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Viruses
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Viral Replication Complexes
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Viral Replication Complexes

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 53362

Special Issue Editors

Prof. Dr. Núria Verdaguer

E-Mail Website
Guest Editor
CSIC - Instituto de Biologia Molecular de Barcelona (IBMB), Structural Biology Unit, Barcelona, Spain
Interests: structure and dynamics of viral capsids; RNA-dependent RNA polymerases; viral capsids
Dr. Diego Sebastian Ferrero

E-Mail Website
Guest Editor
CSIC - Instituto de Biologia Molecular de Barcelona (IBMB), Structural Biology Unit, Barcelona, Spain
Interests: viral replication; RNA-dependent RNA polymerase

Special Issue Information

Dear Colleagues,

Most emerging and re-emerging human and animal viral diseases are associated with RNA viruses. All these pathogens, with the exception of retroviruses, encode a specialized enzyme, the RNA-dependent RNA polymerase (RdRP), which catalyzes phosphodiester bond formation between ribonucleotides (NTPs) in an RNA template-dependent manner. These enzymes function either as single polypeptides or in complex with other viral or host components to transcribe and replicate the viral RNA genome. RdRP function is critical not only for the virus lifecycle but also for its adaptive potential.

In fact, the low fidelity accompanying viral RNA synthesis results in the high mutation frequencies that allow RNA viruses to rapidly adaptat to changing environments. The RdRP and other components of replication complexes are excellent antiviral targets; indeed, many nucleotide analogs binding the RdRP are proving to be effective antivirals.

In this Special Issue, we seek to highlight recent advances in understanding of the structure and function of viral replication complexes and their role in viral infection and as antiviral targets.

Prof. Dr. Núria Verdaguer
Dr. Diego Sebastian Ferrero
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • viral replication
  • polymerase
  • RNA synthesis
  • fidelity
  • RNA-dependent RNA polymerase
  • replication complexes
  • structure
  • antivirals

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Published Papers (12 papers)

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2 pages, 193 KiB  
Editorial
Special Issue: “Viral Replication Complexes”
by Núria Verdaguer and Diego S. Ferrero
Viruses 2021, 13(10), 1902; https://0-doi-org.brum.beds.ac.uk/10.3390/v13101902 - 23 Sep 2021
Viewed by 1781
Abstract
Viruses are extraordinary biological entities that can only thrive as obligate intracellular parasites, exploiting other living cellular components in order to reproduce [...] Full article
(This article belongs to the Special Issue Viral Replication Complexes)
21 pages, 19127 KiB  
Article
The Picornavirus Precursor 3CD Has Different Conformational Dynamics Compared to 3Cpro and 3Dpol in Functionally Relevant Regions
by Dennis S. Winston and David D. Boehr
Viruses 2021, 13(3), 442; https://0-doi-org.brum.beds.ac.uk/10.3390/v13030442 - 09 Mar 2021
Cited by 9 | Viewed by 2956
Abstract
Viruses have evolved numerous strategies to maximize the use of their limited genetic material, including proteolytic cleavage of polyproteins to yield products with different functions. The poliovirus polyprotein 3CD is involved in important protein-protein, protein-RNA and protein-lipid interactions in viral replication and infection. [...] Read more.
Viruses have evolved numerous strategies to maximize the use of their limited genetic material, including proteolytic cleavage of polyproteins to yield products with different functions. The poliovirus polyprotein 3CD is involved in important protein-protein, protein-RNA and protein-lipid interactions in viral replication and infection. It is a precursor to the 3C protease and 3D RNA-dependent RNA polymerase, but has different protease specificity, is not an active polymerase, and participates in other interactions differently than its processed products. These functional differences are poorly explained by the known X-ray crystal structures. It has been proposed that functional differences might be due to differences in conformational dynamics between 3C, 3D and 3CD. To address this possibility, we conducted nuclear magnetic resonance spectroscopy experiments, including multiple quantum relaxation dispersion, chemical exchange saturation transfer and methyl spin-spin relaxation, to probe conformational dynamics across multiple timescales. Indeed, these studies identified differences in conformational dynamics in functionally important regions, including enzyme active sites, and RNA and lipid binding sites. Expansion of the conformational ensemble available to 3CD may allow it to perform additional functions not observed in 3C and 3D alone despite having nearly identical lowest-energy structures. Full article
(This article belongs to the Special Issue Viral Replication Complexes)
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22 pages, 2630 KiB  
Review
Hepatitis C Viral Replication Complex
by Hui-Chun Li, Chee-Hing Yang and Shih-Yen Lo
Viruses 2021, 13(3), 520; https://0-doi-org.brum.beds.ac.uk/10.3390/v13030520 - 22 Mar 2021
Cited by 15 | Viewed by 4334
Abstract
The life cycle of the hepatitis C virus (HCV) can be divided into several stages, including viral entry, protein translation, RNA replication, viral assembly, and release. HCV genomic RNA replication occurs in the replication organelles (RO) and is tightly linked to ER membrane [...] Read more.
The life cycle of the hepatitis C virus (HCV) can be divided into several stages, including viral entry, protein translation, RNA replication, viral assembly, and release. HCV genomic RNA replication occurs in the replication organelles (RO) and is tightly linked to ER membrane alterations containing replication complexes (proteins NS3 to NS5B). The amplification of HCV genomic RNA could be regulated by the RO biogenesis, the viral RNA structure (i.e., cis-acting replication elements), and both viral and cellular proteins. Studies on HCV replication have led to the development of direct-acting antivirals (DAAs) targeting the replication complex. This review article summarizes the viral and cellular factors involved in regulating HCV genomic RNA replication and the DAAs that inhibit HCV replication. Full article
(This article belongs to the Special Issue Viral Replication Complexes)
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13 pages, 4286 KiB  
Article
Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HIV Replication and PD-1 Expression on CD4+ T Cells
by Mohammad Haque, Fengyang Lei, Xiaofang Xiong, Yijie Ren, Hao-Yun Peng, Liqing Wang, Anil Kumar, Jugal Kishore Das and Jianxun Song
Viruses 2021, 13(5), 753; https://0-doi-org.brum.beds.ac.uk/10.3390/v13050753 - 25 Apr 2021
Cited by 3 | Viewed by 2559
Abstract
The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress the human immunodeficiency virus (HIV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the local tissues to suppress HIV replication. Nevertheless, [...] Read more.
The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress the human immunodeficiency virus (HIV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the local tissues to suppress HIV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs elicit the antiviral response remain to be fully elucidated. In this study, we generated the functional HIV-1 Gag epitope SL9-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the suppression of SL9-specific iPSC-CTLs on viral replication and the protection of CD4+ T cells. A chimeric HIV-1, i.e., EcoHIV, was used to produce HIV replication in mice. We show that adoptive transfer of SL9-specific iPSC-CTLs greatly suppressed EcoHIV replication in the peritoneal macrophages and spleen in the animal model. Furthermore, we demonstrate that the adoptive transfer significantly reduced expression of PD-1 on CD4+ T cells in the spleen and generated persistent anti-HIV memory T cells. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the local tissues to suppress HIV replication and prevent CD4+ T cell exhaustion through reduction of PD-1 expression. Full article
(This article belongs to the Special Issue Viral Replication Complexes)
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16 pages, 1814 KiB  
Review
Influenza Virus RNA Synthesis and the Innate Immune Response
by Sabrina Weis and Aartjan J. W. te Velthuis
Viruses 2021, 13(5), 780; https://0-doi-org.brum.beds.ac.uk/10.3390/v13050780 - 28 Apr 2021
Cited by 16 | Viewed by 6503
Abstract
Infection with influenza A and B viruses results in a mild to severe respiratory tract infection. It is widely accepted that many factors affect the severity of influenza disease, including viral replication, host adaptation, innate immune signalling, pre-existing immunity, and secondary infections. In [...] Read more.
Infection with influenza A and B viruses results in a mild to severe respiratory tract infection. It is widely accepted that many factors affect the severity of influenza disease, including viral replication, host adaptation, innate immune signalling, pre-existing immunity, and secondary infections. In this review, we will focus on the interplay between influenza virus RNA synthesis and the detection of influenza virus RNA by our innate immune system. Specifically, we will discuss the generation of various RNA species, host pathogen receptors, and host shut-off. In addition, we will also address outstanding questions that currently limit our knowledge of influenza virus replication and host adaption. Understanding the molecular mechanisms underlying these factors is essential for assessing the pandemic potential of future influenza virus outbreaks. Full article
(This article belongs to the Special Issue Viral Replication Complexes)
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14 pages, 4568 KiB  
Review
Structural Insights into the Respiratory Syncytial Virus RNA Synthesis Complexes
by Dongdong Cao, Yunrong Gao and Bo Liang
Viruses 2021, 13(5), 834; https://0-doi-org.brum.beds.ac.uk/10.3390/v13050834 - 05 May 2021
Cited by 13 | Viewed by 5951
Abstract
RNA synthesis in respiratory syncytial virus (RSV), a negative-sense (−) nonsegmented RNA virus, consists of viral gene transcription and genome replication. Gene transcription includes the positive-sense (+) viral mRNA synthesis, 5′-RNA capping and methylation, and 3′ end polyadenylation. Genome replication includes (+) RNA [...] Read more.
RNA synthesis in respiratory syncytial virus (RSV), a negative-sense (−) nonsegmented RNA virus, consists of viral gene transcription and genome replication. Gene transcription includes the positive-sense (+) viral mRNA synthesis, 5′-RNA capping and methylation, and 3′ end polyadenylation. Genome replication includes (+) RNA antigenome and (−) RNA genome synthesis. RSV executes the viral RNA synthesis using an RNA synthesis ribonucleoprotein (RNP) complex, comprising four proteins, the nucleoprotein (N), the large protein (L), the phosphoprotein (P), and the M2-1 protein. We provide an overview of the RSV RNA synthesis and the structural insights into the RSV gene transcription and genome replication process. We propose a model of how the essential four proteins coordinate their activities in different RNA synthesis processes. Full article
(This article belongs to the Special Issue Viral Replication Complexes)
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17 pages, 5083 KiB  
Article
Akt Kinase Intervenes in Flavivirus Replication by Interacting with Viral Protein NS5
by Laura Albentosa-González, Nereida Jimenez de Oya, Armando Arias, Pilar Clemente-Casares, Miguel Ángel Martin-Acebes, Juan Carlos Saiz, Rosario Sabariegos and Antonio Mas
Viruses 2021, 13(5), 896; https://0-doi-org.brum.beds.ac.uk/10.3390/v13050896 - 12 May 2021
Cited by 9 | Viewed by 2444
Abstract
Arthropod-borne flaviviruses, such as Zika virus (ZIKV), Usutu virus (USUV), and West Nile virus (WNV), are a growing cause of human illness and death around the world. Presently, no licensed antivirals to control them are available and, therefore, search for broad-spectrum antivirals, including [...] Read more.
Arthropod-borne flaviviruses, such as Zika virus (ZIKV), Usutu virus (USUV), and West Nile virus (WNV), are a growing cause of human illness and death around the world. Presently, no licensed antivirals to control them are available and, therefore, search for broad-spectrum antivirals, including host-directed compounds, is essential. The PI3K/Akt pathway controls essential cellular functions involved in cell metabolism and proliferation. Moreover, Akt has been found to participate in modulating replication in different viruses including the flaviviruses. In this work we studied the interaction of flavivirus NS5 polymerases with the cellular kinase Akt. In vitro NS5 phosphorylation experiments with Akt showed that flavivirus NS5 polymerases are phosphorylated and co-immunoprecipitate by Akt. Polymerase activity assays of Ala- and Glu-generated mutants for the Akt-phosphorylated residues also indicate that Glu mutants of ZIKV and USUV NS5s present a reduced primer-extension activity that was not observed in WNV mutants. Furthermore, treatment with Akt inhibitors (MK-2206, honokiol and ipatasertib) reduced USUV and ZIKV titers in cell culture but, except for honokiol, not WNV. All these findings suggest an important role for Akt in flavivirus replication although with specific differences among viruses and encourage further investigations to examine the PI3K/Akt/mTOR pathway as an antiviral potential target. Full article
(This article belongs to the Special Issue Viral Replication Complexes)
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28 pages, 38776 KiB  
Review
Molecular Insights into the Flavivirus Replication Complex
by Kaïn van den Elsen, Jun Ping Quek and Dahai Luo
Viruses 2021, 13(6), 956; https://0-doi-org.brum.beds.ac.uk/10.3390/v13060956 - 21 May 2021
Cited by 31 | Viewed by 7536
Abstract
Flaviviruses are vector-borne RNA viruses, many of which are clinically relevant human viral pathogens, such as dengue, Zika, Japanese encephalitis, West Nile and yellow fever viruses. Millions of people are infected with these viruses around the world each year. Vaccines are only available [...] Read more.
Flaviviruses are vector-borne RNA viruses, many of which are clinically relevant human viral pathogens, such as dengue, Zika, Japanese encephalitis, West Nile and yellow fever viruses. Millions of people are infected with these viruses around the world each year. Vaccines are only available for some members of this large virus family, and there are no effective antiviral drugs to treat flavivirus infections. The unmet need for vaccines and therapies against these flaviviral infections drives research towards a better understanding of the epidemiology, biology and immunology of flaviviruses. In this review, we discuss the basic biology of the flavivirus replication process and focus on the molecular aspects of viral genome replication. Within the virus-induced intracellular membranous compartments, flaviviral RNA genome replication takes place, starting from viral poly protein expression and processing to the assembly of the virus RNA replication complex, followed by the delivery of the progeny viral RNA to the viral particle assembly sites. We attempt to update the latest understanding of the key molecular events during this process and highlight knowledge gaps for future studies. Full article
(This article belongs to the Special Issue Viral Replication Complexes)
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15 pages, 981 KiB  
Review
Membrane-Associated Flavivirus Replication Complex—Its Organization and Regulation
by Eiji Morita and Youichi Suzuki
Viruses 2021, 13(6), 1060; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061060 - 03 Jun 2021
Cited by 12 | Viewed by 3729
Abstract
Flavivirus consists of a large number of arthropod-borne viruses, many of which cause life-threatening diseases in humans. A characteristic feature of flavivirus infection is to induce the rearrangement of intracellular membrane structure in the cytoplasm. This unique membranous structure called replication organelle is [...] Read more.
Flavivirus consists of a large number of arthropod-borne viruses, many of which cause life-threatening diseases in humans. A characteristic feature of flavivirus infection is to induce the rearrangement of intracellular membrane structure in the cytoplasm. This unique membranous structure called replication organelle is considered as a microenvironment that provides factors required for the activity of the flaviviral replication complex. The replication organelle serves as a place to coordinate viral RNA amplification, protein translation, and virion assembly and also to protect the viral replication complex from the cellular immune defense system. In this review, we summarize the current understanding of how the formation and function of membrane-associated flaviviral replication organelle are regulated by cellular factors. Full article
(This article belongs to the Special Issue Viral Replication Complexes)
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10 pages, 1752 KiB  
Review
The Role of the Stem-Loop A RNA Promoter in Flavivirus Replication
by Kyung H. Choi
Viruses 2021, 13(6), 1107; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061107 - 09 Jun 2021
Cited by 13 | Viewed by 3409
Abstract
An essential challenge in the lifecycle of RNA viruses is identifying and replicating the viral genome amongst all the RNAs present in the host cell cytoplasm. Yet, how the viral polymerase selectively recognizes and copies the viral RNA genome is poorly understood. In [...] Read more.
An essential challenge in the lifecycle of RNA viruses is identifying and replicating the viral genome amongst all the RNAs present in the host cell cytoplasm. Yet, how the viral polymerase selectively recognizes and copies the viral RNA genome is poorly understood. In flaviviruses, the 5′-end of the viral RNA genome contains a 70 nucleotide-long stem-loop, called stem-loop A (SLA), which functions as a promoter for genome replication. During replication, flaviviral polymerase NS5 specifically recognizes SLA to both initiate viral RNA synthesis and to methylate the 5′ guanine cap of the nascent RNA. While the sequences of this region vary between different flaviviruses, the three-way junction arrangement of secondary structures is conserved in SLA, suggesting that viruses recognize a common structural feature to replicate the viral genome rather than a particular sequence. To better understand the molecular basis of genome recognition by flaviviruses, we recently determined the crystal structures of flavivirus SLAs from dengue virus (DENV) and Zika virus (ZIKV). In this review, I will provide an overview of (1) flaviviral genome replication; (2) structures of viral SLA promoters and NS5 polymerases; and (3) and describe our current model of how NS5 polymerases specifically recognize the SLA at the 5′ terminus of the viral genome to initiate RNA synthesis at the 3′ terminus. Full article
(This article belongs to the Special Issue Viral Replication Complexes)
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16 pages, 6101 KiB  
Article
Snapshots of a Non-Canonical RdRP in Action
by Diego S. Ferrero, Michela Falqui and Nuria Verdaguer
Viruses 2021, 13(7), 1260; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071260 - 28 Jun 2021
Cited by 3 | Viewed by 2407
Abstract
RNA viruses typically encode their own RNA-dependent RNA polymerase (RdRP) to ensure genome replication and transcription. The closed “right hand” architecture of RdRPs encircles seven conserved structural motifs (A to G) that regulate the polymerization activity. The four palm motifs, arranged in the [...] Read more.
RNA viruses typically encode their own RNA-dependent RNA polymerase (RdRP) to ensure genome replication and transcription. The closed “right hand” architecture of RdRPs encircles seven conserved structural motifs (A to G) that regulate the polymerization activity. The four palm motifs, arranged in the sequential order A to D, are common to all known template dependent polynucleotide polymerases, with motifs A and C containing the catalytic aspartic acid residues. Exceptions to this design have been reported in members of the Permutotetraviridae and Birnaviridae families of positive single stranded (+ss) and double-stranded (ds) RNA viruses, respectively. In these enzymes, motif C is located upstream of motif A, displaying a permuted C–A–B–D connectivity. Here we study the details of the replication elongation process in the non-canonical RdRP of the Thosea asigna virus (TaV), an insect virus from the Permutatetraviridae family. We report the X-ray structures of three replicative complexes of the TaV polymerase obtained with an RNA template-primer in the absence and in the presence of incoming rNTPs. The structures captured different replication events and allowed to define the critical interactions involved in: (i) the positioning of the acceptor base of the template strand, (ii) the positioning of the 3’-OH group of the primer nucleotide during RNA replication and (iii) the recognition and positioning of the incoming nucleotide. Structural comparisons unveiled a closure of the active site on the RNA template-primer binding, before rNTP entry. This conformational rearrangement that also includes the repositioning of the motif A aspartate for the catalytic reaction to take place is maintained on rNTP and metal ion binding and after nucleotide incorporation, before translocation. Full article
(This article belongs to the Special Issue Viral Replication Complexes)
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15 pages, 1475 KiB  
Review
Mutation Rates, Mutation Frequencies, and Proofreading-Repair Activities in RNA Virus Genetics
by Esteban Domingo, Carlos García-Crespo, Rebeca Lobo-Vega and Celia Perales
Viruses 2021, 13(9), 1882; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091882 - 21 Sep 2021
Cited by 52 | Viewed by 8190
Abstract
The error rate displayed during template copying to produce viral RNA progeny is a biologically relevant parameter of the replication complexes of viruses. It has consequences for virus–host interactions, and it represents the first step in the diversification of viruses in nature. Measurements [...] Read more.
The error rate displayed during template copying to produce viral RNA progeny is a biologically relevant parameter of the replication complexes of viruses. It has consequences for virus–host interactions, and it represents the first step in the diversification of viruses in nature. Measurements during infections and with purified viral polymerases indicate that mutation rates for RNA viruses are in the range of 10−3 to 10−6 copying errors per nucleotide incorporated into the nascent RNA product. Although viruses are thought to exploit high error rates for adaptation to changing environments, some of them possess misincorporation correcting activities. One of them is a proofreading-repair 3′ to 5′ exonuclease present in coronaviruses that may decrease the error rate during replication. Here we review experimental evidence and models of information maintenance that explain why elevated mutation rates have been preserved during the evolution of RNA (and some DNA) viruses. The models also offer an interpretation of why error correction mechanisms have evolved to maintain the stability of genetic information carried out by large viral RNA genomes such as the coronaviruses. Full article
(This article belongs to the Special Issue Viral Replication Complexes)
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