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Molecular Biology of RNA Viruses

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

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 25526

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Prof. Dr. Yiping Li

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Guest Editor

Institute of Human Virology, Zhongshan School of Medicine, Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Sun Yat-sen University, Guangzhou 510080, China
Interests: life cycle of RNA viruses; virus–host interaction; Flaviviridae viruses; coronaviruses; vector-borne viruses; RNA modifications; reverse genetic systems; infection models; antiviral drugs; antiviral immunity; antibodies

Prof. Dr. Yuliang Liu

E-Mail Website
Guest Editor

China Animal Disease Control Center (CADC), Beijing 102618, China
Interests: virus–host interactions; reverse-genetics; vaccine development; reference material; avian influenza virus; Ebola virus; Newcastle disease virus; African swine fever virus; diagnostic technology; animal diseases

Special Issue Information

Dear Colleagues,

RNA viruses possess ribonucleic acid as their genetic material and constitute a large proportion of the known viruses. New RNA viruses are continually discovered, accelerated by the establishment and application of novel genetic identification technology, such as next-generation sequencing. RNA viruses infect humans, animals, plants, and other microorganisms, and medically and agriculturally important RNA viruses have caused immeasurable health problems and socioeconomic losses worldwide. The worst example is probably the ongoing COVID-19 pandemic.

RNA viruses are diverse mostly in their genomic organization, including segmented or non-segmented; positive, negative, or ambisense; and single- or double-stranded RNAs. Other characteristics include their replication mechanisms, which commonly depend on the RNA-dependent RNA-polymerase to generate RNA intermediates required to replicate their RNA genomes. The viral life cycle includes, at a minimum, RNA replication, translation, precursor protein processing, RNA packaging, morphogenesis and the release of virions, which is completed in the infected host cells. The functions of viral RNA elements and proteins, as well as their interaction with host factors, also correlate with the pathogenesis of the virus. Understanding the molecular virology of RNA viruses is vitally important, as it lays the foundation for the development of strategies of therapeutics, prevention and control or of maintaining a balance of commensalism without causing harm or damage to the host.

Research on the molecular biology of RNA viruses has achieved great progression, especially in animal and human pathogenic RNA viruses (human immunodeficiency virus, hepatitis C virus, dengue virus, Zika virus, influenza virus, coronaviruses, etc.). Scientists worldwide have developed new technologies or adopted state-of-the-art technology and interdisciplinary concepts to study RNA viruses at the molecular level. Accumulating research outcomes have rapidly improved our understanding of various aspects of RNA viruses, particularly our knowledge of the molecular biology of RNA viruses.

To present and share the most up-to-date progress on the molecular biology of RNA viruses with the community, it is expedient to launch a Special Issue on "Molecular Biology of RNA Viruses" in the journal Viruses. This Special Issue will collect excellent and high-impact research findings on RNA viruses including, but not limited to, the life cycle of RNA viruses, functions of viral RNA or proteins, virus–host interaction, host tropism, RNA modifications, reverse genetic platforms, infection models, antiviral drugs, drug resistance, antiviral immunity, and the pathogenesis of RNA viruses.

Aims and Scope (not an exhaustive list):

Mechanism of viral life cycle (e.g., infection, replication, packaging, budding).
Virus–host interactions.
Virus–viral protein interactions.
RNA modification.
Viral protein biology.
Emerging and reemerging RNA viruses.
Infection models.

We thank you in advance for your contributions.

Prof. Dr. Yiping Li
Prof. Dr. Yuliang Liu
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

RNA viruses
Molecular biology
Viral membrane/capsid/structural protein
Viral gene functions
Viral life cycle

Published Papers (11 papers)

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Research

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12 pages, 2087 KiB

Open AccessArticle

Allosteric Inhibitors of Zika Virus NS2B-NS3 Protease Targeting Protease in “Super-Open” Conformation

by Ittipat Meewan, Sergey A. Shiryaev, Julius Kattoula, Chun-Teng Huang, Vivian Lin, Chiao-Han Chuang, Alexey V. Terskikh and Ruben Abagyan

Viruses 2023, 15(5), 1106; https://doi.org/10.3390/v15051106 - 30 Apr 2023

Cited by 1 | Viewed by 1873

Abstract

The Zika virus (ZIKV), a member of the Flaviviridae family, is considered a major health threat causing multiple cases of microcephaly in newborns and Guillain-Barré syndrome in adults. In this study, we targeted a transient, deep, and hydrophobic pocket of the “super-open” conformation of ZIKV NS2B-NS3 protease to overcome the limitations of the active site pocket. After virtual docking screening of approximately seven million compounds against the novel allosteric site, we selected the top six candidates and assessed them in enzymatic assays. Six candidates inhibited ZIKV NS2B-NS3 protease proteolytic activity at low micromolar concentrations. These six compounds, targeting the selected protease pocket conserved in ZIKV, serve as unique drug candidates and open new opportunities for possible treatment against several flavivirus infections. Full article

(This article belongs to the Special Issue Molecular Biology of RNA Viruses)

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15 pages, 6010 KiB

Open AccessEditor’s ChoiceArticle

Noncoding RNA of Zika Virus Affects Interplay between Wnt-Signaling and Pro-Apoptotic Pathways in the Developing Brain Tissue

by Andrii Slonchak, Harman Chaggar, Julio Aguado, Ernst Wolvetang and Alexander A. Khromykh

Viruses 2023, 15(5), 1062; https://doi.org/10.3390/v15051062 - 26 Apr 2023

Cited by 1 | Viewed by 1879

Abstract

Zika virus (ZIKV) has a unique ability among flaviviruses to cross the placental barrier and infect the fetal brain causing severe abnormalities of neurodevelopment known collectively as congenital Zika syndrome. In our recent study, we demonstrated that the viral noncoding RNA (subgenomic flaviviral RNA, sfRNA) of the Zika virus induces apoptosis of neural progenitors and is required for ZIKV pathogenesis in the developing brain. Herein, we expanded on our initial findings and identified biological processes and signaling pathways affected by the production of ZIKV sfRNA in the developing brain tissue. We employed 3D brain organoids generated from induced human pluripotent stem cells (ihPSC) as an ex vivo model of viral infection in the developing brain and utilized wild type (WT) ZIKV (producing sfRNA) and mutant ZIKV (deficient in the production of sfRNA). Global transcriptome profiling by RNA-Seq revealed that the production of sfRNA affects the expression of >1000 genes. We uncovered that in addition to the activation of pro-apoptotic pathways, organoids infected with sfRNA-producing WT, but not sfRNA-deficient mutant ZIKV, which exhibited a strong down-regulation of genes involved in signaling pathways that control neuron differentiation and brain development, indicating the requirement of sfRNA for the suppression of neurodevelopment associated with the ZIKV infection. Using gene set enrichment analysis and gene network reconstruction, we demonstrated that the effect of sfRNA on pathways that control brain development occurs via crosstalk between Wnt-signaling and proapoptotic pathways. Full article

(This article belongs to the Special Issue Molecular Biology of RNA Viruses)

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23 pages, 11375 KiB

Open AccessEditor’s ChoiceArticle

Development and Characterization of Efficient Cell Culture Systems for Genotype 1 Hepatitis E Virus and Its Infectious cDNA Clone

by Putu Prathiwi Primadharsini, Shigeo Nagashima, Toshinori Tanaka, Suljid Jirintai, Masaharu Takahashi, Kazumoto Murata and Hiroaki Okamoto

Viruses 2023, 15(4), 845; https://doi.org/10.3390/v15040845 - 26 Mar 2023

Cited by 2 | Viewed by 2049

Abstract

Hepatitis E virus (HEV) is a major cause of acute viral hepatitis globally. Genotype 1 HEV (HEV-1) is responsible for multiple outbreaks in developing countries, causing high mortality rates in pregnant women. However, studies on HEV-1 have been hindered by its poor replication in cultured cells. The JE04-1601S strain recovered from a Japanese patient with fulminant hepatitis E who contracted HEV-1 while traveling to India was serially passaged 12 times in human cell lines. The cell-culture-generated viruses (passage 12; p12) grew efficiently in human cell lines, but the replication was not fully supported in porcine cells. A full-length cDNA clone was constructed using JE04-1601S_p12 as a template. It was able to produce an infectious virus, and viral protein expression was detectable in the transfected PLC/PRF/5 cells and culture supernatants. Consistently, HEV-1 growth was also not fully supported in the cell culture of cDNA-derived JE04-1601S_p12 progenies, potentially recapitulating the narrow tropism of HEV-1 observed in vivo. The availability of an efficient cell culture system for HEV-1 and its infectious cDNA clone will be useful for studying HEV species tropism and mechanisms underlying severe hepatitis in HEV-1-infected pregnant women as well as for discovering and developing safer treatment options for this condition. Full article

(This article belongs to the Special Issue Molecular Biology of RNA Viruses)

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14 pages, 4014 KiB

Open AccessArticle

Host Desmin Interacts with RABV Matrix Protein and Facilitates Virus Propagation

by Wen Zhang, Yuming Liu, Mengru Li, Jian Zhu, Xiaoning Li, Ting Rong Luo and Jingjing Liang

Viruses 2023, 15(2), 434; https://doi.org/10.3390/v15020434 - 04 Feb 2023

Cited by 2 | Viewed by 1539

Abstract

Microfilaments and microtubules, two crucial structures of cytoskeletal networks, are usurped by various viruses for their entry, egress, and/or intracellular trafficking, including the Rabies virus (RABV). Intermediate filaments (IFs) are the third major component of cytoskeletal filaments; however, little is known about the role of IFs during the RABV infection. Here, we identified the IF protein desmin as a novel host interactor with the RABV matrix protein, and we show that this physical interaction has a functional impact on the virus lifecycle. We found that the overexpression of desmin facilitates the RABV infection by increasing the progeny virus yield, and the suppression of endogenous desmin inhibits virus replication. Furthermore, we used confocal microscopy to observe that the RABV-M co-localizes with desmin in IF bundles in the BHK-21 cells. Lastly, we found that mice challenged with RABV displayed an enhanced expression of desmin in the brains of infected animals. These findings reveal a desmin/RABV-M interaction that positively regulates the virus infection and suggests that the RABV may utilize cellular IFs as tracks for the intracellular transport of viral components and efficient budding. Full article

(This article belongs to the Special Issue Molecular Biology of RNA Viruses)

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16 pages, 2608 KiB

Open AccessArticle

Putative Mitoviruses without In-Frame UGA(W) Codons: Evolutionary Implications

by Andrés Gustavo Jacquat, Martín Gustavo Theumer and José Sebastián Dambolena

Viruses 2023, 15(2), 340; https://doi.org/10.3390/v15020340 - 25 Jan 2023

Cited by 2 | Viewed by 1578

Abstract

Mitoviruses are small vertically transmitted RNA viruses found in fungi, plants and animals. Taxonomically, a total of 105 species and 4 genera have been formally recognized by ICTV, and recently, 18 new putative species have been included in a new proposed genus. Transcriptomic and metatranscriptomic studies are a major source of countless new virus-like sequences that are continually being added to open databases and these may be good sources for identifying new putative mitoviruses. The search for mitovirus-like sequences in the NCBI databases resulted in the discovery of more than one hundred new putative mitoviruses, with important implications for taxonomy and also for the evolutionary scenario. Here, we propose the inclusion of four new putative members to the genus Kvaramitovirus, and the existence of a new large basally divergent lineage composed of 144 members that lack internal UGA codons (subfamily “Arkeomitovirinae”), a feature not shared by the vast majority of mitoviruses. Finally, a taxonomic categorization proposal and a detailed description of the evolutionary history of mitoviruses were carried out. This in silico study supports the hypothesis of the existence of a basally divergent lineage that could have had an impact on the early evolutionary history of mitoviruses. Full article

(This article belongs to the Special Issue Molecular Biology of RNA Viruses)

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19 pages, 3572 KiB

Open AccessArticle

Comparison of a Genotype 1 and a Genotype 2 Macaque Foamy Virus env Gene Indicates Distinct Infectivity and Cell-Cell Fusion but Similar Tropism and Restriction of Cell Entry by Interferon-Induced Transmembrane Proteins

by Thomas Fricke, Sarah Schlagowski, Shanchuan Liu, Xiaoliang Yang, Uwe Fiebig, Artur Kaul, Armin Ensser and Alexander S. Hahn

Viruses 2023, 15(2), 262; https://doi.org/10.3390/v15020262 - 17 Jan 2023

Viewed by 1384

Abstract

Foamy viruses (FVs) are naturally found in many different animals and also in primates with the notable exception of humans, but zoonotic infections are common. In several species, two different envelope (env) gene sequence clades or genotypes exist. We constructed a simian FV (SFV) clone containing a reporter gene cassette. In this background, we compared the env genes of the SFVmmu-DPZ9524 (genotype 1) and of the SFVmmu_R289hybAGM (genotype 2) isolates. SFVmmu_R289hybAGM env-driven infection was largely resistant to neutralization by SFVmmu-DPZ9524-neutralizing sera. While SFVmmu_R289hybAGM env consistently effected higher infectivity and cell-cell fusion, we found no differences in the cell tropism conferred by either env across a range of different cells. Infection by both viruses was weakly and non-significantly enhanced by simultaneous knockout of interferon-induced transmembrane proteins (IFITMs) 1, 2, and 3 in A549 cells, irrespective of prior interferon stimulation. Infection was modestly reduced by recombinant overexpression of IFITM3, suggesting that the SFV entry step might be weakly restricted by IFITM3 under some conditions. Overall, our results suggest that the different env gene clades in macaque foamy viruses induce genotype-specific neutralizing antibodies without exhibiting overt differences in cell tropism, but individual env genes may differ significantly with regard to fitness. Full article

(This article belongs to the Special Issue Molecular Biology of RNA Viruses)

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13 pages, 2942 KiB

Open AccessArticle

ZDHHC11 Suppresses Zika Virus Infections by Palmitoylating the Envelope Protein

by Dingwen Hu, Haimei Zou, Weijie Chen, Yuting Li, Ziqing Luo, Xianyang Wang, Dekuan Guo, Yu Meng, Feng Liao, Wenbiao Wang, Ying Zhu, Jianguo Wu and Geng Li

Viruses 2023, 15(1), 144; https://doi.org/10.3390/v15010144 - 02 Jan 2023

Cited by 1 | Viewed by 1847

Abstract

Zika virus (ZIKV) is an RNA-enveloped virus that belongs to the Flavivirus genus, and ZIKV infections potentially induce severe neurodegenerative diseases and impair male fertility. Palmitoylation is an important post-translational modification of proteins that is mediated by a series of DHHC-palmitoyl transferases, which are implicated in various biological processes and viral infections. However, it remains to be investigated whether palmitoylation regulates ZIKV infections. In this study, we initially observed that the inhibition of palmitoylation by 2-bromopalmitate (2-BP) enhanced ZIKV infections, and determined that the envelope protein of ZIKV is palmitoylated at Cys308. ZDHHC11 was identified as the predominant enzyme that interacts with the ZIKV envelope protein and catalyzes its palmitoylation. Notably, ZDHHC11 suppressed ZIKV infections in an enzymatic activity-dependent manner and ZDHHC11 knockdown promoted ZIKV infection. In conclusion, we proposed that the envelope protein of ZIKV undergoes a novel post-translational modification and identified a distinct mechanism in which ZDHHC11 suppresses ZIKV infections via palmitoylation of the ZIKV envelope protein. Full article

(This article belongs to the Special Issue Molecular Biology of RNA Viruses)

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17 pages, 1901 KiB

Open AccessArticle

Development and Characterization of a Genetically Stable Infectious Clone for a Genotype I Isolate of Dengue Virus Serotype 1

by Mingyue Hu, Tiantian Wu, Yang Yang, Tongling Chen, Jiawei Hao, Youchuan Wei, Tingrong Luo, De Wu and Yi-Ping Li

Viruses 2022, 14(9), 2073; https://doi.org/10.3390/v14092073 - 18 Sep 2022

Cited by 2 | Viewed by 2536

Abstract

Dengue virus (DENV) is primarily transmitted by the bite of an infected mosquito of Aedes aegypti and Aedes albopictus, and symptoms caused may range from mild dengue fever to severe dengue hemorrhagic fever and dengue shock syndrome. Reverse genetic system represents a valuable tool for the study of DENV virology, infection, pathogenesis, etc. Here, we generated and characterized an eukaryotic-activated full-length infectious cDNA clone for a DENV serotype 1 (DENV-1) isolate, D19044, collected in 2019. Initially, nearly the full genome was determined by sequencing overlapping RT-PCR products, and was classified to be genotype I DENV-1. D19044 wild-type cDNA clone (D19044_WT) was assembled by four subgenomic fragments, in a specific order, into a low-copy vector downstream the CMV promoter. D19044_WT released the infectious virus at a low level (1.26 × 10³ focus forming units per milliliter [FFU/mL]) following plasmid transfection of BHK-21 cells. Further adaptation by consecutive virus passages up to passage 37, and seven amino acid substitutions (7M) were identified from passage-recovered viruses. The addition of 7M (D19044_7M) greatly improved viral titer (7.5 × 10⁴ FFU/mL) in transfected BHK-21 culture, and virus infections in 293T, Huh7.5.1, and C6/36 cells were also efficient. D19044_7M plasmid was genetically stable in transformant bacteria after five transformation-purification cycles, which did not change the capacity of producing infectious virus. Moreover, the D19044_7M virus was inhibited by mycophenolic acid in a dose-dependent manner. In conclusion, we have developed a DNA-launched full-length infectious clone for a genotype I isolate of DENV-1, with genetic stability in transformant bacteria, thus providing a useful tool for the study of DENV-1. Full article

(This article belongs to the Special Issue Molecular Biology of RNA Viruses)

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Review

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38 pages, 2207 KiB

Open AccessReview

Host Responses to Respiratory Syncytial Virus Infection

by Ayse Agac, Sophie M. Kolbe, Martin Ludlow, Albert D. M. E. Osterhaus, Robert Meineke and Guus F. Rimmelzwaan

Viruses 2023, 15(10), 1999; https://doi.org/10.3390/v15101999 - 26 Sep 2023

Cited by 5 | Viewed by 3080

Abstract

Respiratory syncytial virus (RSV) infections are a constant public health problem, especially in infants and older adults. Virtually all children will have been infected with RSV by the age of two, and reinfections are common throughout life. Since antigenic variation, which is frequently observed among other respiratory viruses such as SARS-CoV-2 or influenza viruses, can only be observed for RSV to a limited extent, reinfections may result from short-term or incomplete immunity. After decades of research, two RSV vaccines were approved to prevent lower respiratory tract infections in older adults. Recently, the FDA approved a vaccine for active vaccination of pregnant women to prevent severe RSV disease in infants during their first RSV season. This review focuses on the host response to RSV infections mediated by epithelial cells as the first physical barrier, followed by responses of the innate and adaptive immune systems. We address possible RSV-mediated immunomodulatory and pathogenic mechanisms during infections and discuss the current vaccine candidates and alternative treatment options. Full article

(This article belongs to the Special Issue Molecular Biology of RNA Viruses)

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15 pages, 1407 KiB

Open AccessReview

Molecular Interaction of Nonsense-Mediated mRNA Decay with Viruses

by Md Robel Ahmed and Zhiyou Du

Viruses 2023, 15(4), 816; https://doi.org/10.3390/v15040816 - 23 Mar 2023

Cited by 1 | Viewed by 2395

Abstract

The virus–host interaction is dynamic and evolutionary. Viruses have to fight with hosts to establish successful infection. Eukaryotic hosts are equipped with multiple defenses against incoming viruses. One of the host antiviral defenses is the nonsense-mediated mRNA decay (NMD), an evolutionarily conserved mechanism for RNA quality control in eukaryotic cells. NMD ensures the accuracy of mRNA translation by removing the abnormal mRNAs harboring pre-matured stop codons. Many RNA viruses have a genome that contains internal stop codon(s) (iTC). Akin to the premature termination codon in aberrant RNA transcripts, the presence of iTC would activate NMD to degrade iTC-containing viral genomes. A couple of viruses have been reported to be sensitive to the NMD-mediated antiviral defense, while some viruses have evolved with specific cis-acting RNA features or trans-acting viral proteins to overcome or escape from NMD. Recently, increasing light has been shed on the NMD–virus interaction. This review summarizes the current scenario of NMD-mediated viral RNA degradation and classifies various molecular means by which viruses compromise the NMD-mediated antiviral defense for better infection in their hosts. Full article

(This article belongs to the Special Issue Molecular Biology of RNA Viruses)

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18 pages, 2879 KiB

Open AccessReview

Host Cell Targets for Unconventional Antivirals against RNA Viruses

by Vicky C. Roa-Linares, Manuela Escudero-Flórez, Miguel Vicente-Manzanares and Juan C. Gallego-Gómez

Viruses 2023, 15(3), 776; https://doi.org/10.3390/v15030776 - 17 Mar 2023

Cited by 7 | Viewed by 3173

Abstract

The recent COVID-19 crisis has highlighted the importance of RNA-based viruses. The most prominent members of this group are SARS-CoV-2 (coronavirus), HIV (human immunodeficiency virus), EBOV (Ebola virus), DENV (dengue virus), HCV (hepatitis C virus), ZIKV (Zika virus), CHIKV (chikungunya virus), and influenza A virus. With the exception of retroviruses which produce reverse transcriptase, the majority of RNA viruses encode RNA-dependent RNA polymerases which do not include molecular proofreading tools, underlying the high mutation capacity of these viruses as they multiply in the host cells. Together with their ability to manipulate the immune system of the host in different ways, their high mutation frequency poses a challenge to develop effective and durable vaccination and/or treatments. Consequently, the use of antiviral targeting agents, while an important part of the therapeutic strategy against infection, may lead to the selection of drug-resistant variants. The crucial role of the host cell replicative and processing machinery is essential for the replicative cycle of the viruses and has driven attention to the potential use of drugs directed to the host machinery as therapeutic alternatives to treat viral infections. In this review, we discuss small molecules with antiviral effects that target cellular factors in different steps of the infectious cycle of many RNA viruses. We emphasize the repurposing of FDA-approved drugs with broad-spectrum antiviral activity. Finally, we postulate that the ferruginol analog (18-(phthalimide-2-yl) ferruginol) is a potential host-targeted antiviral. Full article

(This article belongs to the Special Issue Molecular Biology of RNA Viruses)

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