sense single-stranded RNA viruses
Group V: (–) sense single-stranded RNA viruses
Group VI: Retroviruses (RNA reverse-transcribing viruses)
Group VII: Pararetroviruses (DNA reverse-transcribing viruses)
Molecular Evolution of Viruses
The relatedness of different herpes viruses that evolved from a common ancestor can be measured by comparing
their genome sequences.Comparison is based on orthologs, genes of common ancestry in two genomes that share the same function
Proteomic classification is useful for viruses because their small genomes encode few proteins.
Statistical analysis reveals common descent of viruses with shared infected hosts.
6.4 Bacteriophages: The Gut Biome
Viruses display a remarkable diversity of ways to replicate within a host cell.
Here, we discuss the key modes of bacteriophage replication, and their consequences for host cells.
We focus on the best-known bacteriophages, those of the mammalian intestinal community.
Gut bacteriophages, or “coliphages,” are part of a microbial community that modulates human digestion, the immune system, and mental health.
Bacteriophage Infection
To commence an infection cycle, bacteriophages need to contact and attach to the surface of an appropriate host cell.
Contact and attachment are mediated by cell-surface receptors, proteins on the host cell surface that are specific to the host and that bind to a specific viral component.
Cell-surface receptors are proteins with important functions for the host cell that have been co-opted by the virus.
Host bacteria can evolve resistance to phage attachment by mutating the amino acid sequences of its surface receptors.
Most bacteriophages (phages) deliver only their genome into a cell through the cell envelope.
The phage capsid (now termed a “ghost”) remains outside, attached to the cell surface
Bacteriophages exhibit two different types of replication cycles:
Lytic cycle
Lysogenic cycle
The “decision” of which replication cycle to utilize is dictated by environmental cues that either activate or repress transcription of genes for virus replication.
In general, events that threaten host cell survival trigger a lytic burst.
The lytic replication cycle requires these steps:
Host recognition and attachment
Genome entry
Assembly of phages
Exit and transmission
In a lytic cycle, when a phage particle delivers its genome into a cell, it immediately reproduces as many progeny phage particles as possible.
A temperate phage, such as phage lambda, can infect and lyse cells like a virulent phage, but it also has the unique ability to integrate its genome as a prophage.
The phage is said to “lysogenized” the host, leading to a state called lysogeny.
Bacteriophage is not replicating.
The phage can reactivate to become lytic.
A slow-release replication cycle differs from lysis and lysogeny in that phage particles reproduce without destroying the host cell.
Filamentous phages can extrude individual progeny through the cell envelope.
Host cells grow slowly but do not die.
Integrated Virus as Host Cell Parts
Many prophages and endogenous viruses function as part of their host cell.
Bacterial Defense
Bacteria have evolved several forms of defense against bacteriophage infection:
Genetic resistance
Altered receptor proteins
Restriction endonucleases
Cleave viral DNA lacking methylation
CRISPR integration of phage DNA sequences
Clustered regularly interspaced short palindromic repeats
A bacterial immune system
Gut Bacterial Phage Community
The best-understood phage community is that of the gut virome.
Research yields intriguing evidence for phage effects that are positive:
Phages may limit the bacterial numbers to levels that the human immune system can tolerate.
Phage particles may modulate immune system activity by suppressing T-cell activation and tumor formation.
Phages may attack biofilms.
6.5 Animal and Plant Viruses
Animal and plant viruses solve problems similar to those faced by bacteriophages:
Host attachment, genome entry and gene expression, virion assembly, and virion release
However, eukaryotic cells have a more complex structure than prokaryotic cells.
Therefore, animal and plant viruses have greater complexity and diversity of viral replication cycles than we see in bacteriophages.
Tissue Tropism
Animal viruses bind specific receptor proteins on their host cell.
Receptors determine the viral tropism, or ability to infect a particular tissue type within a host.
For example, Ebola virus exhibits broad tropism by infecting many kinds of host tissues, whereas papillomavirus shows tropism for only epithelial tissues.
Most animal viruses enter their host cells as virions.
Internalized virions undergo uncoating, a process that refers to the release of the genome from its capsid.
Animal Virus Replication Cycles
The primary factor that dictates the details of a replication cycle of an animal virus is the form of its genome.
DNA viruses
Utilize some or all of the host replication machinery
RNA viruses
Use an RNA-dependent RNA polymerase to transcribe their mRNA
Retroviruses
Use a reverse transcriptase to copy their genomic sequence into DNA for insertion in the host chromosome
No virus is capable of synthesizing proteins and requires the host cell translational machinery.
Translation occurs in the cytoplasm.
Assembly of new virions
Capsid and genome
May occur in the cytoplasm or nucleus
Envelope proteins are inserted into a membrane (either the cell membrane or an organelle membrane).
Release of progeny viruses from host cell
Lysis of cell
Budding
Virus passes through the membrane.
Membrane lipids surround capsid to form an envelope.
All enveloped viruses bud from a membrane (either the cell membrane or an organelle membrane).
The replication cycle of human papillomavirus (HPV) is representative of DNA viruses.
HPV is a double-stranded DNA virus that causes warts and, in some cases, cancer.
The replication cycle of human picornaviruses is representative of (+) sense single-stranded RNA viruses.
Picornaviruses include the RNA viruses that cause poliomyelitis and the common cold.
The replication cycle of human immunodeficiency virus (HIV) is representative of retroviruses.
HIV is an RNA virus that uses reverse transcriptase to copy its RNA genome into double-stranded DNA.
HIV causes the syndrome known as AIDS.
Many human cancers are caused by oncogenic viruses such as the Epstein-Barr virus (which causes lymphomas) and hepatitis C virus (which causes liver cancer).
Oncogenic viruses transform the host cell to proliferate abnormally and form tumors.
Mechanisms of oncogenesis include:
Expression of a virally-encoded oncogene
Integration of the viral genome into a host cell chromosome
Expression of viral proteins that interfere with host cell-cycle regulation
Emergence of Viral Pathogens
Certain human-infecting viruses are well known to persist in the wild, such as rabies virus and West Nile virus.
Their persistence requires a broad host range.
How do new viruses emerge to cause disease in humans?
As a result of human consumption of wildlife
For example, SARS coronavirus
As variants of endemic milder pathogens
For example, the avian influenza strain H7N9
6.6 Culturing Viruses
Culturing viruses requires growth in host cells.
Plant and animal viruses are especially difficult to culture because they show tropism for particular tissues.
In the laboratory, viruses are cultured either in batch culture (in liquid) or plate culture (on a solid medium with agar).
Batch culture of viruses generates a step curve.
Plate culture of viruses generates plaques, or clearing zones, in a lawn of cells.
Batch Culture
This figure shows a one-step growth curve for a bacteriophage.
The burst size, or number of viruses produced per host cell, is characteristic of the bacteriophage.
After initial infection of a liquid culture of host cells, the titer of virus drops to near zero as all virions attach to the host. During the eclipse period, progeny phages are being assembled within the cell. As cells lyse (the rise period), virions are released until they reach the final plateau.