Physical Description And Classification, Infection Outcomes, Viral Cancers, VaccinesVirus Replication Cycle
A virus is a parasite that must infect a living cell to reproduce. Although viruses share several features with living organisms, such as the presence of genetic material (DNA or RNA), they are not considered to be alive. Unlike cells, which contain all the structures needed for growth and reproduction, viruses are composed of only an outer coat (capsid), the genome, and, in some cases, a few enzymes. Together these make up the virion, or virus particle. Many illnesses in humans, including AIDS, influenza, Ebola fever, the common cold, and certain cancers, are caused by viruses. Viruses also exist that infect animals, plants, bacteria, and fungi.
For a virus to multiply it must infect a living cell. All viruses employ a common set of steps in their replication cycle. These steps are: attachment, penetration, uncoating, replication, assembly, maturation, and release.
Attachment and Penetration.
A virion surface protein must bind to one or more components of the cell surface, the viral receptors. The presence or absence of receptors generally determines the type of cell in which a virus is able to replicate. This is called viral tropism. For example, the poliovirus receptor is present only on cells of higher primates and then in a limited subset of these, such as intestine and brain cells. While called virus receptors, these are actually used by the cell for its own purposes, but are exploited by the virus for entry.
Entry of the viral genome into the cell can occur by direct penetration of the virion at the cell surface or by a process called endocytosis, which is the engulfment of the particle into a membrane-based vesicle. If the latter, the virus is released when the vesicle is acidified inside the cell. Enveloped viruses may also fuse with the cellular surface membrane, which results in release of the capsid into the cytoplasm. Surface proteins of several viruses contain "fusion peptides," which are capable of interacting with the lipid bilayers of the host cell.
Uncoating and Replication.
After penetration, viral capsid proteins must be removed, at least partly, to express and replicate the viral genome. In the case of most DNA viruses, the capsid is routed to the nucleus prior to uncoating. An example can be seen in the poxviruses, whose large DNA genomes encode most of the proteins needed for DNA replication. These viruses uncoat and replicate completely in the cytoplasm. RNA viruses typically lose the protective envelope and capsid proteins upon penetration into the cytoplasm. In reoviruses, only an outer protein shell is removed and replication takes place inside a structured subviral particle.
Viral genomes must be expressed as mRNAs in order to be translated into structural proteins for the capsids and, in some cases, as replicative proteins for replicating the virus genome. Viral genomes must also provide templates that can be replicated to produce progeny genomes that will be packaged into newly produced virions. Replication details vary among the different types of viruses.
The ss positive-sense DNA of parvoviruses is copied by host DNA polymerase (the enzyme that replicates DNA) in the nucleus into a negative-sense DNA strand. This in turn serves as a template for mRNA and progeny DNA synthesis. The genomes of larger DNA viruses, with the exception of the poxviruses, are also transcribed and replicated in the nucleus by a combination of viral and host enzymes (for example, DNA-dependent RNA polymerses for transcription of mRNAs, DNA-dependent DNA polymerase for genome replication).
Positive-polarity RNA virus genomes can be translated directly, but for effective progeny production additional rounds of RNA replication via a negative-stranded intermediate are required. This is accomplished by a viral transcriptase (RNA-dependent RNA polymerase) and associated cofactors. Single-stranded negative-sense RNA viruses of animals must also carry a viral transcriptase to transcribe functional mRNAs and subsequently produce proteins, since this RNA-to-RNA enzymatic activity is typically lacking in animal cells.
Retroviruses are unique among viruses in that the genome is diploid, meaning that two copies of the positive-polarity RNA genome are in each virus particle. The genomic RNA is not translated into protein, but rather serves as a template for reverse transcription, which produces a double-stranded DNA via a viral reverse transcription enzyme. The DNA is subsequently integrated into the host cell chromosomal DNA. Hepadnaviruses also encode a reverse transcriptase, but replication occurs inside the virus particle producing the particle-associated genomic DNA.
Assembly, Maturation, and Release.
As viral proteins and nucleic acids accumulate in the cell, they begin a process of self-assembly. Viral self-assembly was first demonstrated in a seminal series of experiments in 1955, wherein infectious particles of tobacco mosaic virus spontaneously formed when purified coat protein and genomic RNA were mixed. Likewise, poliovirus capsomers are known to self-assemble to form a procapsid in the cytoplasm. Progeny positive-strand poliovirus RNAs then enter this nascent particle. "Chaperone" proteins (chaparonins) of the cell play a critical role in facilitating the assembly of some viruses. Their normal role is to help fold cellular proteins after synthesis.
The maturation and release stages of the replication cycle may occur simultaneously with the previous step, or may follow in either order. Many viruses assemble their various components into "immature" particles. Further intracellular or extracellular processing is required to produce a mature infectious particle. This may involve cleavage of precursors to the structural proteins, as in the case of retroviruses.
Viruses that are not enveloped usually depend upon disintegration or lysis of the cell for release. Enveloped viruses can be released from the cell by the process of budding. In this process the viral capsid and usually a matrix layer are directed to a modified patch of cellular membrane. Interactions between the matrix proteins and/or envelope proteins drive envelopment. In the case of viruses that bud at the cell surface, such as some togaviruses and retroviruses (including HIV), this also results in release of the virus particles. If the virus acquires a patch of the nuclear membrane (as is the case with herpesviruses), then additional steps involving vesicular transport may be required for the virus to exit the cell.
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