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Viruses
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Advances in Alphavirus Research
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Advances in Alphavirus Research

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

Deadline for manuscript submissions: closed (31 March 2018) | Viewed by 126992

Special Issue Editors

Dr. Tero Ahola

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Guest Editor
Department of Food and Environmental Sciences, Division of Microbiology and Biotechnology, University of Helsinki, Helsinki, Finland
Interests: RNA virus replication; alphaviruses; antivirals
Dr. Beate M. Kümmerer

E-Mail
Guest Editor
Institute of Virology, University of Bonn Medical Centre, Bonn, Germany
Interests: alpha- and flaviviruses; virus–host interaction; antivirals

Special Issue Information

Dear Colleagues,

Alphaviruses are common in nature, existing on most continents and in marine environments. In several countries, the usually-mosquito-borne alphaviruses cause sporadic cases or small epidemics of human disease. Larger epidemics have also occurred, most notably in the case of the worldwide spread of chikungunya virus in the recent past. The alphaviruses can easily be cultivated in the laboratory, and therefore they have served as important models for deciphering some of the basic aspects of the virus life cycle. To understand the pathogenesis of alphaviruses, which can cause different types of diseases, excellent model systems have been developed. However, there are still important gaps in understanding alphavirus replication, and host interactions. Notably, there are no approved antivirals or vaccines against any alphavirus. In this Special Issue, we hope to assemble a collection of research papers and reviews that together will offer a comprehensive view on alphaviruses. The topics can include any aspects of alphavirus biology.

Dr. Tero Ahola
Dr. Beate M. Kümmerer
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

  • alphavirus life cycle

  • alphavirus structural biology

  • alphavirus pathogenesis and animal models

  • alphavirus-host interactions

  • antivirals and vaccines against alphaviruses

  • alphavirus epidemiology

Published Papers (17 papers)

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Research

Jump to: Review

13 pages, 1242 KiB  
Article
Following Acute Encephalitis, Semliki Forest Virus is Undetectable in the Brain by Infectivity Assays but Functional Virus RNA Capable of Generating Infectious Virus Persists for Life
by Rennos Fragkoudis, Catherine M. Dixon-Ballany, Adrian K. Zagrajek, Lukasz Kedzierski and John K. Fazakerley
Viruses 2018, 10(5), 273; https://doi.org/10.3390/v10050273 - 18 May 2018
Cited by 11 | Viewed by 4791
Abstract
Alphaviruses are mosquito-transmitted RNA viruses which generally cause acute disease including mild febrile illness, rash, arthralgia, myalgia and more severely, encephalitis. In the mouse, peripheral infection with Semliki Forest virus (SFV) results in encephalitis. With non-virulent strains, infectious virus is detectable in the [...] Read more.
Alphaviruses are mosquito-transmitted RNA viruses which generally cause acute disease including mild febrile illness, rash, arthralgia, myalgia and more severely, encephalitis. In the mouse, peripheral infection with Semliki Forest virus (SFV) results in encephalitis. With non-virulent strains, infectious virus is detectable in the brain, by standard infectivity assays, for around ten days. As we have shown previously, in severe combined immunodeficient (SCID) mice, infectious virus is detectable for months in the brain. Here we show that in MHC-II-/- mice, with no functional CD4 T-cells, infectious virus is also detectable in the brain for long periods. In contrast, in the brains of CD8-/- mice, virus RNA persists but infectious virus is not detectable. In SCID mice infected with SFV, repeated intraperitoneal administration of anti-SFV immune serum rapidly reduced the titer of infectious virus in the brain to undetectable, however virus RNA persisted. Repeated intraperitoneal passive transfer of immune serum resulted in maintenance of brain virus RNA, with no detectable infectious virus, for several weeks. When passive antibody transfer was stopped, antibody levels declined and infectious virus was again detectable in the brain. In aged immunocompetent mice, previously infected with SFV, immunosuppression of antibody responses many months after initial infection also resulted in renewed ability to detect infectious virus in the brain. In summary, antiviral antibodies control and determine whether infectious virus is detectable in the brain but immune responses cannot clear this infection from the brain. Functional virus RNA capable of generating infectious virus persists and if antibody levels decline, infectious virus is again detectable. Full article
(This article belongs to the Special Issue Advances in Alphavirus Research)
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18 pages, 2525 KiB  
Article
Paradoxical Effect of Chloroquine Treatment in Enhancing Chikungunya Virus Infection
by Pierre Roques, Simon-Djamel Thiberville, Laurence Dupuis-Maguiraga, Fok-Moon Lum, Karine Labadie, Frédéric Martinon, Gabriel Gras, Pierre Lebon, Lisa F. P. Ng, Xavier De Lamballerie and Roger Le Grand
Viruses 2018, 10(5), 268; https://doi.org/10.3390/v10050268 - 17 May 2018
Cited by 121 | Viewed by 17522
Abstract
Since 2005, Chikungunya virus (CHIKV) re-emerged and caused numerous outbreaks in the world, and finally, was introduced into the Americas in 2013. The lack of CHIKV-specific therapies has led to the use of non-specific drugs. Chloroquine, which is commonly used to treat febrile [...] Read more.
Since 2005, Chikungunya virus (CHIKV) re-emerged and caused numerous outbreaks in the world, and finally, was introduced into the Americas in 2013. The lack of CHIKV-specific therapies has led to the use of non-specific drugs. Chloroquine, which is commonly used to treat febrile illnesses in the tropics, has been shown to inhibit CHIKV replication in vitro. To assess the in vivo effect of chloroquine, two complementary studies were performed: (i) a prophylactic study in a non-human primate model (NHP); and (ii) a curative study “CuraChik”, which was performed during the Reunion Island outbreak in 2006 in a human cohort. Clinical, biological, and immunological data were compared between treated and placebo groups. Acute CHIKV infection was exacerbated in NHPs treated with prophylactic administration of chloroquine. These NHPs displayed a higher viremia and slower viral clearance (p < 0.003). Magnitude of viremia was correlated to the type I IFN response (Rho = 0.8, p < 0.001) and severe lymphopenia (Rho = 0.8, p < 0.0001), while treatment led to a delay in both CHIKV-specific cellular and IgM responses (p < 0.02 and p = 0.04, respectively). In humans, chloroquine treatment did not affect viremia or clinical parameters during the acute stage of the disease (D1 to D14), but affected the levels of C-reactive Protein (CRP), IFNα, IL-6, and MCP1 over time (D1 to D16). Importantly, no positive effect could be detected on prevalence of persistent arthralgia at Day 300. Although inhibitory in vitro, chloroquine as a prophylactic treatment in NHPs enhances CHIKV replication and delays cellular and humoral response. In patients, curative chloroquine treatment during the acute phase decreases the levels of key cytokines, and thus may delay adaptive immune responses, as observed in NHPs, without any suppressive effect on peripheral viral load. Full article
(This article belongs to the Special Issue Advances in Alphavirus Research)
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12 pages, 1211 KiB  
Article
Encapsidated Host Factors in Alphavirus Particles Influence Midgut Infection of Aedes aegypti
by David Mackenzie-Liu, Kevin J. Sokoloski, Sarah Purdy and Richard W. Hardy
Viruses 2018, 10(5), 263; https://doi.org/10.3390/v10050263 - 16 May 2018
Cited by 7 | Viewed by 3428
Abstract
Transmission of mosquito-borne viruses requires the efficient infection of both a permissive vertebrate host and a competent mosquito vector. The infectivity of Sindbis virus (SINV), the type species of the Alphavirus genus, is influenced by both the original and new host cell. We [...] Read more.
Transmission of mosquito-borne viruses requires the efficient infection of both a permissive vertebrate host and a competent mosquito vector. The infectivity of Sindbis virus (SINV), the type species of the Alphavirus genus, is influenced by both the original and new host cell. We have shown that infection of vertebrate cells by SINV, chikungunya virus (CHIKV), and Ross River virus (RRV) produces two subpopulations of virus particles separable based on density. In contrast, a single population of viral particles is produced by mosquito cells. Previous studies demonstrated that the denser vertebrate-derived particles and the mosquito-derived particles contain components of the small subunit of the host cell ribosome, whereas the less dense vertebrate-derived particles do not. Infection of mice with RRV showed that both particle subpopulations are produced in an infected vertebrate, but in a tissue specific manner with serum containing only the less dense version of the virus particles. Previous infectivity studies using SINV particles have shown that the denser particles (SINVHeavy) and mosquito derived particles SINVC6/36 are significantly more infectious in vertebrate cells than the less dense vertebrate derived particles (SINVLight). The current study shows that SINVLight particles, initiate the infection of the mosquito midgut more efficiently than SINVHeavy particles and that this enhanced infectivity is associated with an exacerbated immune response to SINVLight infection in midgut tissues. The enhanced infection of SINVLight is specific to the midgut as intrathoracically injected virus do not exhibit the same fitness advantage. Together, our data indicate a biologically significant role for the SINVLight subpopulation in the efficient transmission from infected vertebrates to the mosquito vector. Full article
(This article belongs to the Special Issue Advances in Alphavirus Research)
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21 pages, 9244 KiB  
Article
Mutation of CD2AP and SH3KBP1 Binding Motif in Alphavirus nsP3 Hypervariable Domain Results in Attenuated Virus
by Margit Mutso, Ainhoa Moliner Morro, Cecilia Smedberg, Sergo Kasvandik, Muriel Aquilimeba, Mona Teppor, Liisi Tarve, Aleksei Lulla, Valeria Lulla, Sirle Saul, Bastian Thaa, Gerald M McInerney, Andres Merits and Margus Varjak
Viruses 2018, 10(5), 226; https://doi.org/10.3390/v10050226 - 27 Apr 2018
Cited by 29 | Viewed by 6850
Abstract
Infection by Chikungunya virus (CHIKV) of the Old World alphaviruses (family Togaviridae) in humans can cause arthritis and arthralgia. The virus encodes four non-structural proteins (nsP) (nsP1, nsp2, nsP3 and nsP4) that act as subunits of the virus replicase. These proteins also interact [...] Read more.
Infection by Chikungunya virus (CHIKV) of the Old World alphaviruses (family Togaviridae) in humans can cause arthritis and arthralgia. The virus encodes four non-structural proteins (nsP) (nsP1, nsp2, nsP3 and nsP4) that act as subunits of the virus replicase. These proteins also interact with numerous host proteins and some crucial interactions are mediated by the unstructured C-terminal hypervariable domain (HVD) of nsP3. In this study, a human cell line expressing EGFP tagged with CHIKV nsP3 HVD was established. Using quantitative proteomics, it was found that CHIKV nsP3 HVD can bind cytoskeletal proteins, including CD2AP, SH3KBP1, CAPZA1, CAPZA2 and CAPZB. The interaction with CD2AP was found to be most evident; its binding site was mapped to the second SH3 ligand-like element in nsP3 HVD. Further assessment indicated that CD2AP can bind to nsP3 HVDs of many different New and Old World alphaviruses. Mutation of the short binding element hampered the ability of the virus to establish infection. The mutation also abolished ability of CD2AP to co-localise with nsP3 and replication complexes of CHIKV; the same was observed for Semliki Forest virus (SFV) harbouring a similar mutation. Similar to CD2AP, its homolog SH3KBP1 also bound the identified motif in CHIKV and SFV nsP3. Full article
(This article belongs to the Special Issue Advances in Alphavirus Research)
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14 pages, 2456 KiB  
Article
Spindle-E Acts Antivirally Against Alphaviruses in Mosquito Cells
by Margus Varjak, Isabelle Dietrich, Vattipally B. Sreenu, Bethan Eluned Till, Andres Merits, Alain Kohl and Esther Schnettler
Viruses 2018, 10(2), 88; https://doi.org/10.3390/v10020088 - 18 Feb 2018
Cited by 26 | Viewed by 5902
Abstract
Mosquitoes transmit several human- and animal-pathogenic alphaviruses (Togaviridae family). In alphavirus-infected mosquito cells two different types of virus-specific small RNAs are produced as part of the RNA interference response: short-interfering (si)RNAs and PIWI-interacting (pi)RNAs. The siRNA pathway is generally thought to be [...] Read more.
Mosquitoes transmit several human- and animal-pathogenic alphaviruses (Togaviridae family). In alphavirus-infected mosquito cells two different types of virus-specific small RNAs are produced as part of the RNA interference response: short-interfering (si)RNAs and PIWI-interacting (pi)RNAs. The siRNA pathway is generally thought to be the main antiviral pathway. Although an antiviral activity has been suggested for the piRNA pathway its role in host defences is not clear. Knock down of key proteins of the piRNA pathway (Ago3 and Piwi5) in Aedes aegypti-derived cells reduced the production of alphavirus chikungunya virus (CHIKV)-specific piRNAs but had no effect on virus replication. In contrast, knock down of the siRNA pathway key protein Ago2 resulted in an increase in virus replication. Similar results were obtained when expression of Piwi4 was silenced. Knock down of the helicase Spindle-E (SpnE), an essential co-factor of the piRNA pathway in Drosophila melanogaster, resulted in increased virus replication indicating that SpnE acts as an antiviral against alphaviruses such as CHIKV and the related Semliki Forest virus (SFV). Surprisingly, this effect was found to be independent of the siRNA and piRNA pathways in Ae. aegypti cells and specific for alphaviruses. This suggests a small RNA-independent antiviral function for this protein in mosquitoes. Full article
(This article belongs to the Special Issue Advances in Alphavirus Research)
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10 pages, 3840 KiB  
Communication
Chondrocytes Contribute to Alphaviral Disease Pathogenesis as a Source of Virus Replication and Soluble Factor Production
by Elisa X. Y. Lim, Aroon Supramaniam, Hayman Lui, Peta Coles, Wai Suet Lee, Xiang Liu, Penny A. Rudd and Lara J. Herrero
Viruses 2018, 10(2), 86; https://doi.org/10.3390/v10020086 - 15 Feb 2018
Cited by 7 | Viewed by 4302
Abstract
Arthritogenic alphavirus infections often result in debilitating musculoskeletal disorders that affect the joints, muscle, and bone. In order to evaluate the infection profile of primary human skeletal muscle and chondrocyte cells to Ross River virus (RRV) in vitro, cells were infected at a [...] Read more.
Arthritogenic alphavirus infections often result in debilitating musculoskeletal disorders that affect the joints, muscle, and bone. In order to evaluate the infection profile of primary human skeletal muscle and chondrocyte cells to Ross River virus (RRV) in vitro, cells were infected at a multiplicity of infection (MOI) of 1 over a period of two days. Viral titers were determined by plaque assay and cytokine expression by Bio-Plex® assays using the supernatants harvested. Gene expression studies were conducted using total RNA isolated from cells. Firstly, we show that RRV RNA is detected in chondrocytes from infected mice in vivo. Both human primary skeletal muscle and chondrocyte cells are able to support productive RRV infection in vitro. We also report the production of soluble host factors including the upregulation of heparanase (HPSE) and inflammatory host factors such as interleukin-6 (IL-6), monocyte chemoattractant protein 1 (MCP-1), RANTES (regulated on activation, normal T cell expressed and secreted), interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α), which are also present during clinical disease in humans. Our study is the first to demonstrate that human chondrocyte cells are permissive to RRV infection, support the production of infectious virus, and produce soluble factors including HPSE, which may contribute to joint degradation and the pathogenesis of disease. Full article
(This article belongs to the Special Issue Advances in Alphavirus Research)
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3472 KiB  
Communication
Mutation of a Conserved Nuclear Export Sequence in Chikungunya Virus Capsid Protein Disrupts Host Cell Nuclear Import
by Susan C. Jacobs, Adam Taylor, Lara J. Herrero, Suresh Mahalingam and John K. Fazakerley
Viruses 2017, 9(10), 306; https://doi.org/10.3390/v9100306 - 20 Oct 2017
Cited by 7 | Viewed by 4694
Abstract
Transmitted by mosquitoes; chikungunya virus (CHIKV) is responsible for frequent outbreaks of arthritic disease in humans. CHIKV is an arthritogenic alphavirus of the Togaviridae family. Capsid protein, a structural protein encoded by the CHIKV RNA genome, is able to translocate to the host [...] Read more.
Transmitted by mosquitoes; chikungunya virus (CHIKV) is responsible for frequent outbreaks of arthritic disease in humans. CHIKV is an arthritogenic alphavirus of the Togaviridae family. Capsid protein, a structural protein encoded by the CHIKV RNA genome, is able to translocate to the host cell nucleus. In encephalitic alphaviruses nuclear translocation induces host cell shut off; however, the role of capsid protein nuclear localisation in arthritogenic alphaviruses remains unclear. Using replicon systems, we investigated a nuclear export sequence (NES) in the N-terminal region of capsid protein; analogous to that found in encephalitic alphavirus capsid but uncharacterised in CHIKV. The chromosomal maintenance 1 (CRM1) export adaptor protein mediated CHIKV capsid protein export from the nucleus and a region within the N-terminal part of CHIKV capsid protein was required for active nuclear targeting. In contrast to encephalitic alphaviruses, CHIKV capsid protein did not inhibit host nuclear import; however, mutating the NES of capsid protein (∆NES) blocked host protein access to the nucleus. Interactions between capsid protein and the nucleus warrant further investigation. Full article
(This article belongs to the Special Issue Advances in Alphavirus Research)
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2693 KiB  
Article
Polyprotein Processing as a Determinant for in Vitro Activity of Semliki Forest Virus Replicase
by Maija K. Pietilä, Irina C. Albulescu, Martijn J. van Hemert and Tero Ahola
Viruses 2017, 9(10), 292; https://doi.org/10.3390/v9100292 - 07 Oct 2017
Cited by 9 | Viewed by 5897
Abstract
Semliki Forest virus (SFV) is an arthropod-borne alphavirus that induces membrane invaginations (spherules) in host cells. These harbor the viral replication complexes (RC) that synthesize viral RNA. Alphaviruses have four replicase or nonstructural proteins (nsPs), nsP1–4, expressed as polyprotein P1234. An early RC, [...] Read more.
Semliki Forest virus (SFV) is an arthropod-borne alphavirus that induces membrane invaginations (spherules) in host cells. These harbor the viral replication complexes (RC) that synthesize viral RNA. Alphaviruses have four replicase or nonstructural proteins (nsPs), nsP1–4, expressed as polyprotein P1234. An early RC, which synthesizes minus-strand RNA, is formed by the polyprotein P123 and the polymerase nsP4. Further proteolytic cleavage results in a late RC consisting of nsP1–4 and synthesizing plus strands. Here, we show that only the late RCs are highly active in RNA synthesis in vitro. Furthermore, we demonstrate that active RCs can be isolated from both virus-infected cells and cells transfected with the wild-type replicase in combination with a plasmid expressing a template RNA. When an uncleavable polyprotein P123 and polymerase nsP4 were expressed together with a template, high levels of minus-strand RNA were produced in cells, but RCs isolated from these cells were hardly active in vitro. Furthermore, we observed that the uncleavable polyprotein P123 and polymerase nsP4, which have previously been shown to form spherules even in the absence of the template, did not replicate an exogenous template. Consequently, we hypothesize that the replicase proteins were sequestered in spherules and were no longer able to recruit a template. Full article
(This article belongs to the Special Issue Advances in Alphavirus Research)
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Review

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32 pages, 523 KiB  
Review
The Interplay of Viral and Host Factors in Chikungunya Virus Infection: Targets for Antiviral Strategies
by Kai Zhi Wong and Justin Jang Hann Chu
Viruses 2018, 10(6), 294; https://doi.org/10.3390/v10060294 - 30 May 2018
Cited by 38 | Viewed by 5695
Abstract
Chikungunya virus (CHIKV) has re-emerged as one of the many medically important arboviruses that have spread rampantly across the world in the past decade. Infected patients come down with acute fever and rashes, and a portion of them suffer from both acute and [...] Read more.
Chikungunya virus (CHIKV) has re-emerged as one of the many medically important arboviruses that have spread rampantly across the world in the past decade. Infected patients come down with acute fever and rashes, and a portion of them suffer from both acute and chronic arthralgia. Currently, there are no targeted therapeutics against this debilitating virus. One approach to develop potential therapeutics is by understanding the viral-host interactions. However, to date, there has been limited research undertaken in this area. In this review, we attempt to briefly describe and update the functions of the different CHIKV proteins and their respective interacting host partners. In addition, we also survey the literature for other reported host factors and pathways involved during CHIKV infection. There is a pressing need for an in-depth understanding of the interaction between the host environment and CHIKV in order to generate potential therapeutics. Full article
(This article belongs to the Special Issue Advances in Alphavirus Research)
40 pages, 28369 KiB  
Review
Current Strategies for Inhibition of Chikungunya Infection
by Bharat Bhusan Subudhi, Soma Chattopadhyay, Priyadarsee Mishra and Abhishek Kumar
Viruses 2018, 10(5), 235; https://doi.org/10.3390/v10050235 - 03 May 2018
Cited by 73 | Viewed by 9134
Abstract
Increasing incidences of Chikungunya virus (CHIKV) infection and co-infections with Dengue/Zika virus have highlighted the urgency for CHIKV management. Failure in developing effective vaccines or specific antivirals has fuelled further research. This review discusses updated strategies of CHIKV inhibition and provides possible future [...] Read more.
Increasing incidences of Chikungunya virus (CHIKV) infection and co-infections with Dengue/Zika virus have highlighted the urgency for CHIKV management. Failure in developing effective vaccines or specific antivirals has fuelled further research. This review discusses updated strategies of CHIKV inhibition and provides possible future directions. In addition, it analyzes advances in CHIKV lifecycle, drug-target development, and potential hits obtained by in silico and experimental methods. Molecules identified with anti-CHIKV properties using traditional/rational drug design and their potential to succeed in subsequent stages of drug development have also been discussed. Possibilities of repurposing existing drugs based on their in vitro findings have also been elucidated. Probable modes of interference of these compounds at various stages of infection, including entry and replication, have been highlighted. The use of host factors as targets to identify antivirals against CHIKV has been addressed. While most of the earlier antivirals were effective in the early phases of the CHIKV life cycle, this review is also focused on drug candidates that are effective at multiple stages of its life cycle. Since most of these antivirals require validation in preclinical and clinical models, the challenges regarding this have been discussed and will provide critical information for further research. Full article
(This article belongs to the Special Issue Advances in Alphavirus Research)
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15 pages, 2054 KiB  
Review
Alphavirus Nucleocapsid Packaging and Assembly
by Adriano Mendes and Richard J. Kuhn
Viruses 2018, 10(3), 138; https://doi.org/10.3390/v10030138 - 20 Mar 2018
Cited by 36 | Viewed by 6146
Abstract
Alphavirus nucleocapsids are assembled in the cytoplasm of infected cells from 240 copies of the capsid protein and the approximately 11 kb positive strand genomic RNA. However, the challenge of how the capsid specifically selects its RNA package and assembles around it has [...] Read more.
Alphavirus nucleocapsids are assembled in the cytoplasm of infected cells from 240 copies of the capsid protein and the approximately 11 kb positive strand genomic RNA. However, the challenge of how the capsid specifically selects its RNA package and assembles around it has remained an elusive one to solve. In this review, we will summarize what is known about the alphavirus capsid protein, the packaging signal, and their roles in the mechanism of packaging and assembly. We will review the discovery of the packaging signal and how there is as much evidence for, as well as against, its requirement to specify packaging of the genomic RNA. Finally, we will compare this model with those of other viral systems including particular reference to a relatively new idea of RNA packaging based on the presence of multiple minimal packaging signals throughout the genome known as the two stage mechanism. This review will provide a basis for further investigating the fundamental ways of how RNA viruses are able to select their own cargo from the relative chaos that is the cytoplasm. Full article
(This article belongs to the Special Issue Advances in Alphavirus Research)
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26 pages, 1183 KiB  
Review
The Enigmatic Alphavirus Non-Structural Protein 3 (nsP3) Revealing Its Secrets at Last
by Benjamin Götte, Lifeng Liu and Gerald M. McInerney
Viruses 2018, 10(3), 105; https://doi.org/10.3390/v10030105 - 28 Feb 2018
Cited by 75 | Viewed by 8288
Abstract
Alphaviruses encode 4 non-structural proteins (nsPs), most of which have well-understood functions in capping and membrane association (nsP1), polyprotein processing and RNA helicase activity (nsP2) and as RNA-dependent RNA polymerase (nsP4). The function of nsP3 has been more difficult to pin down and [...] Read more.
Alphaviruses encode 4 non-structural proteins (nsPs), most of which have well-understood functions in capping and membrane association (nsP1), polyprotein processing and RNA helicase activity (nsP2) and as RNA-dependent RNA polymerase (nsP4). The function of nsP3 has been more difficult to pin down and it has long been referred to as the more enigmatic of the nsPs. The protein comprises three domains, an N-terminal macro domain, a central zinc-binding domain and a C-terminal hypervariable domain (HVD). In this article, we review old and new literature about the functions of the three domains. Much progress in recent years has contributed to a picture of nsP3, particularly through its HVD as a hub for interactions with host cell molecules, with multiple effects on the biology of the host cell at early points in infection. These and many future discoveries will provide targets for anti-viral therapies as well as strategies for modification of vectors for vaccine and oncolytic interventions. Full article
(This article belongs to the Special Issue Advances in Alphavirus Research)
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21 pages, 1527 KiB  
Review
The Alphavirus Exit Pathway: What We Know and What We Wish We Knew
by Rebecca S. Brown, Judy J. Wan and Margaret Kielian
Viruses 2018, 10(2), 89; https://doi.org/10.3390/v10020089 - 22 Feb 2018
Cited by 61 | Viewed by 8904
Abstract
Alphaviruses are enveloped positive sense RNA viruses and include serious human pathogens, such as the encephalitic alphaviruses and Chikungunya virus. Alphaviruses are transmitted to humans primarily by mosquito vectors and include species that are classified as emerging pathogens. Alphaviruses assemble highly organized, spherical [...] Read more.
Alphaviruses are enveloped positive sense RNA viruses and include serious human pathogens, such as the encephalitic alphaviruses and Chikungunya virus. Alphaviruses are transmitted to humans primarily by mosquito vectors and include species that are classified as emerging pathogens. Alphaviruses assemble highly organized, spherical particles that bud from the plasma membrane. In this review, we discuss what is known about the alphavirus exit pathway during a cellular infection. We describe the viral protein interactions that are critical for virus assembly/budding and the host factors that are involved, and we highlight the recent discovery of cell-to-cell transmission of alphavirus particles via intercellular extensions. Lastly, we discuss outstanding questions in the alphavirus exit pathway that may provide important avenues for future research. Full article
(This article belongs to the Special Issue Advances in Alphavirus Research)
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17 pages, 1315 KiB  
Review
Mosquitoes as Suitable Vectors for Alphaviruses
by Elisa X. Y. Lim, Wai Suet Lee, Eugene T. Madzokere and Lara J. Herrero
Viruses 2018, 10(2), 84; https://doi.org/10.3390/v10020084 - 14 Feb 2018
Cited by 22 | Viewed by 8103
Abstract
Alphaviruses are arthropod-borne viruses and are predominantly transmitted via mosquito vectors. This vector preference by alphaviruses raises the important question of the determinants that contribute to vector competence. There are several tissue barriers of the mosquito that the virus must overcome in order [...] Read more.
Alphaviruses are arthropod-borne viruses and are predominantly transmitted via mosquito vectors. This vector preference by alphaviruses raises the important question of the determinants that contribute to vector competence. There are several tissue barriers of the mosquito that the virus must overcome in order to establish a productive infection. Of importance are the midgut, basal lamina and the salivary glands. Infection of the salivary glands is crucial for virus transmission during the mosquito’s subsequent bloodfeed. Other factors that may contribute to vector competence include the microflora and parasites present in the mosquito, environmental conditions, the molecular determinants of the virus to adapt to the vector, as well as the effect of co-infection with other viruses. Though mosquito innate immunity is a contributing factor to vector competence, it will not be discussed in this review. Detailed understanding of these factors will be instrumental in minimising transmission of alphaviral diseases. Full article
(This article belongs to the Special Issue Advances in Alphavirus Research)
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15 pages, 1791 KiB  
Review
Nonstructural Proteins of Alphavirus—Potential Targets for Drug Development
by Farhana Abu Bakar and Lisa F. P. Ng
Viruses 2018, 10(2), 71; https://doi.org/10.3390/v10020071 - 09 Feb 2018
Cited by 46 | Viewed by 8092
Abstract
Alphaviruses are enveloped, positive single-stranded RNA viruses, typically transmitted by arthropods. They often cause arthralgia or encephalitic diseases in infected humans and there is currently no targeted antiviral treatment available. The re-emergence of alphaviruses in Asia, Europe, and the Americas over the last [...] Read more.
Alphaviruses are enveloped, positive single-stranded RNA viruses, typically transmitted by arthropods. They often cause arthralgia or encephalitic diseases in infected humans and there is currently no targeted antiviral treatment available. The re-emergence of alphaviruses in Asia, Europe, and the Americas over the last decade, including chikungunya and o’nyong’nyong viruses, have intensified the search for selective inhibitors. In this review, we highlight key molecular determinants within the alphavirus replication complex that have been identified as viral targets, focusing on their structure and functionality in viral dissemination. We also summarize recent structural data of these viral targets and discuss how these could serve as templates to facilitate structure-based drug design and development of small molecule inhibitors. Full article
(This article belongs to the Special Issue Advances in Alphavirus Research)
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28 pages, 5845 KiB  
Review
The Regulation of Translation in Alphavirus-Infected Cells
by Luis Carrasco, Miguel Angel Sanz and Esther González-Almela
Viruses 2018, 10(2), 70; https://doi.org/10.3390/v10020070 - 08 Feb 2018
Cited by 50 | Viewed by 9337
Abstract
Sindbis virus (SINV) contains an RNA genome of positive polarity with two open reading frames (ORFs). The first ORF is translated from the genomic RNA (gRNA), rendering the viral non-structural proteins, whereas the second ORF is translated from a subgenomic mRNA (sgRNA), which [...] Read more.
Sindbis virus (SINV) contains an RNA genome of positive polarity with two open reading frames (ORFs). The first ORF is translated from the genomic RNA (gRNA), rendering the viral non-structural proteins, whereas the second ORF is translated from a subgenomic mRNA (sgRNA), which directs the synthesis of viral structural proteins. SINV infection strongly inhibits host cell translation through a variety of different mechanisms, including the phosphorylation of the eukaryotic initiation factor eIF2α and the redistribution of cellular proteins from the nucleus to the cytoplasm. A number of motifs have been identified in SINV sgRNA, including a hairpin downstream of the AUG initiation codon, which is involved in the translatability of the viral sgRNA when eIF2 is inactivated. Moreover, a 3′-UTR motif containing three stem-loop structures is involved in the enhancement of translation in insect cells, but not in mammalian cells. Accordingly, SINV sgRNA has evolved several structures to efficiently compete for the cellular translational machinery. Mechanistically, sgRNA translation involves scanning of the 5′-UTR following a non-canonical mode and without the requirement for several initiation factors. Indeed, sgRNA-directed polypeptide synthesis occurs even after eIF4G cleavage or inactivation of eIF4A by selective inhibitors. Remarkably, eIF2α phosphorylation does not hamper sgRNA translation during the late phase of SINV infection. SINV sgRNA thus constitutes a unique model of a capped viral mRNA that is efficiently translated in the absence of several canonical initiation factors. The present review will mainly focus in the non-canonical mechanism of translation of SINV sgRNA. Full article
(This article belongs to the Special Issue Advances in Alphavirus Research)
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3055 KiB  
Review
Disentangling the Frames, the State of Research on the Alphavirus 6K and TF Proteins
by Jolene Ramsey and Suchetana Mukhopadhyay
Viruses 2017, 9(8), 228; https://doi.org/10.3390/v9080228 - 18 Aug 2017
Cited by 35 | Viewed by 7773
Abstract
For 30 years it was thought the alphavirus 6K gene encoded a single 6 kDa protein. However, through a bioinformatics search 10 years ago, it was discovered that there is a frameshifting event and two proteins, 6K and transframe (TF), are translated from [...] Read more.
For 30 years it was thought the alphavirus 6K gene encoded a single 6 kDa protein. However, through a bioinformatics search 10 years ago, it was discovered that there is a frameshifting event and two proteins, 6K and transframe (TF), are translated from the 6K gene. Thus, many functions attributed to the 6K protein needed reevaluation to determine if they properly belong to 6K, TF, or both proteins. In this mini-review, we reevaluate the past research on 6K and put those results in context where there are two proteins, 6K and TF, instead of one. Additionally, we discuss the most cogent outstanding questions for 6K and TF research, including their collective importance in alphavirus budding and their potential importance in disease based on the latest virulence data. Full article
(This article belongs to the Special Issue Advances in Alphavirus Research)
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