The Experts below are selected from a list of 4923 Experts worldwide ranked by ideXlab platform
Kenneth Lundstrom - One of the best experts on this subject based on the ideXlab platform.
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Alphaviruses in gene therapy.
Viruses, 2015Co-Authors: Kenneth LundstromAbstract:Alphavirus vectors present an attractive approach for gene therapy applications due to the rapid and simple recombinant virus particle production and their broad range of mammalian host cell transduction. Mainly three types of alphavirus vectors, namely naked RNA, recombinant particles and DNA/RNA layered vectors, have been subjected to preclinical studies with the goal of achieving prophylactic or therapeutic efficacy, particularly in oncology. In this context, immunization with alphavirus vectors has provided protection against challenges with tumor cells. Moreover, alphavirus intratumoral and systemic delivery has demonstrated substantial tumor regression and significant prolonged survival rates in various animal tumor models. Recent discoveries of the strong association of RNA interference and disease have accelerated gene therapy based approaches, where alphavirus-based gene delivery can play an important role.
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Alphavirus-Based Vaccines
Viruses, 2014Co-Authors: Kenneth LundstromAbstract:Alphavirus vectors have demonstrated high levels of transient heterologous gene expression both in vitro and in vivo and, therefore, possess attractive features for vaccine development. The most commonly used delivery vectors are based on three single-stranded encapsulated Alphaviruses, namely Semliki Forest virus, Sindbis virus and Venezuelan equine encephalitis virus. Alphavirus vectors have been applied as replication-deficient recombinant viral particles and, more recently, as replication-proficient particles. Moreover, in vitro transcribed RNA, as well as layered DNA vectors have been applied for immunization. A large number of highly immunogenic viral structural proteins expressed from alphavirus vectors have elicited strong neutralizing antibody responses in multispecies animal models. Furthermore, immunization studies have demonstrated robust protection against challenges with lethal doses of virus in rodents and primates. Similarly, vaccination with alphavirus vectors expressing tumor antigens resulted in prophylactic protection against challenges with tumor-inducing cancerous cells. As certain Alphaviruses, such as Chikungunya virus, have been associated with epidemics in animals and humans, attention has also been paid to the development of vaccines against Alphaviruses themselves. Recent progress in alphavirus vector development and vaccine technology has allowed conducting clinical trials in humans.
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Determination of Alphaviral Titers
CSH Protocols, 2012Co-Authors: Kenneth LundstromAbstract:The Alphaviruses Semliki Forest virus and Sindbis virus have been used frequently as expression vectors in vitro and in vivo. Usually, these systems consist of replication-deficient vectors that require a helper vector for packaging of recombinant particles. Replication-proficient vectors have also been engineered. Alphaviral vectors can be used as nucleic-acid-based vectors (DNA and RNA) or infectious particles. The broad host range of Alphaviruses facilitates studies in mammalian and nonmammalian cell lines, primary cells in culture, and in vivo. The strong preference for expression in neuronal cells has made Alphaviruses particularly useful in neurobiological studies. Unfortunately, their strong cytotoxic effect on host cells, relatively short-term transient expression patterns, and the reasonably high cost of viral production remain drawbacks. However, novel mutant Alphaviruses have showed reduced cytotoxicity and prolonged expression. Alphaviruses have also been applied in vaccine development and gene therapy. Before use in vitro or in vivo, it is essential to determine the titer of the generated alphaviral particles. Because defective Alphaviruses do not produce plaques, their titers cannot be determined by conventional methods. However, viral titers can be determined readily in cases where the recombinant viruses express reporter genes such as green fluorescent protein or β-galactosidase, as well as indirectly by immunofluorescence methods. The potency of viral stocks can also be evaluated by light microscopic analysis. Alphavirus-infected cells show a dramatic decrease in growth and can be easily distinguished from noninfected control cells through their rounded morphology.
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Alphaviruses in gene therapy.
Viruses, 2009Co-Authors: Kenneth LundstromAbstract:Alphaviruses are enveloped single stranded RNA viruses, which as gene therapy vectors provide high-level transient gene expression. Semliki Forest virus (SFV), Sindbis virus (SIN) and Venezuelan Equine Encephalitis (VEE) virus have been engineered as efficient replication-deficient and -competent expression vectors. Alphavirus vectors have frequently been used as vehicles for tumor vaccine generation. Moreover, SFV and SIN vectors have been applied for intratumoral injections in animals implanted with tumor xenografts. SIN vectors have demonstrated natural tumor targeting, which might permit systemic vector administration. Another approach for systemic delivery of SFV has been to encapsulate replication-deficient viral particles in liposomes, which can provide passive targeting to tumors and allow repeated administration without host immune responses. This approach has demonstrated safe delivery of encapsulated SFV particles to melanoma and kidney carcinoma patients in a phase I trial. Finally, the prominent neurotropism of Alphaviruses make them attractive for the treatment of CNS-related diseases.
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Alphaviruses as expression vectors.
Current opinion in biotechnology, 1997Co-Authors: Kenneth LundstromAbstract:Alphavirus vectors have been used for efficient high-level expression of a variety of topologically different proteins, allowing studies of protein transport, localization and functional activity in a broad range of host cells. Complex transmembrane proteins have been produced in large quantities through the establishment of scale-up technology. Alphavirus vectors have also shown promising potential in vaccine production and preliminary gene therapy applications.
Andres Merits - One of the best experts on this subject based on the ideXlab platform.
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Sensitivity of Alphaviruses to G3BP Deletion Correlates with Efficiency of Replicase Polyprotein Processing.
Journal of virology, 2020Co-Authors: Benjamin Götte, Andres Merits, Age Utt, Rennos Fragkoudis, Gerald M. McinerneyAbstract:We present a comprehensive overview of the dependency of several Old World Alphaviruses for the host protein G3BP. Based on their replication ability in G3BP-deleted cells, Old World Alphaviruses can be categorized into two groups, being either resistant or sensitive to G3BP deletion. We observed that all sensitive viruses have an Arg residue at the P4 position of the cleavage site between the nonstructural protein P1 (nsP1) and nsP2 regions of the replicase precursor polyprotein (1/2 site), while a different residue is found at this site in viruses resistant to G3BP deletion. Swapping this residue between resistant and sensitive viruses also switches the G3BP deletion sensitivity. In the absence of G3BP, chikungunya virus (CHIKV) replication is at the limit of detection. The P4 Arg-to-His substitution partially rescues this defect. The P4 residue of the 1/2 site is known to play a regulatory role during processing at this site, and we found that if processing is blocked, the influence of the P4 residue on the sensitivity to G3BP deletion is abolished. Immunofluorescence experiments with CHIKV replicase with manipulated processing indicate that the synthesis of double-stranded RNA is defective in the absence of G3BP and suggest a role of G3BP during negative-strand RNA synthesis. This study provides a functional link between the host protein G3BP and the P4 residue of the 1/2 site for viral RNA replication of Old World Alphaviruses. While this suggests a link between G3BP proteins and viral replicase polyprotein processing, we propose that G3BP proteins do not have a regulatory role during polyprotein processing.IMPORTANCE Old World Alphaviruses comprise several medically relevant viruses, including chikungunya virus and Ross River virus. Recurrent outbreaks and the lack of antivirals and vaccines demand ongoing research to fight the emergence of these infectious diseases. In this context, a thorough investigation of virus-host interactions is critical. Here, we highlight the importance of the host protein G3BP for several Old World Alphaviruses. Our data strongly suggest that G3BP plays a crucial role for the activity of the viral replicase and, thus, the amplification of the viral RNA genome. To our knowledge, the present work is the first to provide a functional link between the regulation of viral polyprotein processing and RNA replication and a host factor for Alphaviruses. Moreover, the results of this study raise several questions about the fundamental regulatory mechanisms that dictate the activity of the viral replicase, thereby paving the way for future studies.
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VCP/p97 Is a Proviral Host Factor for Replication of Chikungunya Virus and Other Alphaviruses
Frontiers in microbiology, 2019Co-Authors: Guillaume Carissimo, Yi-hao Chan, Age Utt, Tze-kwang Chua, Farhana Abu Bakar, Andres MeritsAbstract:The evolutionarily conserved AAA+ ATPase valosin-containing protein (VCP) was previously shown to be a proviral host factor for several viruses from different viral families such as Flaviviridae, Picornaviridae, and Herpesviridae. VCP was shown to affect trafficking of Sindbis virus receptor and functions as a component of Semliki Forest virus (SFV) replicase compartment. However, the role of this cellular protein was not evaluated during replication of Alphaviruses including chikungunya virus (CHIKV). Using siRNA, chemical inhibitors, and trans-replication assays, we show here that VCP is a proviral factor involved in the replication of CHIKV. Immunofluorescence assays confirmed that VCP co-localized with non-structural replicase proteins but not with dsRNA foci possibly due to VCP epitope unavailability. VCP pro-viral role is also observed with other Alphaviruses such as o'nyong'nyong virus (ONNV) and SFV in different human cell lines. VCP proviral roles on several viral families now extend to replication of Alphaviruses CHIKV and ONNV, emphasizing the pivotal role of VCP in virus-host interaction biology.
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vcp p97 is a proviral host factor for replication of chikungunya virus and other Alphaviruses
Frontiers in Microbiology, 2019Co-Authors: Guillaume Carissimo, Yi-hao Chan, Age Utt, Tze-kwang Chua, Farhana Abu Bakar, Andres MeritsAbstract:The evolutionarily conserved AAA+ ATPase valosin-containing protein (VCP) was previously shown to be a proviral host factor for several viruses from different viral families such as Flaviviridae, Picornaviridae, and Herpesviridae. VCP was shown to affect trafficking of Sindbis virus receptor and functions as a component of Semliki Forest virus (SFV) replicase compartment. However, the role of this cellular protein was not evaluated during replication of Alphaviruses including chikungunya virus (CHIKV). Using siRNA, chemical inhibitors, and trans-replication assays, we show here that VCP is a proviral factor involved in the replication of CHIKV. Immunofluorescence assays confirmed that VCP co-localized with non-structural replicase proteins but not with dsRNA foci possibly due to VCP epitope unavailability. VCP pro-viral role is also observed with other Alphaviruses such as o'nyong'nyong virus (ONNV) and SFV in different human cell lines. VCP proviral roles on several viral families now extend to replication of Alphaviruses CHIKV and ONNV, emphasizing the pivotal role of VCP in virus-host interaction biology.
Scott C. Weaver - One of the best experts on this subject based on the ideXlab platform.
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Arthritogenic Alphaviruses: epidemiological and clinical perspective on emerging arboviruses.
The Lancet. Infectious diseases, 2020Co-Authors: Ali Zaid, Scott C. Weaver, Andreas Suhrbier, Felicity J. Burt, Xiang Liu, Yee Suan Poo, Keivan Zandi, Mauro M Texeira, Suresh MahalingamAbstract:Mosquito-borne viruses, or arboviruses, have been part of the infectious disease landscape for centuries, and are often, but not exclusively, endemic to equatorial and subtropical regions of the world. The past two decades saw the re-emergence of arthritogenic Alphaviruses, a genus of arboviruses that includes several members that cause severe arthritic disease. Recent outbreaks further highlight the substantial public health burden caused by these viruses. Arthritogenic Alphaviruses are often reported in the context of focused outbreaks in specific regions (eg, Caribbean, southeast Asia, and Indian Ocean) and cause debilitating acute disease that can extend to chronic manifestations for years after infection. These viruses are classified among several antigenic complexes, span a range of hosts and mosquito vectors, and can be distributed along specific geographical locations. In this Review, we highlight key features of Alphaviruses that are known to cause arthritic disease in humans and outline the present findings pertaining to classification, immunogenicity, pathogenesis, and experimental approaches aimed at limiting disease manifestations. Although the most prominent alphavirus outbreaks in the past 15 years featured chikungunya virus, and a large body of work has been dedicated to understanding chikungunya disease mechanisms, this Review will instead focus on other arthritogenic Alphaviruses that have been identified globally and provide a comprehensive appraisal of present and future research directions.
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Alphaviruses in Latin America and the introduction of chikungunya virus
Human Virology in Latin America, 2017Co-Authors: Juan Carlos Navarro, Jean-paul Carrera, Jonathan Liria, Albert J. Auguste, Scott C. WeaverAbstract:Alphaviruses are enveloped, single-stranded, plus-strand RNA viruses belonging to the Togaviridae family. These are zoonotics and arthropod-borne viruses (mainly mosquitoes) that are distributed nearly worldwide. Many of the New World Alphaviruses occur throughout Latin America: Venezuelan and eastern equine encephalitis viruses (VEEV, EEEV) in both North and South America, and western equine encephalitis virus (WEEV) from Canada to Argentina. Others such as Mayaro (MAYV), UNA (UNAV), and Aura (AURA) viruses have a more restricted distribution, and chikungunya virus (CHIKV) was recently introduced into Latin America. The evolutionary patterns show clades correlated with host/reservoirs (nonhuman primates, birds, and rodents) and distinctive human disease syndromes such as fever/rash/arthralgia and encephalomyelitis. The majority of Alphaviruses cause at least mild febrile disease in humans and several produce severe, life-threatening diseases, whereas others are little studied epidemiologically and their public health importance is unknown. Recent studies in Latin America of “dengue-like” illness in several locations have revealed that many Alphaviruses such as VEEV, EEEV, MAYV, and CHIKV are misdiagnosed as dengue; moreover, with the recent introduction of Zika virus, diagnosis based only on signs and symptoms is even more complicated in areas where these viruses are circulating simultaneously. This chapter describes important aspects of the Alphaviruses in the region including evolution, outbreaks, vector–host, and eco-epidemiological/molecular determinants of their emergence from the New World viruses and chikungunya.
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ifit1 differentially interferes with translation and replication of alphavirus genomes and promotes induction of type i interferon
PLOS Pathogens, 2015Co-Authors: Josephine M Reynaud, Scott C. Weaver, Dal Young Kim, Svetlana Atasheva, Elena I Frolova, Aliaksandra Rasalouskaya, James P White, Michael S Diamond, Ilya FrolovAbstract:Alphaviruses are a group of widely distributed human and animal pathogens. It is well established that their replication is sensitive to type I IFN treatment, but the mechanism of IFN inhibitory function remains poorly understood. Using a new experimental system, we demonstrate that in the presence of IFN-β, activation of interferon-stimulated genes (ISGs) does not interfere with either attachment of alphavirus virions to the cells, or their entry and nucleocapsid disassembly. However, it strongly affects translation of the virion-delivered virus-specific RNAs. One of the ISG products, IFIT1 protein, plays a major role in this translation block, although an IFIT1-independent mechanism is also involved. The 5’UTRs of the alphavirus genomes were found to differ significantly in their ability to drive translation in the presence of increased concentration of IFIT1. Prior studies have shown that adaptation of naturally circulating Alphaviruses to replication in tissue culture results in accumulation of mutations in the 5’UTR, which increase the efficiency of the promoter located in the 5’end of the genome. Here, we show that these mutations also decrease resistance of viral RNA to IFIT1-induced translation inhibition. In the presence of higher levels of IFIT1, Alphaviruses with wt 5’UTRs became potent inducers of type I IFN, suggesting a new mechanism of type I IFN induction. We applied this knowledge of IFIT1 interaction with Alphaviruses to develop new attenuated variants of Venezuelan equine encephalitis and chikungunya viruses that are more sensitive to the antiviral effects of IFIT1, and thus could serve as novel vaccine candidates.
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Alphaviruses: Population genetics and determinants of emergence
Antiviral research, 2012Co-Authors: Scott C. Weaver, Richard A. Winegar, Ian D. Manger, Naomi L. ForresterAbstract:Alphaviruses are responsible for several medically important emerging diseases and are also significant veterinary pathogens. Due to the aerosol infectivity of some Alphaviruses and their ability to cause severe, sometimes fatal neurologic diseases, they are also of biodefense importance. This review discusses the ecology, epidemiology and molecular virology of the Alphaviruses, then focuses on three of the most important members of the genus: Venezuelan and eastern equine encephalitis and chikungunya viruses, with emphasis on their genetics and emergence mechanisms, and how current knowledge as well as gaps influence our ability to detect and determine the source of both natural outbreaks and potential use for bioterrorism. This article is one of a series in Antiviral Research on the genetic diversity of emerging viruses.
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Genome-Scale Phylogeny of the Alphavirus Genus Suggests a Marine Origin
Journal of Virology, 2011Co-Authors: Naomi L. Forrester, Scott C. Weaver, Gustavo Palacios, Robert B. Tesh, Nazir Savji, Hilda Guzman, Michael B. Sherman, W. I. LipkinAbstract:The genus Alphavirus comprises a diverse group of viruses, including some that cause severe disease. Using full-length sequences of all known Alphaviruses, we produced a robust and comprehensive phylogeny of the Alphavirus genus, presenting a more complete evolutionary history of these viruses compared to previous studies based on partial sequences. Our phylogeny suggests the origin of the Alphaviruses occurred in the southern oceans and spread equally through the Old and New World. Since lice appear to be involved in aquatic alphavirus transmission, it is possible that we are missing a louse-borne branch of the Alphaviruses. Complete genome sequencing of all members of the genus also revealed conserved residues forming the structural basis of the E1 and E2 protein dimers.
Ilya Frolov - One of the best experts on this subject based on the ideXlab platform.
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both rig i and mda5 detect alphavirus replication in concentration dependent mode
Virology, 2016Co-Authors: Ivan Akhrymuk, Ilya Frolov, Elena I FrolovaAbstract:Abstract Alphaviruses are a family of positive-strand RNA viruses that circulate on all continents between mosquito vectors and vertebrate hosts. Despite a significant public health threat, their biology is not sufficiently investigated, and the mechanisms of alphavirus replication and virus–host interaction are insufficiently understood. In this study, we have applied a variety of experimental systems to further understand the mechanism by which infected cells detect replicating Alphaviruses. Our new data strongly suggest that activation of the antiviral response by alphavirus-infected cells is determined by the integrity of viral genes encoding proteins with nuclear functions, and by the presence of two cellular pattern recognition receptors (PRRs), RIG-I and MDA5. No type I IFN response is induced in their absence. The presence of either of these PRRs is sufficient for detecting virus replication. However, type I IFN activation in response to pathogenic Alphaviruses depends on the basal levels of RIG-I or MDA5.
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ifit1 differentially interferes with translation and replication of alphavirus genomes and promotes induction of type i interferon
PLOS Pathogens, 2015Co-Authors: Josephine M Reynaud, Scott C. Weaver, Dal Young Kim, Svetlana Atasheva, Elena I Frolova, Aliaksandra Rasalouskaya, James P White, Michael S Diamond, Ilya FrolovAbstract:Alphaviruses are a group of widely distributed human and animal pathogens. It is well established that their replication is sensitive to type I IFN treatment, but the mechanism of IFN inhibitory function remains poorly understood. Using a new experimental system, we demonstrate that in the presence of IFN-β, activation of interferon-stimulated genes (ISGs) does not interfere with either attachment of alphavirus virions to the cells, or their entry and nucleocapsid disassembly. However, it strongly affects translation of the virion-delivered virus-specific RNAs. One of the ISG products, IFIT1 protein, plays a major role in this translation block, although an IFIT1-independent mechanism is also involved. The 5’UTRs of the alphavirus genomes were found to differ significantly in their ability to drive translation in the presence of increased concentration of IFIT1. Prior studies have shown that adaptation of naturally circulating Alphaviruses to replication in tissue culture results in accumulation of mutations in the 5’UTR, which increase the efficiency of the promoter located in the 5’end of the genome. Here, we show that these mutations also decrease resistance of viral RNA to IFIT1-induced translation inhibition. In the presence of higher levels of IFIT1, Alphaviruses with wt 5’UTRs became potent inducers of type I IFN, suggesting a new mechanism of type I IFN induction. We applied this knowledge of IFIT1 interaction with Alphaviruses to develop new attenuated variants of Venezuelan equine encephalitis and chikungunya viruses that are more sensitive to the antiviral effects of IFIT1, and thus could serve as novel vaccine candidates.
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conservation of a packaging signal and the viral genome rna packaging mechanism in alphavirus evolution
Journal of Virology, 2011Co-Authors: Dal Young Kim, Andrew E Firth, Svetlana Atasheva, Elena I Frolova, Ilya FrolovAbstract:Alphaviruses are a group of small, enveloped viruses which are widely distributed on all continents. In infected cells, Alphaviruses display remarkable specificity in RNA packaging by encapsidating only their genomic RNA while avoiding packaging of the more abundant viral subgenomic (SG), cellular messenger and transfer RNAs into released virions. In this work, we demonstrate that in spite of evolution in geographically isolated areas and accumulation of considerable diversity in the nonstructural and structural genes, many Alphaviruses belonging to different serocomplexes harbor RNA packaging signals (PSs) which contain the same structural and functional elements. Their characteristic features are as follows. (i) Sindbis, eastern, western, and Venezuelan equine encephalitis and most likely many other Alphaviruses, except those belonging to the Semliki Forest virus (SFV) clade, have PSs which can be recognized by the capsid proteins of heterologous Alphaviruses. (ii) The PS consists of 4 to 6 stem-loop RNA structures bearing conserved GGG sequences located at the base of the loop. These short motifs are integral elements of the PS and can function even in the artificially designed PS. (iii) Mutagenesis of the entire PS or simply the GGG sequences has strong negative effects on viral genome packaging and leads to release of viral particles containing mostly SG RNAs. (iv) Packaging of RNA appears to be determined to some extent by the number of GGG-containing stem-loops, and more than one stem-loop is required for efficient RNA encapsidation. (v) Viruses of the SFV clade are the exception to the general rule. They contain PSs in the nsP2 gene, but their capsid protein retains the ability to use the nsP1-specific PS of other Alphaviruses. These new discoveries regarding alphavirus PS structure and function provide an opportunity for the development of virus variants, which are irreversibly attenuated in terms of production of infectious virus but release high levels of genome-free virions.
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Persistent infection and suppression of host response by Alphaviruses.
Archives of virology. Supplementum, 2004Co-Authors: Ilya FrolovAbstract:Alphaviruses cause chronic noncytopathic infection in mosquito cells and develop a highly cytopathic infection in a wide variety of cells of vertebrate origin. Upon infection, Alphaviruses modify cellular processes to meet the virus needs for propagation. Downregulation of translation and transcription caused by viral infection appears to reduce interferon (IFN) and cytokine gene expression and allows more efficient dissemination of infection. Alphaviruses with mutations in non structural protein nsP2 can become less cytopathic and capable of persisting in some vertebrate cell lines for a number of passages. nsP2 likely functions as an important regulator of virus-host cell interactions and plays a significant role in suppressing the antiviral response. Mammalian cells having no defects in type I IFN system react to replication of the nsP2 viral mutants by more efficient activation oflFN and IFN-dependent genes and are capable of eliminating established alphavirus infection. Blocking of IFN-α/β signaling makes mouse fibroblasts unable to stop replication of Sindbis virus (SINV) with mutated nsP2 and leads to persistent infection. Downregulation of transcription and translation during alphavirus infection are quite independent events, and both probably are involved in inhibition of the antiviral response.
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Packaging signals in Alphaviruses.
Journal of virology, 1997Co-Authors: Elena I Frolova, Ilya Frolov, Sondra SchlesingerAbstract:Alphaviruses synthesize large amounts of both genomic and subgenomic RNA in infected cells, but usually only the genomic RNA is packaged. This implies the existence of an encapsidation or packaging signal which would be responsible for selectivity. Previously, we had identified a region of the Sindbis virus genome that interacts specifically with the viral capsid protein. This 132-nucleotide (nt) fragment lies within the coding region of the nsP1 gene (nt 945 to 1076). We proposed that the 132-mer is important for capsid recognition and initiates the formation of the viral nucleocapsid. To study the encapsidation of Sindbis virus RNAs in infected cells, we designed a new assay that uses the self-replicating Sindbis virus genomes (replicons) which lack the viral structural protein genes and contain heterologous sequences under the control of the subgenomic RNA promoter. These replicons can be packaged into viral particles by using defective helper RNAs that contain the structural protein genes (P. Bredenbeek, I. Frolov, C. M. Rice, and S. Schlesinger, J. Virol. 67:6439-6446, 1993). Insertion of the 132-mer into the subgenomic RNA significantly increased the packaging of this RNA into viral particles. We have used this assay and defective helpers that contain the structural protein genes of Ross River virus (RRV) to investigate the location of the encapsidation signal in the RRV genome. Our results show that there are several fragments that could act as packaging signals. They are all located in a different region of the genome than the signal for the Sindbis virus genome. For RRV, the strongest packaging signal lies between nt 2761 and 3062 in the nsP2 gene. This is the same region that was proposed to contain the packaging signal for Semliki Forest virus genomic RNA.
Yi-hao Chan - One of the best experts on this subject based on the ideXlab platform.
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vcp p97 is a proviral host factor for replication of chikungunya virus and other Alphaviruses
Frontiers in Microbiology, 2019Co-Authors: Guillaume Carissimo, Yi-hao Chan, Age Utt, Tze-kwang Chua, Farhana Abu Bakar, Andres MeritsAbstract:The evolutionarily conserved AAA+ ATPase valosin-containing protein (VCP) was previously shown to be a proviral host factor for several viruses from different viral families such as Flaviviridae, Picornaviridae, and Herpesviridae. VCP was shown to affect trafficking of Sindbis virus receptor and functions as a component of Semliki Forest virus (SFV) replicase compartment. However, the role of this cellular protein was not evaluated during replication of Alphaviruses including chikungunya virus (CHIKV). Using siRNA, chemical inhibitors, and trans-replication assays, we show here that VCP is a proviral factor involved in the replication of CHIKV. Immunofluorescence assays confirmed that VCP co-localized with non-structural replicase proteins but not with dsRNA foci possibly due to VCP epitope unavailability. VCP pro-viral role is also observed with other Alphaviruses such as o'nyong'nyong virus (ONNV) and SFV in different human cell lines. VCP proviral roles on several viral families now extend to replication of Alphaviruses CHIKV and ONNV, emphasizing the pivotal role of VCP in virus-host interaction biology.
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VCP/p97 Is a Proviral Host Factor for Replication of Chikungunya Virus and Other Alphaviruses
Frontiers in microbiology, 2019Co-Authors: Guillaume Carissimo, Yi-hao Chan, Age Utt, Tze-kwang Chua, Farhana Abu Bakar, Andres MeritsAbstract:The evolutionarily conserved AAA+ ATPase valosin-containing protein (VCP) was previously shown to be a proviral host factor for several viruses from different viral families such as Flaviviridae, Picornaviridae, and Herpesviridae. VCP was shown to affect trafficking of Sindbis virus receptor and functions as a component of Semliki Forest virus (SFV) replicase compartment. However, the role of this cellular protein was not evaluated during replication of Alphaviruses including chikungunya virus (CHIKV). Using siRNA, chemical inhibitors, and trans-replication assays, we show here that VCP is a proviral factor involved in the replication of CHIKV. Immunofluorescence assays confirmed that VCP co-localized with non-structural replicase proteins but not with dsRNA foci possibly due to VCP epitope unavailability. VCP pro-viral role is also observed with other Alphaviruses such as o'nyong'nyong virus (ONNV) and SFV in different human cell lines. VCP proviral roles on several viral families now extend to replication of Alphaviruses CHIKV and ONNV, emphasizing the pivotal role of VCP in virus-host interaction biology.
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Age has a role in driving host immunopathological response to alphavirus infection.
Immunology, 2017Co-Authors: Yi-hao ChanAbstract:Alphaviruses are a group of arthropod-borne pathogens capable of causing a wide spectrum of clinical symptoms, ranging from milder symptoms like rashes, fever and polyarthralgia, to life-threatening encephalitis. This genus of viruses is prevalent globally, and can infect patients across a wide age range. Interestingly, disease severity of virus-infected patients is wide-ranging. Definitions of the pathogenesis of Alphaviruses, as well as the host factors influencing disease severity, remain limited. The innate and adaptive immune systems are important host defences against alphavirus infections. Several reports have highlighted the roles of specific immune subsets in contributing to the immune pathogenesis of these viruses. However, immunosenescence, a gradual deterioration of the immune system brought about by the natural advancement of age, affects the functional roles of these immune subsets. This phenomenon compromises the host's ability to defend against alphavirus infection and pathogenesis. In addition, the lack of maturity in the immune system in newborns and infants also results in more severe disease outcomes. In this review, we will summarize the subtle yet diverse physiological changes in the immune system during aging, and how these changes underlie the differences in disease severity for common Alphaviruses.