Replication of Viruses: An overview
المؤلف:
Stefan Riedel, Jeffery A. Hobden, Steve Miller, Stephen A. Morse, Timothy A. Mietzner, Barbara Detrick, Thomas G. Mitchell, Judy A. Sakanari, Peter Hotez, Rojelio Mejia
المصدر:
Jawetz, Melnick, & Adelberg’s Medical Microbiology
الجزء والصفحة:
28e , p426-430
2025-10-25
60
Viruses multiply only in living cells. The host cell provides the energy and synthetic machinery and the low-molecular-weight precursors for the synthesis of viral proteins and nucleic acids. The viral nucleic acid carries the genetic specificity to code for all of the virus-specific macromolecules in a highly organized fashion.
For a virus to replicate, viral proteins must be synthesized by the host cell protein-synthesizing machinery. Therefore, the virus genome must be able to produce a functional mRNA. Various mechanisms have been identified that allow viral RNAs to compete successfully with cellular mRNAs to produce adequate amounts of viral proteins.
The unique feature of viral multiplication is that soon after interaction with a host cell the infecting virion is disrupted and its measurable infectivity is lost. This phase of the growth cycle is called the eclipse period; its duration varies depending on both the particular virus and the host cell, and it is followed by an interval of rapid accumulation of infectious progeny virus particles. The eclipse period is actually one of intense synthetic activity as the cell is redirected toward fulfilling the needs of the viral parasite. In some cases, as soon as the viral nucleic acid enters the host cell, the cellular metabolism is redirected exclusively toward the synthesis of new virus particles and the cell is destroyed. In other cases, the metabolic processes of the host cell are not altered significantly, although the cell synthesizes viral proteins and nucleic acids, and the cell is not killed.
After the synthesis of viral nucleic acid and viral proteins, the components assemble to form new infectious virions. The yield of infectious virus per cell ranges widely, from modest numbers to more than 100,000 particles. The duration of the virus replication cycle also varies widely, from 6 to 8 hours (picornaviruses) to more than 40 hours (some herpesviruses).
Not all infections lead to new progeny virus. Productive infections occur in permissive cells and result in the production of infectious virus. Abortive infections fail to produce infectious progeny, either because the cell may be nonpermissive and unable to support the expression of all viral genes or because the infecting virus may be defective, lacking some functional viral gene. A latent infection may ensue, with the persistence of viral genomes, the expression of no or a few viral genes, and the survival of the infected cell. The pattern of replication may vary for a given virus, depending on the type of host cell infected.
General Steps in Viral Replication Cycles
A variety of different viral strategies have evolved for accomplishing multiplication in parasitized host cells. Although the details vary from group to group, the general outline of the replication cycles is similar. The growth cycles of a double stranded DNA virus and a positive-sense, single-stranded RNA virus are shown in Figure 1. Details are included in the following chapters devoted to specific virus groups.
Fig1. Example of viral growth cycles. A: The growth cycle of a nonenveloped, double-stranded DNA virus. In this example multiple steps in the replication cycle take place in the nucleus. (1) After penetrating the host cell, viral DNA is uncoated and enters the nucleus. (2) Viral genes are transcribed. (3) The mRNAs are translated in the cytoplasm. Newly synthesized proteins enter the nucleus. (4) Viral DNA is replicated in the nucleus, sometimes with the help of newly synthesized viral replication proteins. (5) Viral DNA and viral structural proteins assemble in the nucleus to produce new progeny virions. (6) On rare occasions, viral DNA may be incorporated into cellular DNA as a side effect of infection. B: The growth cycle of a positive-sense, single-stranded RNA virus. In this example, the replication cycle occurs in the cytoplasm. (1) The virus enters the cell and the viral RNA genome is uncoated. (2) As a positive-sense, single-stranded genome, the RNA is directly translated, producing viral proteins. (3) A negative-sense RNA copy of the positive template is synthesized. (4) It is used to produce many positive-sense copies. (5) The newly synthesized positive-sense RNA molecules are assembled with viral structural proteins to produce new progeny virions. (Reproduced with permission from Talaro KP: Foundations in Microbiology: Basic Principles, 6th ed. McGraw-Hill, 2008. © McGraw-Hill Education.)
A. Attachment, Penetration, and Uncoating
The first step in viral infection is attachment, interaction of a virion with a specific receptor site on the surface of a cell. Receptor molecules differ for different viruses but are generally glycoproteins. In some cases, the virus binds protein sequences (eg, picornaviruses) and in others oligosaccharides (eg, ortho myxoviruses and paramyxoviruses). The presence or absence of receptors plays an important determining role in cell tropism and viral pathogenesis. Not all cells in a susceptible host will express the necessary receptors; for example, poliovirus is able to attach only to cells in the central nervous system and intestinal tract of primates. Each susceptible cell may contain up to 100,000 receptor sites for a given virus.
After binding, the virus particle is taken up inside the cell. This step is referred to as penetration or engulfment. In some systems, this is accomplished by receptor-mediated endocytosis, with uptake of the ingested virus particles within endosomes. There are also examples of direct penetration of virus particles across the plasma membrane. In other cases, there is fusion of the virion envelope with the plasma membrane of the cell. Those systems involve the interaction of a viral fusion protein with a second cellular receptor or coreceptor.
Uncoating occurs concomitantly with or shortly after penetration. Uncoating is the physical separation of the viral nucleic acid from the outer structural components of the virion so that it can function. The genome may be released as free nucleic acid (picornaviruses) or as a nucleocapsid (reoviruses). The nucleocapsids usually contain polymerases. Uncoating may require acidic pH in the endosome. The infectivity of the parental virus is lost at the uncoating stage. Viruses are the only infectious agents for which dissolution of the infecting agent is an obligatory step in the replicative pathway.
B. Expression of Viral Genomes and Synthesis of Viral Components
The synthetic phase of the viral replicative cycle ensues after uncoating of the viral genome. The essential theme in viral replication is that specific mRNAs must be transcribed from the viral nucleic acid for successful expression and duplication of genetic information. After this is accomplished, viruses use cell components to translate the mRNA. Various classes of viruses use different pathways to synthesize the mRNAs depending on the structure of the viral nucleic acid. Table 1 summarizes various pathways of transcription (but not necessarily those of replication) of the nucleic acids of different classes of viruses. Some viruses (eg, rhabdoviruses) carry RNA polymerases to synthesize mRNAs. RNA viruses of this type are called negative-strand (negative sense) viruses because their single-strand RNA genome is complementary to mRNA, which is conventionally designated positive strand (positive sense). The negative-strand viruses must supply their own RNA polymerase because eukaryotic cells lack enzymes able to synthesize mRNA from an RNA template.
Table1. Pathways of Nucleic Acid Transcription for Various Virus Classes
In the course of viral replication, all of the virus-specified macromolecules are synthesized in a highly organized sequence. In some viral infections, notably those involving double-stranded DNA-containing viruses, early viral proteins are synthesized soon after infection and late proteins are made only late in infection after viral DNA synthesis begins. Early genes may or may not be shut off when late products are made. In contrast, most, if not all, of the genetic information of RNA-containing viruses is expressed at the same time. In addition to these temporal controls, quantitative controls also exist because not all viral proteins are made in the same amounts. Viral microRNAs or virus-specific proteins may regulate the extent of transcription of the genome or the translation of viral mRNA.
Small animal viruses and bacteriophages are good models for studies of gene expression. The total nucleotide sequences of many viruses have been elucidated. This led to the discovery of overlapping genes in which some sequences in DNA are used in the synthesis of two different polypeptides, either by the use of two different reading frames or by two mRNA molecules using the same reading frame but different starting points. A viral system (adenovirus) first revealed the mRNA processing phenomenon called “splicing,” whereby the mRNA sequences that code for a given protein are generated from separated sequences in the template, with noncoding intervening sequences spliced out of the transcript. Recently, several DNA viruses (herpesviruses, polyomaviruses) were found to encode microRNAs; these small (~22 nucleotide) RNAs function at a new level of posttranscriptional gene regulation, either by mediating degradation of target mRNAs or by inducing inhibition of translation of those mRNAs.
The widest variation in strategies of gene expression is found among RNA-containing viruses (Table 2). Some virions carry polymerases (orthomyxoviruses, reoviruses); some systems use subgenomic messages, sometimes generated by splicing (orthomyxoviruses, retroviruses); and some viruses synthesize large polyprotein precursors that are processed and cleaved to generate the final gene products (picornaviruses, retroviruses). In HIV, the viral protease is required for this function, enabling it to be targeted by protease inhibitor drugs.
Table2. Comparison of Replication Strategies of Several Important RNA Virus Families
The extent to which virus-specific enzymes are involved in these processes varies from group to group. DNA viruses that replicate in the nucleus generally use host cell DNA and RNA polymerases and processing enzymes. The larger viruses (herpesviruses, poxviruses) are more independent of cellular functions than are the smaller viruses. This is one reason the larger viruses are more susceptible to antiviral chemotherapy —because more virus-specific processes are available as targets for drug action.
The intracellular sites where the different events in viral replication take place vary from group to group (Table 3). A few generalizations are possible. Viral protein is synthesized in the cytoplasm on polyribosomes composed of virus specific mRNA and host cell ribosomes. Many viral proteins undergo modifications (glycosylation, acylation, cleavages, etc). Viral DNA is usually replicated in the nucleus. Viral genomic RNA is generally duplicated in the cell cytoplasm, although there are exceptions.
Table3. Summary of Replication Cycles of Major Virus Families
C. Morphogenesis and Release
Newly synthesized viral genomes and capsid polypeptides assemble together to form progeny viruses. Whereas icosahedral capsids can condense in the absence of nucleic acid, nucleocapsids of viruses with helical symmetry cannot form without viral RNA. In general, nonenveloped viruses accumulate in infected cells, and the cells eventually lyse and release the virus particles.
Enveloped viruses mature by a budding process. Virus specific envelope glycoproteins are inserted into cellular membranes; viral nucleocapsids then bud through the mem brane at these modified sites and in so doing acquire an envelope. Budding frequently occurs at the plasma membrane but may involve other membranes in the cell. Enveloped viruses are not infectious until they have acquired their envelopes. Therefore, infectious progeny virions typically do not accumulate within the infected cell.
Viral maturation is sometimes an inefficient process. Excess amounts of viral components may accumulate and be involved in the formation of inclusion bodies in the cell. As a result of the profound deleterious effects of viral replication, cellular cytopathic effects eventually develop and the cell dies. However, there are instances in which the cell is not damaged by the virus and long-term, persistent infections evolve. Virus-induced mechanisms may regulate apoptosis, a genetically programmed event that makes cells undergo self-destruction. Some virus infections delay early apoptosis, which allows time for the production of high yields of progeny virus. Additionally, some viruses actively induce apoptosis at late stages, which facilitates spread of progeny virus to new cells.
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