Brody, Ph. Featured Content. Introduction to Genomics. Polygenic Risk Scores. The replication cycle of all viruses involves three key phases: initiation of infection, genome replication and expression, and finally, egress or release of mature virions from the infected cell. From the perspective of the virus, the purpose of viral replication is to allow production and survival of its kind. By generating abundant copies of its genome and packaging these copies into virions, the virus is able to continue infecting new hosts.
All viruses must therefore express their genes as functional mRNAs early in infection in order to direct the cellular translational machinery to synthesize viral proteins. The pathways leading from genome to message vary among different viruses Fig. Viral genomes provide examples of almost every structural variation imaginable. These categories are further divided on the basis of distinct modes of transcription.
Summary of replication and transcription modes of different classes of viruses. Both pathways require enzymatic activities that are not usually found in uninfected host cells and as a result, these viruses code for the requisite enzymes, which are either expressed early in infection or they are copackaged with the viral genome during the assembly of virions in preparation for the next round of infection. The virus genome integrates into the host genome and can be passed from parent to offspring should integration occur in germline cells.
The integrated virus genome, referred to as a provirus, is transcribed as a cellular gene some may require splicing and translated by the cellular synthesis machinery on export to the cytoplasm. It should be noted that in all these examples, the balance between the processes of transcription and genome replication must be properly maintained to allow efficient viral proliferation.
It appears that the transition occurs by the 1 action of trans -acting proteins that are either absent, or at low levels in virions, but which accumulate over the course of infection; 2 regulatory role of promoter RNA secondary structure along with the action of specific viral e. Many use host enzymes for these processes, while some larger viruses code for their own enzymes.
Cellular splicing machinery typically generates mature viral mRNAs. The switch from transcription to replication, that is the switch from antigenome production to genomic nucleic acid for packaging, is highly regulated, and unlike RNA viruses, there is the strict demarcation with respect to timing of genomic DNA replication.
Early genes, which code for catalytic e. Late genes that code for the structural components of the capsid and envelope are transcribed only after viral DNA replication.
Large DNA viruses, for example, members of Herpesviridae, Adenoviridae , and Poxviridae , and giant viruses, are among those viruses that encode most of their own proteins for replication. Proteins encoded by these viruses are those involved in recognition of the origin of replication, DNA-binding proteins, helicases and primases, DNA polymerase and accessory proteins, exonucleases, thymidine kinase, and dUTPase.
Small DNA viruses, for example, Papillomaviridae, Polyomaviridae , and Parvoviridae , do not encode the entire repertoire of proteins required for viral replication because of their limited genome size. They do, however, encode proteins that usurp and control cellular activities.
Viruses that do not replicate in the nucleus and do not have access to host polymerases, typically encode their own polymerases for replication. RT is virus-encoded as the host cell does not require this enzyme for its nuclear metabolism.
Although high fidelity of virus genome replication is crucial for the long-term survival of viruses, some polymerases are less faithful than others when incorporating the correct nucleotide during replication. The rate by which mutations occur is universally determined as the number of nucleotide substitutions per base per generation. DNA viruses experience low mutation rates. This is because of the proofreading ability of the polymerase.
With the exception of nidoviruses, the replicative enzymes of RNA viruses RdRps lack proofreading ability and these viruses exhibit the highest mutation rates.
Not all mutations generated will persist in a virus population, however. Mutations may be neutral or silent because of genetic code redundancy and those that interfere with viral replicative mechanisms are eliminated from the viral population. Mutations that do not affect essential viral functions may persist and eventually become fixed within the viral population see Chapter 4: Origins and Evolution of Viruses.
Unlike cellular DNA and RNA polymerases, which require oligonucleotides to initiate nucleic acid synthesis, viral polymerases initiate genome replication using a variety of mechanisms, that presumably reflect their adaptation to the host cell. Nucleic acid synthesis by polymerases is divided into three phases: initiation, elongation, and termination. Both virus genome transcription and mRNA synthesis occur in three stages.
Two different start sites are used in the synthesis of mRNA and viral genome RNA in a primer-independent de novo , or a primer-dependent mechanism. Structures in the polymerase or conformational changes apparently contribute to the process. Another capping mechanism used by negative-sense RNA viruses e. Poliovirus RdRp, for example, adds about nucleotides and so in a single-binding event it can synthesize the entire genome.
Termination leads to the release of the newly synthesized RNA strand and the dissociation of the polymerase from the template.
Transcription termination involves secondary structure mechanisms or in eukaryotic cells, RNA signals direct polyadenylation and termination. Unlike polyadenylation of host mRNAs, which is carried out by a specific poly A polymerase, polyadenylation of viral mRNAs is catalyzed by the viral polymerase.
In nonsegmented negative RNA viruses, obligatory sequential transcription dictates that termination of each upstream gene is required for initiation of downstream genes. Therefore, termination is a means of regulating expression of individual genes within the framework of a single transcriptional promoter. As will be seen, the mechanisms are dictated by the nature and structure of the viral genomes.
The DNA polymerase involved must exhibit a high level of processivity and strand displacement characteristics. A duplex or r eplicative f orm RF results. Here, multiple cycles of continuous copying of a circular template, followed by discontinuous DNA synthesis on the displaced strand template produces linear dsDNA molecules containing multiple copies of the genome concatemers. Rolling circle genome replication. Concatemeric DNA molecules are synthesized from a circular template by a rolling circle mechanism in which nicking of one strand allows the other to be copied continuously multiple times.
Discontinuous DNA synthesis on the displaced strand template produces linear dsDNA containing multiple copies of the genome. That is, the dsDNA molecules generated consist of head-to-tail linked genomes.
They are eventually cleaved at precise locations to release unit length genomes. Non-circular genomes may also replicate using an RC-like mechanism, that is, a variation of RCR named rolling-hairpin replication.
ITRs are seen as terminal hairpin structures. These ITR regions interact with the viral-encoded Rep protein at specific binding sites to initiate replication using the host replication machinery. Rep creates a nick between the hairpin and coding sequences. Refolding of the termini generates the same secondary structures present in the template DNA. The end result is a fully replicated viral genome with the same secondary structures. This is the classical mode of replication used by eukaryotes and most nuclear dsDNA viruses, including the majority of phages.
The step-wise assembly of replication initiation complexes at these ori sites then occurs followed by recruitment of topoisomerases that unwind dsDNA at each ori , and prevents supercoiling and torsional stress of the partially unwound template DNA. A replication fork or bubble is produced. Copying of the lagging strand requires discontinuous DNA synthesis that results in production of short DNA Okazaki fragments, which must then be ligated after the primers are removed by RNase H degradation.
Pararetroviruses e. Replication involves two phases; transcription of the pgRNA from virus DNA in the nucleus followed by reverse transcription in the cytoplasm.
In contrast to retroviruses, virus DNA remains episomal and does not integrate into the host genome. Covalently closed virus dsDNA serves as a template for host polymerase transcription and the generation of viral pgRNA. Upon transportation to the cytoplasm, capped and polyadenylated pgRNA is translated to viral proteins including the RT and is also used as template for subsequent reverse transcription catalyzed by virus RT. The resulting dsDNA is either packaged into a new virion or targeted to the nucleus for another round of transcription.
This mechanism pertains to all members of the family Retroviridae. The process takes place in the cytoplasm, after viral entry. Only a small stretch of polypurines is resistant to degradation and this serves as a primer to initiate the synthesis of the cDNA. Integration is a key event in the replicative process of all retroviruses.
In some retroviruses, nuclear localization signals facilitate migration to the nucleus. Depending upon the retrovirus, preintegration complexes either enter the nuclei of nondividing cells through the n uclear p ore c omplex NPC e.
Moloney murine sarcoma virus, Murine leukemia virus ]. Once inside the nucleus and after association with host chromosomes, viral IN catalyzes insertion of viral sequences into the host DNA Fig. Integration of viral DNA e. A viral polyprotein is typically produced, which encodes the proteins required for replication. The replication process results in the formation of a dsRNA intermediate that is detected by the immune system. Depending on the virus, sgRNAs may be generated during internal initiation on a minus-strand RNA template and require an internal promoter or there is the generation of a prematurely terminated minus-strand RNA that is used as template to make the sgRNAs.
The resulting chimeric sg minus-strand RNA can in turn function as a template for the production of subgenomic positive-strand RNAs.
Translation of this mRNA generates proteins required for replication and viral encapsidation. As such, many dsRNA viruses undergo replication within their icosahedral capsids. The replicating RNA polymerases are located within the capsid and produce mRNA strands that are extruded from the particle. Replication occurs in the cytoplasm. The viral RdRP complex is assumed to be the same for both replication and transcription and can switch off functions as required.
Of note, two genome subgroups can be distinguished in this group: nonsegmented and segmented. Viruses with segmented genomes replicate in the nucleus, and the RdRp produces one monocistronic mRNA strand from each genome segment. Enveloped viruses, such as influenza A virus, are typically released from the host cell by budding. It is this process that results in the acquisition of the viral phospholipid envelope.
These types of virus do not usually kill the infected cell and are termed cytopathic viruses. Residual viral proteins that remain within the cytoplasm of the host cell can be processed and presented at the cell surface on MHC class-I molecules, where they are recognised by T cells. Register Log in. Virus replication Download Virus replication. Download Virus replication. Bitesize category Pathogens and Disease. Viruses versus vaccines: the economics of herd immunity.
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