Which virus replicates in the cytoplasm

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Pathogenic Yersiniae. Immune responses to viruses. Intestinal nematode parasites: mechanisms of resistance. Immune responses to fungal pathogens. Immune responses to bacteria. Chlamydia Trachomatis. Candida albicans. Aspergillus fumigatus. Nevertheless, strong spatial and functional links between genome replication and virion assembly exist for these viruses also.

Beyond close coordination of viral genome replication and virion assembly, for at least some positive-strand RNA viruses, the membrane-associated RNA replication complexes themselves show general parallels with virion assembly and structure and particular parallels with the replicative cores of dsRNA virus and reverse-transcribing virus virions Ahlquist, Figure 5.

A—C Schematic representations of A the cytoplasmic replicative core of a dsRNA virus, B the invaginated, ER membrane-associated RNA replication complex of brome mosaic virus, and C a retrovirus virion in the midst of budding from the plasma membrane into the extracellular space. Red arrows represent the positive-strand i. Additional parallels exist with retrovirus virion assembly Bieniasz, , Waheed and Freed, Figure 5 C.

When so arrested, retroviruses remain attached to the plasma membrane by neck-like membrane stalks that are strikingly similar to the necked membrane connections that the spherular RNA replication vesicles of FHV, BMV, alphaviruses, and many other positive-strand RNA viruses maintain to the cytoplasm. Moreover, multiple functions of the major retrovirus capsid protein Gag in virion assembly parallel roles of BMV 1a in replication complex spherule formation Figures 5 B and 5C.

Many, though not all, of these similarities are shared by nodavirus protein A Dye et al. Particularly striking are the parallels between the above positive-strand RNA virus RNA replication complexes and assembling virions of the foamy retroviruses Figure 5 C. Foamy virus replication is distinct from that of orthoretroviruses such as HIV in several ways Delelis et al. For example, whereas orthoretroviruses release virions carrying an RNA genome and delay reverse transcription until after entering a newly infected cell, newly assembled foamy retrovirus virions reverse transcribe their encapsidated RNA prior to virion release Moebes et al.

Thus, foamy retrovirus virions are actively involved in genome replication within the same cell in which they assemble, further paralleling positive-strand RNA virus replication complexes such as the BMV and FHV spherules described above.

Another distinction is that, whereas orthoretoroviruses translate their reverse transcriptase Pol as a fusion protein with Gag, foamy viruses translate Gag and Pol as separate proteins from independent mRNAs. From an evolutionary perspective, the similarities of positive-strand RNA virus replication complexes with the replicative cores of dsRNA and retrovirus virions suggest that all of these viruses may have diverged from a common precursor that also used a viral protein shell to organize and sequester the replication of an mRNA-sense genomic RNA template.

In subsequent evolution, these viruses would then have diverged with regard to which replication cycle intermediate to export in infectious virions: for retroviruses and dsRNA viruses, the RNA replication complex before and after negative-strand synthesis, respectively, and for positive-strand RNA viruses, the mRNA-sense genomic RNA before assembly into the replication complex Ahlquist, , Schwartz et al.

Building novel intracellular structures to support viral replication is an integral part of the life cycle of many, if not all, viruses. Nevertheless, many of these DNA viruses also assemble cytoplasmic factory-like structures to complete their replication cycles and assemble progeny virus, often in close vicinity to ER membranes where viral proteins are produced Novoa et al. Moreover, unusually among large double-strand DNA viruses, poxviruses such as vaccinia virus carry out their replication entirely in the cytoplasm in membrane-bound viral complexes Schramm and Locker, Upon infection, vaccinia virus cores are released and accumulate in close proximity to ER membranes.

The incoming genomic DNA leaves the core and preferentially associates with the cytosolic side of the ER membranes Mallardo et al. DNA replication is initiated in distinct cytoplasmic sites, often referred to as viral factories, formed through gradual envelopment by rough ER membranes. Occasional small gaps in the surrounding membranes have been observed, presumably allowing the exchange of molecules between the interior DNA replication compartments and the cytoplasm Tolonen et al.

In further analogy with positive-strand RNA and dsRNA viruses, poxvirus genome replication, transcription and translation, and virus assembly are all coordinated within or associated with the DNA replication factories. Although early viral mRNAs are transcribed in the original viral cores Mallardo et al. Late in infection, the ER around the viral factories disassembles, coinciding with a dramatic decrease in DNA synthesis and the formation of virion precursors Tolonen et al.

The studies reviewed above have substantially enhanced the understanding of the replication structures and pathways of many important viruses and have revealed some common principles. Simultaneously, many fundamental questions remain or have become evident from this work. Among these unresolved questions are the detailed molecular mechanisms by which specific viruses target their replication factors and their RNAs to particular membranes or other intracellular sites to assemble replication complexes or factories, as well as how different viruses orchestrate the varied and often complex membrane rearrangements associated with their replication processes.

Related issues include the specific advantages or adaptations associated with the use by diverse viruses of different intracellular sites for similar replication purposes. Different positive-strand RNA viruses, e. However, the implications of such choices for replicative efficiency, virus-host interactions, and pathology remain poorly understood.

Recent findings on how picornaviruses, flaviviruses and coronaviruses manipulate components of the secretory pathway and related pathways to create novel membrane environments with specific lipid enrichments and other replication-supportive characteristics are examples of these essential research directions Belov et al.

Such efforts will be critical to identify and understand the roles of cellular factors and molecular pathways in efficient viral replication. A second class of challenges and opportunities is associated with using growing knowledge in these areas to improve virus control or beneficial uses of viruses.

For virus control, growing recognition of the intimate coordination of many successive virus replication steps with each other and with cellular pathways offers many additional points at which to disrupt infection. In this regard, one important area will be further defining the roles and interactions of viral replication compartments as barriers to host defenses, including host systems for detecting viruses through dsRNA, etc. Though the emerging complexities exceed the expectations of earlier stages of investigation, such questions offer challenging but satisfying directions and a fulfilling future for these important areas in the cell biology of virus replication.

We thank members of our laboratory, Eric Snijder, Marjolein Kikkert, Ellie Ehrenfeld, and many others for valuable discussions on the areas of this review. National Center for Biotechnology Information , U. Cell Host Microbe. Published online Jul Johan A.

Author information Copyright and License information Disclaimer. Paul Ahlquist: ude. All rights reserved. Elsevier hereby grants permission to make all its COVIDrelated research that is available on the COVID resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source.

This article has been cited by other articles in PMC. Abstract Many viruses that replicate in the cytoplasm compartmentalize their genome replication and transcription in organelle-like structures that enhance replication efficiency and protection from host defenses. Main Text Introduction Whereas eukaryotic cells sequester and organize their genome replication and transcription in the nucleus, many RNA and some DNA viruses carry out viral genome replication and transcription in the cytoplasm.

Picornaviruses Picornaviruses are a large family of human and animal viruses whose best-studied member is poliovirus PV Racaniello, Open in a separate window. Figure 1. Nodaviruses Additional support for a protein shell-supported replication complex model came from similar observations for the replication complex of Flock House virus FHV , the best-studied member of the animal nodaviruses Venter and Schneemann, Figure 2.

Coronaviruses Whereas BMV and FHV present examples of RNA replication complexes in simple vesicular membrane invaginations, members of the coronavirus and arterivirus families within the order Nidovirales induce more complicated mixtures of convoluted membrane rearrangements and large double-membrane vesicles Gosert et al. Figure 3. Flaviviruses Similarly complex replication-associated membrane structures are induced by the Flaviviridae , which include clinically important members such as hepatitis C virus HCV , yellow fever virus and Dengue virus DENV.

Figure 4. Coordination of the Viral Replication Cycle Many viruses coordinate their genome replication with subsequent steps of producing progeny virions. Parallels with Double-Strand RNA Virus and Retrovirus Virions Beyond close coordination of viral genome replication and virion assembly, for at least some positive-strand RNA viruses, the membrane-associated RNA replication complexes themselves show general parallels with virion assembly and structure and particular parallels with the replicative cores of dsRNA virus and reverse-transcribing virus virions Ahlquist, Figure 5.

Figure 5. Late gene products primarily consist of structural proteins needed for progeny virion assembly, as well as those enzymes destined for incorporation into progeny virions, and used for early gene expression during the next round of infection. Assembly of the MV involves more than 80 viral gene products. In addition, during transit through the cytoplasm, a subset of progeny MVs acquires two additional membrane bilayers, one of which is lost during exocytosis of the particle, to yield the less abundant enveloped virion EV.

Thus, an EV is essentially an MV with an additional membrane in which at least six unique proteins are associated. EVs are antigenically distinct from MVs and are important for efficient virus dissemination in the infected host and protection against immune defenses. In contrast, MVs are released upon cell lysis and may be important for animal-to-animal transmission. Girl infected with smallpox. Bangladesh, This is a major distinguishing characteristic of smallpox.

Adenoviruses are non-enveloped, icosahedral DNA viruses which cause upper respiratory infections, primarily in children. Adenoviruses are medium-sized 90— nm , non-enveloped, icosahedral viruses composed of a nucleocapsid and a linear, double-stranded DNA dsDNA genome.

Viruses of the family Adenoviridae infect vertebrates, including humans. Among human-tropic viruses classification can be complex; there are 57 accepted human adenovirus types HAdV-1 to 57 in seven species Human adenovirus A to G. In addition to human viruses, Adenoviridae can be divided into five genera: Mastadenovirus, Aviadenovirus, Atadenovirus, Siadenovirus, and Ichtadenovirus.

Structurally, adenoviruses represent the largest non-enveloped viruses. Entry of adenoviruses into the host cell involves two sets of interactions between the virus and the host cell.

First, entry into the host cell is initiated by the knob domain of the fiber protein binding to a host cell receptor, either CD46 for the group B human adenovirus serotypes, or the coxsackievirus adenovirus receptor for all other serotypes. Following internalization, the endosome acidifies, which alters virus topology, causing capsid components to disassociate. These changes, as well as the toxic nature of the pentons, result in the release of the virion into the cytoplasm.

With the help of cellular microtubules, the virus is transported to the nuclear pore complex, where viral gene expression can occur. The adenovirus life cycle is separated by the DNA replication process into two phases: an early and a late phase. The early genes are responsible for expressing mainly non-structural, regulatory proteins. The goal of these proteins is threefold: to alter the expression of host proteins necessary for DNA synthesis; to activate other viral genes such as the virus-encoded DNA polymerase ; and to avoid premature death of the infected cell by the host-immune defenses blockage of apoptosis, blockage of interferon activity, and blockage of MHC class I translocation and expression.

The late phase of the adenovirus lifecycle is focused on producing sufficient quantities of structural protein to pack all the genetic material produced by DNA replication.

Once the viral components have successfully been replicated, the virus is assembled into its protein shells and released from the cell as a result of virally induced cell lysis. Adenoviruses are unusually stable to chemical or physical agents and adverse pH conditions, allowing for prolonged survival outside of the body and water. Adenoviruses are spread primarily via respiratory droplets; however, they can also be spread by fecal routes. Humans infected with adenoviruses display a wide range of responses, from no symptoms at all to the severe infections typical of Adenovirus serotype In the past, U.

Although the vaccine is no longer manufactured for civilians, military personnel can receive the vaccine as of Viral transmission occurs primarily through expectorate, but can also be transmitted via contact with infected objects.

Most adenovirus infections affect the upper respiratory tract. These often show up as conjunctivitis, tonsillitis, ear infection, or croup. Adenoviruses, types 40 and 41 can also cause gastroenteritis. A combination of conjunctivitis and tonsillitis is particularly common with adenovirus infections.

Some children especially small ones can develop adenovirus bronchiolitis or pneumonia, both of which can be severe. Adenovirus is used as a vehicle to administer targeted therapy in the form of recombinant DNA or protein.

Specific modifications on fiber proteins are used to target Adenovirus to certain cell types; a major effort is made to limit hepatotoxicity and prevent multiple organ failure. A well-studied family of this class of viruses includes the retroviruses. Instead of using the RNA for templates of proteins, they use DNA to create the templates, which is spliced into the host genome using integrase.

A well-studied example of this includes HIV. A special variant of retroviruses are endogenous retroviruses, which are integrated into the genome of the host and inherited across generations. This then serves as a means of delivery of that genome into cells it targets as an obligate parasite, and constitutes the infection. It is difficult to detect the virus until it has infected the host. Retroviruses are proving to be valuable research tools in molecular biology and have been used successfully in gene delivery systems.

Hepadnaviruses are a family of viruses which can cause liver infections in humans and animals. There are two recognized genera:. Hepadnaviruses have very small genomes of partially double-stranded, partially single stranded circular DNA. The genome consists of two uneven strands of DNA.

One has a negative-sense orientation, and the other, shorter, strand has a positive-sense orientation. Hepadnaviruses replicate through an RNA intermediate which they transcribe back into cDNA using reverse transcriptase. The reverse transcriptase becomes covalently linked to a short 3- or 4-nucleotide primer. Most hepadnaviruses will only replicate in specific hosts, and this makes experiments using in vitro methods very difficult.

HBV infection is initiated through viral attachment to an unknown cell surface receptor. The study of animal viruses is important from a veterinary viewpoint. Many animal viruses are also important from a human medical perspective. The emergence of the SARS virus in the human population, coming from an animal source, highlights the importance of animals in bearing infectious agents.

Avian influenza viruses can directly infect humans. In addition research into animal viruses has made an important contribution to our understanding of viruses in general, their replication, molecular biology, evolution, and interaction with the host. Rhabdoviruses are a diverse family of single stranded, negative sense RNA viruses that can successfully utilize a myriad of ecological niches, ranging from plants and insects, to fish and mammals.

This virus family includes pathogens such as rabies virus, vesicular stomatitis virus, and potato yellow dwarf virus that are of tremendous public health, veterinary, and agricultural significance. Due to the relative simplicity of their genomes and morphology, in recent years rhabdoviruses have become powerful model systems for studying molecular virology. This picornavirus is the etiological agent of an acute systemic vesicular disease that affects cattle worldwide, foot-and-mouth disease.

FMDV is a highly variable and transmissible virus. It enters the body through inhalation. Soon after infection, the single stranded positive RNA that constitutes the viral genome is efficiently translated using a cap-independent mechanism driven by the internal ribosome entry site element IRES.

This process occurs concomitantly with the inhibition of cellular protein synthesis, caused by the expression of viral proteases. In depth knowledge of the molecular basis of the viral cycle is needed to control viral pathogenesis and disease spreading. The molecular biology of pestiviruses shares many similarities and peculiarities with the human hepaciviruses. Genome organization and translation strategy are highly similar for the members of both genera.

One hallmark of pestiviruses is their unique strategy to establish persistent infection during pregnancy. Coronavirus CoV genome replication takes place in the cytoplasm in a membrane-protected microenvironment, and starts with the translation of the genome to produce the viral replicase. Vaccines traditionally consist of an attenuated weakened or killed version of the virus, although many vaccines now target specific immunogenic targets unique to a particular pathogen.