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Viruses
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RNA Viruses: Structure, Adaptation, and Evolution
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RNA Viruses: Structure, Adaptation, and Evolution

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

Deadline for manuscript submissions: closed (20 May 2022) | Viewed by 66534

Special Issue Editor

Dr. Hironori Sato

E-Mail Website
Guest Editor
Center for Pathogen Genomics, National Institute of Infectious Diseases, Tokyo, Japan
Interests: mutations; structure; survival strategies of RNA viruses

Special Issue Information

Dear Colleagues,

In an increasingly globalized world, emerging/re-emerging infectious diseases caused by RNA viruses are becoming a very important issue in public health. RNA viruses are generally highly mutable and adaptable. These characteristics allow them to rapidly change structure and biological phenotype via natural selection under a changing environment, sometimes leading to persistent infection in a host or to outbreaks of emerging/re-emerging infectious diseases in populations. Owing to rapid advances in genomics, we now know much more than before on how RNA viruses maintain and alter genetic information for survival in nature. However, we still do not know much about how these genetic changes impact viral phenotypes, and thus, we are insufficiently ready to understand emerging/re-emerging infectious diseases.

In this Special Issue, we welcome a wide range of articles, including original research, short communications, and reviews, that focus on the structure, adaptation, and evolution of RNA viruses. Studies with animal/plant models or computational approaches are also welcome. Topics of interest include observations and/or underlying mechanisms of (i) viral genetic changes in nature, (ii) phenotypical changes with biological/epidemiological/clinical relevance (e.g., drug resistance, immune escape, changes in cell/tissue-tropism or host range, transmissibility, and pathogenesis), (iii) persistent infection in a host or populations, (iv) structural and functional constraints of viral molecules against changes, (v) the allosteric network of viral proteins, (vi) fitness trade-offs and adaptation under antivirals/vaccines/immune pressures, (vii) the co-evolution of viral genes or proteins, and (viii) emerging/re-emerging zoonoses and infectious diseases.

We look forward to receiving your submissions for this Special Issue.

Dr. Hironori Sato
Guest Editor

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

  • RNA viruses
  • structure
  • function
  • mutation
  • adaptation
  • evolution
  • animal model
  • computational science
  • persistent infection
  • emerging/re-emerging infectious diseases

Published Papers (22 papers)

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Research

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17 pages, 3022 KiB  
Article
Development of a Monoclonal Antibody Targeting HTLV-1 Envelope gp46 Glycoprotein and Its Application to Near-Infrared Photoimmuno-Antimicrobial Strategy
by Yasuyoshi Hatayama, Yutaro Yamaoka, Takeshi Morita, Sundararaj Stanleyraj Jeremiah, Kei Miyakawa, Mayuko Nishi, Yayoi Kimura, Makoto Mitsunaga, Tadayuki Iwase, Hirokazu Kimura, Naoki Yamamoto, Akifumi Takaori-Kondo, Hideki Hasegawa and Akihide Ryo
Viruses 2022, 14(10), 2153; https://0-doi-org.brum.beds.ac.uk/10.3390/v14102153 - 29 Sep 2022
Cited by 2 | Viewed by 2311
Abstract
Human T-cell leukemia virus type 1 (HTLV-1), a retrovirus, causes adult T-cell leukemia-lymphoma, HTLV-1 associated myelopathy/tropical spastic paraparesis, and HTLV-1 uveitis. Currently, no antiretroviral therapies or vaccines are available for HTLV-1 infection. This study aimed to develop an antibody against the HTLV-1 envelope [...] Read more.
Human T-cell leukemia virus type 1 (HTLV-1), a retrovirus, causes adult T-cell leukemia-lymphoma, HTLV-1 associated myelopathy/tropical spastic paraparesis, and HTLV-1 uveitis. Currently, no antiretroviral therapies or vaccines are available for HTLV-1 infection. This study aimed to develop an antibody against the HTLV-1 envelope protein (Env) and apply it to a near-infrared photoimmuno-antimicrobial strategy (NIR-PIAS) to eliminate HTLV-1 infected cells. We established mouse monoclonal antibodies (mAbs) against HTLV-1 Env by immunization with a complex of liposome and the recombinant protein. Detailed epitope mapping revealed that one of the mAbs bound to the proline-rich region of gp46 and exhibited no obvious neutralizing activity to inhibit viral infection. Instead, the mAb was rarely internalized intracellularly and remained on the cell surface of HTLV-1-infected cells. The antibody conjugated to the photosensitive dye IRDye700Dx recognized HTLV-1 infected cells and killed them following NIR irradiation. These results suggest that the novel mAb and NIR-PIAS could be developed as a new targeted therapeutic tool against HTLV-1 infected cells. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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12 pages, 3760 KiB  
Article
Characterization and Utilization of Disulfide-Bonded SARS-CoV-2 Receptor Binding Domain of Spike Protein Synthesized by Wheat Germ Cell-Free Production System
by Yutaro Yamaoka, Sundararaj Stanleyraj Jeremiah, Rikako Funabashi, Kei Miyakawa, Takeshi Morita, Yusaku Mihana, Hideaki Kato and Akihide Ryo
Viruses 2022, 14(7), 1461; https://0-doi-org.brum.beds.ac.uk/10.3390/v14071461 - 01 Jul 2022
Cited by 3 | Viewed by 2246
Abstract
The spike protein (SP) of SARS-CoV-2 is an important target for COVID-19 therapeutics and vaccines as it binds to the ACE2 receptor and enables viral infection. Rapid production and functional characterization of properly folded SP is of the utmost importance for studying the [...] Read more.
The spike protein (SP) of SARS-CoV-2 is an important target for COVID-19 therapeutics and vaccines as it binds to the ACE2 receptor and enables viral infection. Rapid production and functional characterization of properly folded SP is of the utmost importance for studying the immunogenicity and receptor-binding activity of this protein considering the emergence of highly infectious viral variants. In this study, we attempted to express the receptor-binding region (RBD) of SARS-CoV-2 SP containing disulfide bonds using the wheat germ cell-free protein synthesis system. By adding protein disulfide isomerase (PDI) and endoplasmic reticulum oxidase (ERO1α) to the translational reaction mixture, we succeeded in synthesizing a functionally intact RBD protein that can interact with ACE2. Using this RBD protein, we have developed a high-throughput AlphaScreen assay to evaluate the RBD–ACE2 interaction, which can be applied for drug screening and mutation analysis. Thus, our method sheds new light on the structural and functional properties of SARS-CoV-2 SP and has the potential to contribute to the development of new COVID-19 therapeutics. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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24 pages, 4022 KiB  
Article
Unique Mode of Antiviral Action of a Marine Alkaloid against Ebola Virus and SARS-CoV-2
by Mai Izumida, Osamu Kotani, Hideki Hayashi, Chris Smith, Tsutomu Fukuda, Koushirou Suga, Masatomo Iwao, Fumito Ishibashi, Hironori Sato and Yoshinao Kubo
Viruses 2022, 14(4), 816; https://0-doi-org.brum.beds.ac.uk/10.3390/v14040816 - 15 Apr 2022
Cited by 4 | Viewed by 2868
Abstract
Lamellarin α 20-sulfate is a cell-impenetrable marine alkaloid that can suppress infection that is mediated by the envelope glycoprotein of human immunodeficiency virus type 1. We explored the antiviral action and mechanisms of this alkaloid against emerging enveloped RNA viruses that use endocytosis [...] Read more.
Lamellarin α 20-sulfate is a cell-impenetrable marine alkaloid that can suppress infection that is mediated by the envelope glycoprotein of human immunodeficiency virus type 1. We explored the antiviral action and mechanisms of this alkaloid against emerging enveloped RNA viruses that use endocytosis for infection. The alkaloid inhibited the infection of retroviral vectors that had been pseudotyped with the envelope glycoprotein of Ebola virus and SARS-CoV-2. The antiviral effects of lamellarin were independent of the retrovirus Gag-Pol proteins. Interestingly, although heparin and dextran sulfate suppressed the cell attachment of vector particles, lamellarin did not. In silico structural analyses of the trimeric glycoprotein of the Ebola virus disclosed that the principal lamellarin-binding site is confined to a previously unappreciated cavity near the NPC1-binding site and fusion loop, whereas those for heparin and dextran sulfate were dispersed across the attachment and fusion subunits of the glycoproteins. Notably, lamellarin binding to this cavity was augmented under conditions where the pH was 5.0. These results suggest that the final action of the alkaloid against Ebola virus is specific to events following endocytosis, possibly during conformational glycoprotein changes in the acidic environment of endosomes. Our findings highlight the unique biological and physicochemical features of lamellarin α 20-sulfate and should lead to the further use of broadly reactive antivirals to explore the structural mechanisms of virus replication. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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20 pages, 13530 KiB  
Article
Detailed Analyses of Molecular Interactions between Favipiravir and RNA Viruses In Silico
by Tatsuya Shirai, Mitsuru Sada, Takeshi Saraya, Daisuke Kurai, Soyoka Sunagawa, Haruyuki Ishii and Hirokazu Kimura
Viruses 2022, 14(2), 338; https://0-doi-org.brum.beds.ac.uk/10.3390/v14020338 - 07 Feb 2022
Viewed by 2056
Abstract
There are currently no antiviral agents for human metapneumovirus (HMPV), respiratory syncytial virus (RSV), mumps virus (MuV), or measles virus (MeV). Favipiravir has been developed as an anti-influenza agent, and this agent may be effective against these viruses in vitro. However, the molecular [...] Read more.
There are currently no antiviral agents for human metapneumovirus (HMPV), respiratory syncytial virus (RSV), mumps virus (MuV), or measles virus (MeV). Favipiravir has been developed as an anti-influenza agent, and this agent may be effective against these viruses in vitro. However, the molecular mechanisms through which the agent affects virus replication remain to be fully elucidated. Thus, to clarify the detailed molecular interactions between favipiravir and the RNA-dependent RNA polymerase (RdRp) of HMPV, RSV, MuV, MeV, and influenza virus, we performed in silico studies using authentic bioinformatics technologies. As a result, we found that the active form of favipiravir (favipiravir ribofuranosyl-5′-triphosphate [F-RTP]) can bind to the RdRp active sites of HMPV, RSV, MuV, and MeV. The aspartic acid residue of RdRp active sites was involved in the interaction. Moreover, F-RTP was incorporated into the growing viral RNA chain in the presence of nucleotide triphosphate and magnesium ions. The results suggested that favipiravir shows two distinct mechanisms in various viruses: RdRp active site inhibition and/or genome replication inhibition. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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12 pages, 8438 KiB  
Article
Detailed Evolutionary Analyses of the F Gene in the Respiratory Syncytial Virus Subgroup A
by Mariko Saito, Hiroyuki Tsukagoshi, Mitsuru Sada, Soyoka Sunagawa, Tatsuya Shirai, Kaori Okayama, Toshiyuki Sugai, Takeshi Tsugawa, Yuriko Hayashi, Akihide Ryo, Makoto Takeda, Hisashi Kawashima, Nobuhiro Saruki and Hirokazu Kimura
Viruses 2021, 13(12), 2525; https://0-doi-org.brum.beds.ac.uk/10.3390/v13122525 - 15 Dec 2021
Cited by 5 | Viewed by 2789
Abstract
We performed evolution, phylodynamics, and reinfection-related antigenicity analyses of respiratory syncytial virus subgroup A (RSV-A) fusion (F) gene in globally collected strains (1465 strains) using authentic bioinformatics methods. The time-scaled evolutionary tree using the Bayesian Markov chain Monte Carlo method estimated that a [...] Read more.
We performed evolution, phylodynamics, and reinfection-related antigenicity analyses of respiratory syncytial virus subgroup A (RSV-A) fusion (F) gene in globally collected strains (1465 strains) using authentic bioinformatics methods. The time-scaled evolutionary tree using the Bayesian Markov chain Monte Carlo method estimated that a common ancestor of the RSV-A, RSV-B, and bovine-RSV diverged at around 450 years ago, and RSV-A and RSV-B diverged around 250 years ago. Finally, the RSV-A F gene formed eight genotypes (GA1-GA7 and NA1) over the last 80 years. Phylodynamics of RSV-A F gene, including all genotype strains, increased twice in the 1990s and 2010s, while patterns of each RSV-A genotype were different. Phylogenetic distance analysis suggested that the genetic distances of the strains were relatively short (less than 0.05). No positive selection sites were estimated, while many negative selection sites were found. Moreover, the F protein 3D structure mapping and conformational epitope analysis implied that the conformational epitopes did not correspond to the neutralizing antibody binding sites of the F protein. These results suggested that the RSV-A F gene is relatively conserved, and mismatches between conformational epitopes and neutralizing antibody binding sites of the F protein are responsible for the virus reinfection. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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15 pages, 1848 KiB  
Article
Constraint of Base Pairing on HDV Genome Evolution
by Saki Nagata, Ryoji Kiyohara and Hiroyuki Toh
Viruses 2021, 13(12), 2350; https://0-doi-org.brum.beds.ac.uk/10.3390/v13122350 - 23 Nov 2021
Viewed by 1482
Abstract
The hepatitis delta virus is a single-stranded circular RNA virus, which is characterized by high self-complementarity. About 70% of the genome sequences can form base-pairs with internal nucleotides. There are many studies on the evolution of the hepatitis delta virus. However, the secondary [...] Read more.
The hepatitis delta virus is a single-stranded circular RNA virus, which is characterized by high self-complementarity. About 70% of the genome sequences can form base-pairs with internal nucleotides. There are many studies on the evolution of the hepatitis delta virus. However, the secondary structure has not been taken into account in these studies. In this study, we developed a method to examine the effect of base pairing as a constraint on the nucleotide substitutions during the evolution of the hepatitis delta virus. The method revealed that the base pairing can reduce the evolutionary rate in the non-coding region of the virus. In addition, it is suggested that the non-coding nucleotides without base pairing may be under some constraint, and that the intensity of the constraint is weaker than that by the base pairing but stronger than that on the synonymous site. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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21 pages, 3052 KiB  
Article
The Expression Level of HIV-1 Vif Is Optimized by Nucleotide Changes in the Genomic SA1D2prox Region during the Viral Adaptation Process
by Takaaki Koma, Naoya Doi, Mai Takemoto, Kyosuke Watanabe, Hideki Yamamoto, Satoshi Nakashima, Akio Adachi and Masako Nomaguchi
Viruses 2021, 13(10), 2079; https://0-doi-org.brum.beds.ac.uk/10.3390/v13102079 - 15 Oct 2021
Cited by 2 | Viewed by 1962
Abstract
HIV-1 Vif plays an essential role in viral replication by antagonizing anti-viral cellular restriction factors, a family of APOBEC3 proteins. We have previously shown that naturally-occurring single-nucleotide mutations in the SA1D2prox region, which surrounds the splicing acceptor 1 and splicing donor 2 sites [...] Read more.
HIV-1 Vif plays an essential role in viral replication by antagonizing anti-viral cellular restriction factors, a family of APOBEC3 proteins. We have previously shown that naturally-occurring single-nucleotide mutations in the SA1D2prox region, which surrounds the splicing acceptor 1 and splicing donor 2 sites of the HIV-1 genome, dramatically alter the Vif expression level, resulting in variants with low or excessive Vif expression. In this study, we investigated how these HIV-1 variants with poor replication ability adapt and evolve under the pressure of APOBEC3 proteins. Adapted clones obtained through adaptation experiments exhibited an altered replication ability and Vif expression level compared to each parental clone. While various mutations were present throughout the viral genome, all replication-competent adapted clones with altered Vif expression levels were found to bear them within SA1D2prox, without exception. Indeed, the mutations identified within SA1D2prox were responsible for changes in the Vif expression levels and altered the splicing pattern. Moreover, for samples collected from HIV-1-infected patients, we showed that the nucleotide sequences of SA1D2prox can be chronologically changed and concomitantly affect the Vif expression levels. Taken together, these results demonstrated the importance of the SA1D2prox nucleotide sequence for modulating the Vif expression level during HIV-1 replication and adaptation. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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19 pages, 2603 KiB  
Article
Patterns of Coevolutionary Adaptations across Time and Space in Mouse Gammaretroviruses and Three Restrictive Host Factors
by Guney Boso, Oscar Lam, Devinka Bamunusinghe, Andrew J. Oler, Kurt Wollenberg, Qingping Liu, Esther Shaffer and Christine A. Kozak
Viruses 2021, 13(9), 1864; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091864 - 18 Sep 2021
Cited by 3 | Viewed by 1930
Abstract
The classical laboratory mouse strains are genetic mosaics of three Mus musculus subspecies that occupy distinct regions of Eurasia. These strains and subspecies carry infectious and endogenous mouse leukemia viruses (MLVs) that can be pathogenic and mutagenic. MLVs evolved in concert with restrictive [...] Read more.
The classical laboratory mouse strains are genetic mosaics of three Mus musculus subspecies that occupy distinct regions of Eurasia. These strains and subspecies carry infectious and endogenous mouse leukemia viruses (MLVs) that can be pathogenic and mutagenic. MLVs evolved in concert with restrictive host factors with some under positive selection, including the XPR1 receptor for xenotropic/polytropic MLVs (X/P-MLVs) and the post-entry restriction factor Fv1. Since positive selection marks host-pathogen genetic conflicts, we examined MLVs for counter-adaptations at sites that interact with XPR1, Fv1, and the CAT1 receptor for ecotropic MLVs (E-MLVs). Results describe different co-adaptive evolutionary paths within the ranges occupied by these virus-infected subspecies. The interface of CAT1, and the otherwise variable E-MLV envelopes, is highly conserved; antiviral protection is afforded by the Fv4 restriction factor. XPR1 and X/P-MLVs variants show coordinate geographic distributions, with receptor critical sites in envelope, under positive selection but with little variation in envelope and XPR1 in mice carrying P-ERVs. The major Fv1 target in the viral capsid is under positive selection, and the distribution of Fv1 alleles is subspecies-correlated. These data document adaptive, spatial and temporal, co-evolutionary trajectories at the critical interfaces of MLVs and the host factors that restrict their replication. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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18 pages, 21651 KiB  
Article
Structure-Guided Creation of an Anti-HA Stalk Antibody F11 Derivative That Neutralizes Both F11-Sensitive and -Resistant Influenza A(H1N1)pdm09 Viruses
by Osamu Kotani, Yasushi Suzuki, Shinji Saito, Akira Ainai, Akira Ueno, Takuya Hemmi, Kaori Sano, Koshiro Tabata, Masaru Yokoyama, Tadaki Suzuki, Hideki Hasegawa and Hironori Sato
Viruses 2021, 13(9), 1733; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091733 - 31 Aug 2021
Cited by 3 | Viewed by 3014
Abstract
The stalk domain of influenza virus envelope glycoprotein hemagglutinin (HA) constitutes the axis connecting the head and transmembrane domains, and plays pivotal roles in conformational rearrangements of HA for virus infection. Here we characterized molecular interactions between the anti-HA stalk neutralization antibody F11 [...] Read more.
The stalk domain of influenza virus envelope glycoprotein hemagglutinin (HA) constitutes the axis connecting the head and transmembrane domains, and plays pivotal roles in conformational rearrangements of HA for virus infection. Here we characterized molecular interactions between the anti-HA stalk neutralization antibody F11 and influenza A(H1N1)pdm09 HA to understand the structural basis of the actions and modifications of this antibody. In silico structural analyses using a model of the trimeric HA ectodomain indicated that the F11 Fab fragment has physicochemical properties, allowing it to crosslink two HA monomers by binding to a region near the proteolytic cleavage site of the stalk domain. Interestingly, the F11 binding allosterically caused a marked suppression of the structural dynamics of the HA cleavage loop and flanking regions. Structure-guided mutagenesis of the F11 antibody revealed a critical residue in the F11 light chain for the F11-mediated neutralization. Finally, the mutagenesis led to identification of a unique F11 derivative that can neutralize both F11-sensitive and F11-resistant A(H1N1)pdm09 viruses. These results raise the possibility that F11 sterically and physically disturbs proteolytic cleavage of HA for the ordered conformational rearrangements and suggest that in silico guiding experiments can be useful to create anti-HA stalk antibodies with new phenotypes. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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10 pages, 1211 KiB  
Article
Dual Promoters Improve the Rescue of Recombinant Measles Virus in Human Cells
by Soroth Chey, Juliane Maria Palmer, Laura Doerr and Uwe Gerd Liebert
Viruses 2021, 13(9), 1723; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091723 - 30 Aug 2021
Cited by 2 | Viewed by 2538
Abstract
Reverse genetics is a technology that allows the production of a virus from its complementary DNA (cDNA). It is a powerful tool for analyzing viral genes, the development of novel vaccines, and gene delivery vectors. The standard reverse genetics protocols are laborious, time-consuming, [...] Read more.
Reverse genetics is a technology that allows the production of a virus from its complementary DNA (cDNA). It is a powerful tool for analyzing viral genes, the development of novel vaccines, and gene delivery vectors. The standard reverse genetics protocols are laborious, time-consuming, and inefficient for negative-strand RNA viruses. A new reverse genetics platform was established, which increases the recovery efficiency of the measles virus (MV) in human 293-3-46 cells. The novel features compared with the standard system involving 293-3-46 cells comprise (a) dual promoters containing the RNA polymerase II promoter (CMV) and the bacteriophage T7 promoter placed in uni-direction on the same plasmid to enhance RNA transcription; (b) three G nucleotides added just after the T7 promoter to increase the T7 RNA polymerase activity; and (c) two ribozymes, the hairpin hammerhead ribozyme (HHRz), and the hepatitis delta virus ribozyme (HDVrz), were used to cleavage the exact termini of the antigenome RNA. Full-length antigenome cDNA of MV of the wild type IC323 strain or the vaccine AIK-C strain was inserted into the plasmid backbone. Both virus strains were easily rescued from their respective cloned cDNA. The rescue efficiency increased up to 80% compared with the use of the standard T7 rescue system. We assume that this system might be helpful in the rescue of other human mononegavirales. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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11 pages, 5006 KiB  
Article
Structural 3D Domain Reconstruction of the RNA Genome from Viruses with Secondary Structure Models
by Simón Poblete and Horacio V. Guzman
Viruses 2021, 13(8), 1555; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081555 - 06 Aug 2021
Cited by 9 | Viewed by 3031
Abstract
Three-dimensional RNA domain reconstruction is important for the assembly, disassembly and delivery functionalities of a packed proteinaceus capsid. However, to date, the self-association of RNA molecules is still an open problem. Recent chemical probing reports provide, with high reliability, the secondary structure of [...] Read more.
Three-dimensional RNA domain reconstruction is important for the assembly, disassembly and delivery functionalities of a packed proteinaceus capsid. However, to date, the self-association of RNA molecules is still an open problem. Recent chemical probing reports provide, with high reliability, the secondary structure of diverse RNA ensembles, such as those of viral genomes. Here, we present a method for reconstructing the complete 3D structure of RNA genomes, which combines a coarse-grained model with a subdomain composition scheme to obtain the entire genome inside proteinaceus capsids based on secondary structures from experimental techniques. Despite the amount of sampling involved in the folded and also unfolded RNA molecules, advanced microscope techniques can provide points of anchoring, which enhance our model to include interactions between capsid pentamers and RNA subdomains. To test our method, we tackle the satellite tobacco mosaic virus (STMV) genome, which has been widely studied by both experimental and computational communities. We provide not only a methodology to structurally analyze the tertiary conformations of the RNA genome inside capsids, but a flexible platform that allows the easy implementation of features/descriptors coming from both theoretical and experimental approaches. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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26 pages, 9243 KiB  
Article
Rotavirus A Genome Segments Show Distinct Segregation and Codon Usage Patterns
by Irene Hoxie and John J. Dennehy
Viruses 2021, 13(8), 1460; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081460 - 27 Jul 2021
Cited by 11 | Viewed by 2879
Abstract
Reassortment of the Rotavirus A (RVA) 11-segment dsRNA genome may generate new genome constellations that allow RVA to expand its host range or evade immune responses. Reassortment may also produce phylogenetic incongruities and weakly linked evolutionary histories across the 11 segments, obscuring reassortment-specific [...] Read more.
Reassortment of the Rotavirus A (RVA) 11-segment dsRNA genome may generate new genome constellations that allow RVA to expand its host range or evade immune responses. Reassortment may also produce phylogenetic incongruities and weakly linked evolutionary histories across the 11 segments, obscuring reassortment-specific epistasis and changes in substitution rates. To determine the co-segregation patterns of RVA segments, we generated time-scaled phylogenetic trees for each of the 11 segments of 789 complete RVA genomes isolated from mammalian hosts and compared the segments’ geodesic distances. We found that segments 4 (VP4) and 9 (VP7) occupied significantly different tree spaces from each other and from the rest of the genome. By contrast, segments 10 and 11 (NSP4 and NSP5/6) occupied nearly indistinguishable tree spaces, suggesting strong co-segregation. Host-species barriers appeared to vary by segment, with segment 9 (VP7) presenting the weakest association with host species. Bayesian Skyride plots were generated for each segment to compare relative genetic diversity among segments over time. All segments showed a dramatic decrease in diversity around 2007 coinciding with the introduction of RVA vaccines. To assess selection pressures, codon adaptation indices and relative codon deoptimization indices were calculated with respect to different host genomes. Codon usage varied by segment with segment 11 (NSP5) exhibiting significantly higher adaptation to host genomes. Furthermore, RVA codon usage patterns appeared optimized for expression in humans and birds relative to the other hosts examined, suggesting that translational efficiency is not a barrier in RVA zoonosis. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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10 pages, 4267 KiB  
Article
A Putative Novel Hepatitis E Virus Genotype 3 Subtype Identified in Rabbit, Germany 2016
by Filip Cierniak, Felicitas von Arnim, Gerald Heckel, Rainer G. Ulrich, Martin H. Groschup and Martin Eiden
Viruses 2021, 13(6), 1065; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061065 - 03 Jun 2021
Cited by 6 | Viewed by 2388
Abstract
Hepatitis E is an emerging viral disease that is the leading cause of viral hepatitis in the world. The vast majority of hepatitis E cases in developed countries are caused by zoonotic genotypes 3 and 4 of hepatitis E virus (HEV) for which [...] Read more.
Hepatitis E is an emerging viral disease that is the leading cause of viral hepatitis in the world. The vast majority of hepatitis E cases in developed countries are caused by zoonotic genotypes 3 and 4 of hepatitis E virus (HEV) for which pig and wild boar and to lesser extent rabbits are the main reservoir. According to recent reports rabbits are a source of human HEV infection and highlight the risk of zoonotic foodborne transmission. Here we report the molecular analysis of a novel HEV strain identified in a rabbit during a countrywide surveillance of rabbits and hares in Germany, 2016. The analysis of the complete genome reveals characteristics of a putative novel recombinant subtype of the species Orthohepevirus A within the clade of genotype 3 but not closely related to any known subtypes. Importantly, the genome of this strain possesses a nucleotide exchange in the overlapping region of open reading frames ORF2/ORF3 interfering with a broadly applied diagnostic real-time RT-PCR. In conclusion, a new type of HEV strain was identified in a German rabbit with atypical and novel sequence characteristics. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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15 pages, 2910 KiB  
Article
Structural Insights into the Interaction of Filovirus Glycoproteins with the Endosomal Receptor Niemann-Pick C1: A Computational Study
by Manabu Igarashi, Takatsugu Hirokawa, Yoshihiro Takadate and Ayato Takada
Viruses 2021, 13(5), 913; https://0-doi-org.brum.beds.ac.uk/10.3390/v13050913 - 14 May 2021
Cited by 3 | Viewed by 2667
Abstract
Filoviruses, including marburgviruses and ebolaviruses, have a single transmembrane glycoprotein (GP) that facilitates their entry into cells. During entry, GP needs to be cleaved by host proteases to expose the receptor-binding site that binds to the endosomal receptor Niemann-Pick C1 (NPC1) protein. The [...] Read more.
Filoviruses, including marburgviruses and ebolaviruses, have a single transmembrane glycoprotein (GP) that facilitates their entry into cells. During entry, GP needs to be cleaved by host proteases to expose the receptor-binding site that binds to the endosomal receptor Niemann-Pick C1 (NPC1) protein. The crystal structure analysis of the cleaved GP (GPcl) of Ebola virus (EBOV) in complex with human NPC1 has demonstrated that NPC1 has two protruding loops (loops 1 and 2), which engage a hydrophobic pocket on the head of EBOV GPcl. However, the molecular interactions between NPC1 and the GPcl of other filoviruses remain unexplored. In the present study, we performed molecular modeling and molecular dynamics simulations of NPC1 complexed with GPcls of two ebolaviruses, EBOV and Sudan virus (SUDV), and one marburgvirus, Ravn virus (RAVV). Similar binding structures were observed in the GPcl–NPC1 complexes of EBOV and SUDV, which differed from that of RAVV. Specifically, in the RAVV GPcl–NPC1 complex, the tip of loop 2 was closer to the pocket edge comprising residues at positions 79–88 of GPcl; the root of loop 1 was predicted to interact with P116 and Q144 of GPcl. Furthermore, in the SUDV GPcl–NPC1 complex, the tip of loop 2 was slightly closer to the residue at position 141 than those in the EBOV and RAVV GPcl–NPC1 complexes. These structural differences may affect the size and/or shape of the receptor-binding pocket of GPcl. Our structural models could provide useful information for improving our understanding the differences in host preference among filoviruses as well as contributing to structure-based drug design. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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17 pages, 2971 KiB  
Article
Structure Unveils Relationships between RNA Virus Polymerases
by Heli A. M. Mönttinen, Janne J. Ravantti and Minna M. Poranen
Viruses 2021, 13(2), 313; https://0-doi-org.brum.beds.ac.uk/10.3390/v13020313 - 17 Feb 2021
Cited by 18 | Viewed by 3943
Abstract
RNA viruses are the fastest evolving known biological entities. Consequently, the sequence similarity between homologous viral proteins disappears quickly, limiting the usability of traditional sequence-based phylogenetic methods in the reconstruction of relationships and evolutionary history among RNA viruses. Protein structures, however, typically evolve [...] Read more.
RNA viruses are the fastest evolving known biological entities. Consequently, the sequence similarity between homologous viral proteins disappears quickly, limiting the usability of traditional sequence-based phylogenetic methods in the reconstruction of relationships and evolutionary history among RNA viruses. Protein structures, however, typically evolve more slowly than sequences, and structural similarity can still be evident, when no sequence similarity can be detected. Here, we used an automated structural comparison method, homologous structure finder, for comprehensive comparisons of viral RNA-dependent RNA polymerases (RdRps). We identified a common structural core of 231 residues for all the structurally characterized viral RdRps, covering segmented and non-segmented negative-sense, positive-sense, and double-stranded RNA viruses infecting both prokaryotic and eukaryotic hosts. The grouping and branching of the viral RdRps in the structure-based phylogenetic tree follow their functional differentiation. The RdRps using protein primer, RNA primer, or self-priming mechanisms have evolved independently of each other, and the RdRps cluster into two large branches based on the used transcription mechanism. The structure-based distance tree presented here follows the recently established RdRp-based RNA virus classification at genus, subfamily, family, order, class and subphylum ranks. However, the topology of our phylogenetic tree suggests an alternative phylum level organization. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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18 pages, 2595 KiB  
Article
A Novel Sub-Lineage of Chikungunya Virus East/Central/South African Genotype Indian Ocean Lineage Caused Sequential Outbreaks in Bangladesh and Thailand
by Juthamas Phadungsombat, Hisham Imad, Mizanur Rahman, Emi E. Nakayama, Sajikapon Kludkleeb, Thitiya Ponam, Rummana Rahim, Abu Hasan, Kanaporn Poltep, Atsushi Yamanaka, Wasin Matsee, Watcharapong Piyaphanee, Weerapong Phumratanaprapin and Tatsuo Shioda
Viruses 2020, 12(11), 1319; https://0-doi-org.brum.beds.ac.uk/10.3390/v12111319 - 17 Nov 2020
Cited by 18 | Viewed by 3520
Abstract
In recent decades, chikungunya virus (CHIKV) has become geographically widespread. In 2004, the CHIKV East/Central/South African (ECSA) genotype moved from Africa to Indian ocean islands and India followed by a large epidemic in Southeast Asia. In 2013, the CHIKV Asian genotype drove an [...] Read more.
In recent decades, chikungunya virus (CHIKV) has become geographically widespread. In 2004, the CHIKV East/Central/South African (ECSA) genotype moved from Africa to Indian ocean islands and India followed by a large epidemic in Southeast Asia. In 2013, the CHIKV Asian genotype drove an outbreak in the Americas. Since 2016, CHIKV has re-emerged in the Indian subcontinent and Southeast Asia. In the present study, CHIKVs were obtained from Bangladesh in 2017 and Thailand in 2019, and their nearly full genomes were sequenced. Phylogenetic analysis revealed that the recent CHIKVs were of Indian Ocean Lineage (IOL) of genotype ECSA, similar to the previous outbreak. However, these CHIKVs were all clustered into a new distinct sub-lineage apart from the past IOL CHIKVs, and they lacked an alanine-to-valine substitution at position 226 of the E1 envelope glycoprotein, which enhances CHIKV replication in Aedes albopictus. Instead, all the re-emerged CHIKVs possessed mutations of lysine-to-glutamic acid at position 211 of E1 and valine-to-alanine at position 264 of E2. Molecular clock analysis suggested that the new sub-lineage CHIKV was introduced to Bangladesh around late 2015 and Thailand in early 2017. These results suggest that re-emerged CHIKVs have acquired different adaptations than the previous CHIKVs. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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Review

Jump to: Research

16 pages, 1654 KiB  
Review
The Role of the Flavivirus Replicase in Viral Diversity and Adaptation
by Haley S. Caldwell, Janice D. Pata and Alexander T. Ciota
Viruses 2022, 14(5), 1076; https://0-doi-org.brum.beds.ac.uk/10.3390/v14051076 - 17 May 2022
Cited by 4 | Viewed by 3513
Abstract
Flaviviruses include several emerging and re-emerging arboviruses which cause millions of infections each year. Although relatively well-studied, much remains unknown regarding the mechanisms and means by which these viruses readily alternate and adapt to different hosts and environments. Here, we review a subset [...] Read more.
Flaviviruses include several emerging and re-emerging arboviruses which cause millions of infections each year. Although relatively well-studied, much remains unknown regarding the mechanisms and means by which these viruses readily alternate and adapt to different hosts and environments. Here, we review a subset of the different aspects of flaviviral biology which impact host switching and viral fitness. These include the mechanism of replication and structural biology of the NS3 and NS5 proteins, which reproduce the viral genome; rates of mutation resulting from this replication and the role of mutational frequency in viral fitness; and the theory of quasispecies evolution and how it contributes to our understanding of genetic and phenotypic plasticity. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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14 pages, 1177 KiB  
Review
Unique Tropism and Entry Mechanism of Mumps Virus
by Marie Kubota and Takao Hashiguchi
Viruses 2021, 13(9), 1746; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091746 - 01 Sep 2021
Cited by 4 | Viewed by 4325
Abstract
Mumps virus (MuV) is an important human pathogen that causes parotitis, orchitis, oophoritis, meningitis, encephalitis, and sensorineural hearing loss. Although mumps is a vaccine-preventable disease, sporadic outbreaks have occurred worldwide, even in highly vaccinated populations. MuV not only causes systemic infection but also [...] Read more.
Mumps virus (MuV) is an important human pathogen that causes parotitis, orchitis, oophoritis, meningitis, encephalitis, and sensorineural hearing loss. Although mumps is a vaccine-preventable disease, sporadic outbreaks have occurred worldwide, even in highly vaccinated populations. MuV not only causes systemic infection but also has a unique tropism to glandular tissues and the central nervous system. In general, tropism can be defined by multiple factors in the viral life cycle, including its entry, interaction with host factors, and host-cell immune responses. Although the underlying mechanisms of MuV tropism remain to be fully understood, recent studies on virus–host interactions have provided insights into viral pathogenesis. This review was aimed at summarizing the entry process of MuV by focusing on the glycan receptors, particularly the recently identified receptors with a trisaccharide core motif, and their interactions with the viral attachment proteins. Here, we describe the receptor structures, their distribution in the human body, and the recently identified host factors for MuV and analyze their relationship with MuV tropism. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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14 pages, 1554 KiB  
Review
Adaptation and Virulence of Enterovirus-A71
by Kyousuke Kobayashi and Satoshi Koike
Viruses 2021, 13(8), 1661; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081661 - 21 Aug 2021
Cited by 9 | Viewed by 3244
Abstract
Outbreaks of hand, foot, and mouth disease caused by enterovirus-A71 (EV-A71) can result in many deaths, due to central nervous system complications. Outbreaks with many fatalities have occurred sporadically in the Asia-Pacific region and have become a serious public health concern. It is [...] Read more.
Outbreaks of hand, foot, and mouth disease caused by enterovirus-A71 (EV-A71) can result in many deaths, due to central nervous system complications. Outbreaks with many fatalities have occurred sporadically in the Asia-Pacific region and have become a serious public health concern. It is hypothesized that virulent mutations in the EV-A71 genome cause these occasional outbreaks. Analysis of EV-A71 neurovirulence determinants is important, but there are no virulence determinants that are widely accepted among researchers. This is because most studies have been done in artificially infected mouse models and because EV-A71 mutates very quickly to adapt to the artificial host environment. Although EV-A71 uses multiple receptors for infection, it is clear that adaptation-related mutations alter the binding specificity of the receptors and allow the virus to adopt the best entry route for each environment. Such mutations have confused interpretations of virulence in animal models. This article will discuss how environment-adapted mutations in EV-A71 occur, how they affect virulence, and how such mutations can be avoided. We also discuss future perspectives for EV-A71 virulence research. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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16 pages, 2281 KiB  
Review
How Do Flaviviruses Hijack Host Cell Functions by Phase Separation?
by Akatsuki Saito, Maya Shofa, Hirotaka Ode, Maho Yumiya, Junki Hirano, Toru Okamoto and Shige H. Yoshimura
Viruses 2021, 13(8), 1479; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081479 - 28 Jul 2021
Cited by 10 | Viewed by 3575
Abstract
Viral proteins interact with different sets of host cell components throughout the viral life cycle and are known to localize to the intracellular membraneless organelles (MLOs) of the host cell, where formation/dissolution is regulated by phase separation of intrinsically disordered proteins and regions [...] Read more.
Viral proteins interact with different sets of host cell components throughout the viral life cycle and are known to localize to the intracellular membraneless organelles (MLOs) of the host cell, where formation/dissolution is regulated by phase separation of intrinsically disordered proteins and regions (IDPs/IDRs). Viral proteins are rich in IDRs, implying that viruses utilize IDRs to regulate phase separation of the host cell organelles and augment replication by commandeering the functions of the organelles and/or sneaking into the organelles to evade the host immune response. This review aims to integrate current knowledge of the structural properties and intracellular localizations of viral IDPs to understand viral strategies in the host cell. First, the properties of viral IDRs are reviewed and similarities and differences with those of eukaryotes are described. The higher IDR content in viruses with smaller genomes suggests that IDRs are essential characteristics of viral proteins. Then, the interactions of the IDRs of flaviviruses with the MLOs of the host cell are investigated with emphasis on the viral proteins localized in the nucleoli and stress granules. Finally, the possible roles of viral IDRs in regulation of the phase separation of organelles and future possibilities for antiviral drug development are discussed. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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12 pages, 3071 KiB  
Review
The Molecular Evolution of Type 2 Vaccine-Derived Polioviruses in Individuals with Primary Immunodeficiency Diseases
by Kouichi Kitamura and Hiroyuki Shimizu
Viruses 2021, 13(7), 1407; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071407 - 20 Jul 2021
Cited by 8 | Viewed by 2373
Abstract
The oral poliovirus vaccine (OPV), which prevents person-to-person transmission of poliovirus by inducing robust intestinal immunity, has been a crucial tool for global polio eradication. However, polio outbreaks, mainly caused by type 2 circulating vaccine-derived poliovirus (cVDPV2), are increasing worldwide. Meanwhile, immunodeficiency-associated vaccine-derived [...] Read more.
The oral poliovirus vaccine (OPV), which prevents person-to-person transmission of poliovirus by inducing robust intestinal immunity, has been a crucial tool for global polio eradication. However, polio outbreaks, mainly caused by type 2 circulating vaccine-derived poliovirus (cVDPV2), are increasing worldwide. Meanwhile, immunodeficiency-associated vaccine-derived poliovirus (iVDPV) is considered another risk factor during the final stage of global polio eradication. Patients with primary immunodeficiency diseases are associated with higher risks for long-term iVDPV infections. Although a limited number of chronic iVDPV excretors were reported, the recent identification of a chronic type 2 iVDPV (iVDPV2) excretor in the Philippines highlights the potential risk of inapparent iVDPV infection for expanding cVDPV outbreaks. Further research on the genetic characterizations and molecular evolution of iVDPV2, based on comprehensive iVDPV surveillance, will be critical for elucidating the remaining risk of iVDPV2 during the post-OPV era. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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22 pages, 6880 KiB  
Review
Mechanism of Cross-Species Transmission, Adaptive Evolution and Pathogenesis of Hepatitis E Virus
by Putu Prathiwi Primadharsini, Shigeo Nagashima and Hiroaki Okamoto
Viruses 2021, 13(5), 909; https://0-doi-org.brum.beds.ac.uk/10.3390/v13050909 - 14 May 2021
Cited by 23 | Viewed by 3653
Abstract
Hepatitis E virus (HEV) is the leading cause of acute hepatitis worldwide. While the transmission in developing countries is dominated by fecal-oral route via drinking contaminated water, the zoonotic transmission is the major route of HEV infection in industrialized countries. The discovery of [...] Read more.
Hepatitis E virus (HEV) is the leading cause of acute hepatitis worldwide. While the transmission in developing countries is dominated by fecal-oral route via drinking contaminated water, the zoonotic transmission is the major route of HEV infection in industrialized countries. The discovery of new HEV strains in a growing number of animal species poses a risk to zoonotic infection. However, the exact mechanism and the determinant factors of zoonotic infection are not completely understood. This review will discuss the current knowledge on the mechanism of cross-species transmission of HEV infection, including viral determinants, such as the open reading frames (ORFs), codon usage and adaptive evolution, as well as host determinants, such as host cellular factors and the host immune status, which possibly play pivotal roles during this event. The pathogenesis of hepatitis E infection will be briefly discussed, including the special forms of this disease, including extrahepatic manifestations, chronic infection, and fulminant hepatitis in pregnant women. Full article
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
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