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Villordo, Sergio M., i Andrea V. Gamarnik. "Genome cyclization as strategy for flavivirus RNA replication". Virus Research 139, nr 2 (luty 2009): 230–39. http://dx.doi.org/10.1016/j.virusres.2008.07.016.
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Meyer, Alexandra, Marie Freier, Tobias Schmidt, Katja Rostowski, Juliane Zwoch, Hauke Lilie, Sven-Erik Behrens i Susann Friedrich. "An RNA Thermometer Activity of the West Nile Virus Genomic 3′-Terminal Stem-Loop Element Modulates Viral Replication Efficiency during Host Switching". Viruses 12, nr 1 (15.01.2020): 104. http://dx.doi.org/10.3390/v12010104.
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The 3′-terminal stem-loop (3′SL) of the RNA genome of the flavivirus West Nile (WNV) harbors, in its stem, one of the sequence elements that are required for genome cyclization. As cyclization is a prerequisite for the initiation of viral replication, the 3′SL was proposed to act as a replication silencer. The lower part of the 3′SL is metastable and confers a structural flexibility that may regulate the switch from the linear to the circular conformation of the viral RNA. In the human system, we previously demonstrated that a cellular RNA-binding protein, AUF1 p45, destabilizes the 3′SL, exposes the cyclization sequence, and thus promotes flaviviral genome cyclization and RNA replication. By investigating mutant RNAs with increased 3′SL stabilities, we showed the specific conformation of the metastable element to be a critical determinant of the helix-destabilizing RNA chaperone activity of AUF1 p45 and of the precision and efficiency of the AUF1 p45-supported initiation of RNA replication. Studies of stability-increasing mutant WNV replicons in human and mosquito cells revealed that the cultivation temperature considerably affected the replication efficiencies of the viral RNA variants and demonstrated the silencing effect of the 3′SL to be temperature dependent. Furthermore, we identified and characterized mosquito proteins displaying similar activities as AUF1 p45. However, as the RNA remodeling activities of the mosquito proteins were found to be considerably lower than those of the human protein, a potential cell protein-mediated destabilization of the 3′SL was suggested to be less efficient in mosquito cells. In summary, our data support a model in which the 3′SL acts as an RNA thermometer that modulates flavivirus replication during host switching.
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Suzuki, Ryosuke, Rafik Fayzulin, Ilya Frolov i Peter W. Mason. "Identification of Mutated Cyclization Sequences That Permit Efficient Replication of West Nile Virus Genomes: Use in Safer Propagation of a Novel Vaccine Candidate". Journal of Virology 82, nr 14 (14.05.2008): 6942–51. http://dx.doi.org/10.1128/jvi.00662-08.
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ABSTRACT Existing live-attenuated flavivirus vaccines (LAV) could be improved by reducing their potential to recombine with naturally circulating viruses in the field. Since the highly conserved cyclization sequences (CS) found in the termini of flavivirus genomes must be complementary to each other to support genome replication, we set out to identify paired mutant CS that could support the efficient replication of LAV but would be unable to support replication in recombinant viruses harboring one wild-type (WT) CS. By systematic evaluation of paired mutated CS encoded in West Nile virus (WNV) replicons, we identified variants having single and double mutations in the 5′- and 3′-CS components that could support genome replication at WT levels. Replicons containing only the double-mutated CS in the 5′ or the 3′ ends of the genome were incapable of replication, indicating that mutated CS could be useful for constructing safer LAV. Despite the identity of the central portion of the CS in all mosquito-borne flaviviruses, viruses carrying complementary the double mutations in both the 5′- and the 3′-CS were indistinguishable from WT WNV in their replication in insect and mammalian cell lines. In addition to the utility of our novel CS pair in constructing safer LAV, we demonstrated that introduction of these mutated CS into one component of a recently described two-component genome system (A. V. Shustov, P. W. Mason, and I. Frolov, J. Virol. 81:11737-11748, 2007) enabled us to engineer a safer single-cycle WNV vaccine candidate with reduced potential for recombination during its propagation.
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Shustov, Alexandr V., Peter W. Mason i Ilya Frolov. "Production of Pseudoinfectious Yellow Fever Virus with a Two-Component Genome". Journal of Virology 81, nr 21 (22.08.2007): 11737–48. http://dx.doi.org/10.1128/jvi.01112-07.
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ABSTRACT Application of genetically modified, deficient-in-replication flaviviruses that are incapable of developing productive, spreading infection is a promising means of designing safe and effective vaccines. Here we describe a two-component genome yellow fever virus (YFV) replication system in which each of the genomes encodes complete sets of nonstructural proteins that form the replication complex but expresses either only capsid or prM/E instead of the entire structural polyprotein. Upon delivery to the same cell, these genomes produce together all of the viral structural proteins, and cells release a combination of virions with both types of genomes packaged into separate particles. In tissue culture, this modified YFV can be further passaged at an escalating scale by using a high multiplicity of infection (MOI). However, at a low MOI, only one of the genomes is delivered into the cells, and infection cannot spread. The replicating prM/E-encoding genome produces extracellular E protein in the form of secreted subviral particles that are known to be an effective immunogen. The presented strategy of developing viruses defective in replication might be applied to other flaviviruses, and these two-component genome viruses can be useful for diagnostic or vaccine applications, including the delivery and expression of heterologous genes. In addition, the achieved separation of the capsid-coding sequence and the cyclization signal in the YFV genome provides a new means for studying the mechanism of the flavivirus packaging process.
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Thurner, Caroline, Christina Witwer, Ivo L. Hofacker i Peter F. Stadler. "Conserved RNA secondary structures in Flaviviridae genomes". Journal of General Virology 85, nr 5 (1.05.2004): 1113–24. http://dx.doi.org/10.1099/vir.0.19462-0.
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Presented here is a comprehensive computational survey of evolutionarily conserved secondary structure motifs in the genomic RNAs of the family Flaviviridae. This virus family consists of the three genera Flavivirus, Pestivirus and Hepacivirus and the group of GB virus C/hepatitis G virus with a currently uncertain taxonomic classification. Based on the control of replication and translation, two subgroups were considered separately: the genus Flavivirus, with its type I cap structure at the 5′ untranslated region (UTR) and a highly structured 3′ UTR, and the remaining three groups, which exhibit translation control by means of an internal ribosomal entry site (IRES) in the 5′ UTR and a much shorter less-structured 3′ UTR. The main findings of this survey are strong hints for the possibility of genome cyclization in hepatitis C virus and GB virus C/hepatitis G virus in addition to the flaviviruses; a surprisingly large number of conserved RNA motifs in the coding regions; and a lower level of detailed structural conservation in the IRES and 3′ UTR motifs than reported in the literature. An electronic atlas organizes the information on the more than 150 conserved, and therefore putatively functional, RNA secondary structure elements.
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Medeiros, Daniele B. A., Márcio R. T. Nunes, Pedro F. C. Vasconcelos, Gwong-Jen J. Chang i Goro Kuno. "Complete genome characterization of Rocio virus (Flavivirus: Flaviviridae), a Brazilian flavivirus isolated from a fatal case of encephalitis during an epidemic in São Paulo state". Journal of General Virology 88, nr 8 (1.08.2007): 2237–46. http://dx.doi.org/10.1099/vir.0.82883-0.
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The flaviviruses of major medical importance in South American countries are yellow fever, dengue, Saint Louis encephalitis, West Nile and Rocio viruses. Rocio virus (ROCV) has been responsible for epidemics of severe encephalitis in Brazil with a case-fatality rate of 10 % and development of sequelae in 20 % of the survivors. We have sequenced and characterized the entire genome of ROCV for the first time, by determining the general traits of the open reading frame and the characteristics of viral genes including the potential cleavage sites, conserved or unique motifs, cysteine residues and potential glycosylation sites. The conserved sequences in the 3′-non-coding region were identified, and the predicted secondary structures during cyclization between 5′- and 3′-non-coding regions were studied. Multiple protein and phylogenetic analyses based on antigenically important and phylogenetically informative genes confirmed a close relationship between ROCV and Ilheus virus (ILHV), together constituting a unique and distinct phylogenetic subgroup as well as the genetic relationship of ROCV with several members of the Japanese encephalitis group. Although ROCV is phylogenetically related to ILHV, our study shows that it is still a virus distinct from the latter virus. This is the first flavivirus uniquely indigenous to Brazil that has been sequenced completely and the genome characterized. The data should be useful for further studies at the molecular level, including construction of infectious clone, identification of gene function, improved disease surveillance based on molecular diagnostic tools and vaccine development.
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Friebe, Peter, i Eva Harris. "Interplay of RNA Elements in the Dengue Virus 5′ and 3′ Ends Required for Viral RNA Replication". Journal of Virology 84, nr 12 (31.03.2010): 6103–18. http://dx.doi.org/10.1128/jvi.02042-09.
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ABSTRACT Dengue virus (DENV) is a member of the Flavivirus genus of positive-sense RNA viruses. DENV RNA replication requires cyclization of the viral genome mediated by two pairs of complementary sequences in the 5′ and 3′ ends, designated 5′ and 3′ cyclization sequences (5′-3′ CS) and the 5′ and 3′ upstream of AUG region (5′-3′ UAR). Here, we demonstrate that another stretch of six nucleotides in the 5′ end is involved in DENV replication and possibly genome cyclization. This new sequence is located downstream of the AUG, designated the 5′ downstream AUG region (5′ DAR); the motif predicted to be complementary in the 3′ end is termed the 3′ DAR. In addition to the UAR, CS and DAR motifs, two other RNA elements are located at the 5′ end of the viral RNA: the 5′ stem-loop A (5′ SLA) interacts with the viral RNA-dependent RNA polymerase and promotes RNA synthesis, and a stem-loop in the coding region named cHP is involved in translation start site selection as well as RNA replication. We analyzed the interplay of these 5′ RNA elements in relation to RNA replication, and our data indicate that two separate functional units are formed; one consists of the SLA, and the other includes the UAR, DAR, cHP, and CS elements. The SLA must be located at the 5′ end of the genome, whereas the position of the second unit is more flexible. We also show that the UAR, DAR, cHP, and CS must act in concert and therefore likely function together to form the tertiary RNA structure of the circularized DENV genome.
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Lodeiro, María F., Claudia V. Filomatori i Andrea V. Gamarnik. "Structural and Functional Studies of the Promoter Element for Dengue Virus RNA Replication". Journal of Virology 83, nr 2 (12.11.2008): 993–1008. http://dx.doi.org/10.1128/jvi.01647-08.
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ABSTRACT The 5′ untranslated region (5′UTR) of the dengue virus (DENV) genome contains two defined elements essential for viral replication. At the 5′ end, a large stem-loop (SLA) structure functions as the promoter for viral polymerase activity. Next to the SLA, there is a short stem-loop that contains a cyclization sequence known as the 5′ upstream AUG region (5′UAR). Here, we analyzed the secondary structure of the SLA in solution and the structural requirements of this element for viral replication. Using infectious DENV clones, viral replicons, and in vitro polymerase assays, we defined two helical regions, a side stem-loop, a top loop, and a U bulge within SLA as crucial elements for viral replication. The determinants for SLA-polymerase recognition were found to be common in different DENV serotypes. In addition, structural elements within the SLA required for DENV RNA replication were also conserved among different mosquito- and tick-borne flavivirus genomes, suggesting possible common strategies for polymerase-promoter recognition in flaviviruses. Furthermore, a conserved oligo(U) track present downstream of the SLA was found to modulate RNA synthesis in transfected cells. In vitro polymerase assays indicated that a sequence of at least 10 residues following the SLA, upstream of the 5′UAR, was necessary for efficient RNA synthesis using the viral 3′UTR as template.
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Pukhovskaya, N. M., O. V. Morozova, N. B. Belozerova, S. V. Bakhmetyeva, N. P. Vysochina, N. I. Zdanovskaya i L. I. Ivanov. "Comparative analysis of genomes of tick-borne encephalitis virus strains isolated from mosquitoes and ticks". Problems of Virology, Russian journal 62, nr 1 (20.02.2017): 30–35. http://dx.doi.org/10.18821/0507-4088-2017-62-1-30-35.
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The tick-borne encephalitis virus (TBEV) strain Lazo MP36 was isolated from the pool of mosquitoes Aedes vexans collected in Lazo region of Khabarovsk territory in August 2014. Phylogenetic analysis of the strain Lazo MP36 complete genome (GenBank accession number KT001073) revealed its correspondence to the TBEV Far Eastern subtype and differences from the following strains: 1) from ticks Ixodes persulcatus P. Schulze, 1930 [vaccine strain 205 (JX498939) and strains Khekhtzir 1230 (KF880805), Chichagovka (KP844724), Birobidzhan 1354 (KF880805) isolated in 2012-2013]; 2) from mosquitoes [strain Malyshevo (KJ744034) isolated in 1978 from Aedes vexans nipponii in Khabarovsk territory; strain Sakhalin 6-11 isolated from the pool of mosquitoes in 2011 (KF826916)]; 3) from human brain [vaccine strain Sofjin (JN229223), Glubinnoe/2004(DQ862460). Kavalerovo (DQ862460), Svetlogorie (DQ862460)]. The fusion peptide necessary for flavivirus entry to cells of the three TBEV strains isolated from mosquitoes (Lazo MP36, Malyshevo and Sakhalin 6-11) has the canonical structure 98-DRGWGNHCGLFGKGSI-113 for the tick-borne flaviviruses. Amino acid transition H104G typical for the mosquito-borne flaviviruses was not found. Structures of 5’- and 3’-untranslated (UTR) regions of the TBEV strains from mosquitoes were 85-98% homologous to the TBEV strains of all subtypes without recombination with mosquito-borne flaviviruses found in the Far East of Russia. Secondary structures of 5’- and 3'-UTR as well as cyclization sequences (CS) of types a and B are highly homologous for all TBEV isolates independently of the biological hosts and vectors. similarity of the genomes of the TBEV isolates from mosquitoes, ticks and patients as well as pathogenicity of the isolates for new-borne laboratory mice and tissue cultures might suggest a possible role of mosquitoes in the TBEV circulation in natural foci as an accidental or additional virus carrier.
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Liu, Z. Y., X. F. Li, T. Jiang, Y. Q. Deng, H. Zhao, H. J. Wang, Q. Ye i in. "Novel cis-Acting Element within the Capsid-Coding Region Enhances Flavivirus Viral-RNA Replication by Regulating Genome Cyclization". Journal of Virology 87, nr 12 (10.04.2013): 6804–18. http://dx.doi.org/10.1128/jvi.00243-13.
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Lin, Kuo-Chih, Huei-Lan Chang i Ruey-Yi Chang. "Accumulation of a 3′-Terminal Genome Fragment in Japanese Encephalitis Virus-Infected Mammalian and Mosquito Cells". Journal of Virology 78, nr 10 (15.05.2004): 5133–38. http://dx.doi.org/10.1128/jvi.78.10.5133-5138.2004.
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ABSTRACT Japanese encephalitis virus (JEV) contains a single positive-strand RNA genome nearly 11 kb in length and is not formally thought to generate subgenomic RNA molecules during replication. Here, we report the abundant accumulation of a 3′-terminal 521- to 523-nucleotide (nt) genome fragment, representing a major portion of the 585-nt 3′ untranslated region, in both mammalian (BHK-21) and mosquito (C6/36) cells infected with any of nine strains of JEV. In BHK-21 cells, the viral genome was detected as early as 24 h postinfection, the small RNA was detected as early as 28 h postinfection, and the small RNA was 0.25 to 1.5 times as abundant as the genome on a molar basis between 28 and 48 h postinfection. In C6/36 cells, the genome and small RNA were present 5 days postinfection and the small RNA was 1.25 to 5.14 times as abundant as the genome. The 3′-terminal 523-nt small RNA contains a 5′-proximal stable hairpin (nt 6 to 56) that may play a role in its formation and the conserved flavivirus 3′-cyclization motif (nt 413 to 420) and the 3′-terminal long stable hairpin structure (nt 440 to 523) that have postulated roles in genome replication. Abundant accumulation of the small RNA during viral replication in both mammalian and mosquito cells suggests that it may play a biological role, perhaps as a regulator of RNA synthesis.
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Lo, Michael K., Mark Tilgner, Kristen A. Bernard i Pei-Yong Shi. "Functional Analysis of Mosquito-Borne Flavivirus Conserved Sequence Elements within 3′ Untranslated Region of West Nile Virus by Use of a Reporting Replicon That Differentiates between Viral Translation and RNA Replication". Journal of Virology 77, nr 18 (15.09.2003): 10004–14. http://dx.doi.org/10.1128/jvi.77.18.10004-10014.2003.
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ABSTRACT We have developed a reporting replicon of West Nile virus (WNV) that could be used to quantitatively distinguish viral translation and RNA replication. A Renilla luciferase (Rluc) gene was fused in-frame with the open reading frame of a subgenomic replicon in the position where the viral structural region was deleted, resulting in RlucRep. Transfection of BHK cells with RlucRep RNA yielded two distinctive Rluc signal peaks, one between 2 and 10 h and the other after 26 h posttransfection. By contrast, only the 2- to 10-h Rluc signal peak was observed in cells transfected with a mutant replicon containing an inactivated viral polymerase NS5 (RlucRep-NS5mt). Immunofluorescence and real-time reverse transcriptase PCR assays showed that the levels of viral protein expression and RNA replication increased in cells transfected with the RlucRep but not in those transfected with the RlucRep-NS5mt. These results suggest that the Rluc signal that occurred at 2 to 10 h posttransfection reflects viral translation of the input replicon, while the Rluc activity after 26 h posttransfection represents RNA replication. Using this system, we showed that mutations of conserved sequence (CS) elements within the 3′ untranslated region of the mosquito-borne flaviviruses did not significantly affect WNV translation but severely diminished or completely abolished RNA replication. Mutations of CS1 that blocked the potential base pairing with a conserved sequence in the 5′ region of the capsid gene (5′CS) abolished RNA replication. Restoration of the 5′CS-CS1 interaction rescued viral replication. Replicons containing individual deletions of CS2, repeated CS2 (RCS2), CS3, or RCS3 were viable, but their RNA replication was dramatically compromised. These results demonstrate that genome cyclization through the 5′CS-CS1 interaction is essential for WNV RNA replication, whereas CS2, RCS2, CS3, and RCS3 facilitate, but are dispensable for, WNV replication.
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Alvarez, Diego E., María F. Lodeiro, Silvio J. Ludueña, Lía I. Pietrasanta i Andrea V. Gamarnik. "Long-Range RNA-RNA Interactions Circularize the Dengue Virus Genome". Journal of Virology 79, nr 11 (1.06.2005): 6631–43. http://dx.doi.org/10.1128/jvi.79.11.6631-6643.2005.
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ABSTRACT Secondary and tertiary RNA structures present in viral RNA genomes play essential regulatory roles during translation, RNA replication, and assembly of new viral particles. In the case of flaviviruses, RNA-RNA interactions between the 5′ and 3′ ends of the genome have been proposed to be required for RNA replication. We found that two RNA elements present at the ends of the dengue virus genome interact in vitro with high affinity. Visualization of individual molecules by atomic force microscopy reveled that physical interaction between these RNA elements results in cyclization of the viral RNA. Using RNA binding assays, we found that the putative cyclization sequences, known as 5′ and 3′ CS, present in all mosquito-borne flaviviruses, were necessary but not sufficient for RNA-RNA interaction. Additional sequences present at the 5′ and 3′ untranslated regions of the viral RNA were also required for RNA-RNA complex formation. We named these sequences 5′ and 3′ UAR (upstream AUG region). In order to investigate the functional role of 5′-3′ UAR complementarity, these sequences were mutated either separately, to destroy base pairing, or simultaneously, to restore complementarity in the context of full-length dengue virus RNA. Nonviable viruses were recovered after transfection of dengue virus RNA carrying mutations either at the 5′ or 3′ UAR, while the RNA containing the compensatory mutations was able to replicate. Since sequence complementarity between the ends of the genome is required for dengue virus viability, we propose that cyclization of the RNA is a required conformation for viral replication.
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Kofler, Regina M., Verena M. Hoenninger, Caroline Thurner i Christian W. Mandl. "Functional Analysis of the Tick-Borne Encephalitis Virus Cyclization ElementsIndicates Major Differences between Mosquito-Borne and Tick-Borne Flaviviruses". Journal of Virology 80, nr 8 (15.04.2006): 4099–113. http://dx.doi.org/10.1128/jvi.80.8.4099-4113.2006.
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ABSTRACT The linear, positive-stranded RNA genome of flaviviruses is thought to adopt a circularized conformation via interactions of short complementary sequence elements located within its terminal regions. This process of RNA cyclization is a crucial precondition for RNA replication. In the case of mosquito-borne flaviviruses, highly conserved cyclization sequences (CS) have been identified, and their functionality has been experimentally confirmed. Here, we provide an experimental identification of CS elements of tick-borne encephalitis virus (TBEV). These elements, termed 5′-CS-A and 3′-CS-A, are conserved among various tick-borne flaviviruses, but they are unrelated to the mosquito-borne CS elements and are located at different genomic positions. The 5′-CS-A element is situated upstream rather than downstream of the AUG start codon and, in contrast to mosquito-borne flaviviruses, it was found that the entire protein C coding region is not essential for TBEV replication. The complementary 3′-CS-A element is located within the bottom stem rather than upstream of the characteristic 3′-terminal stem-loop structure, implying that this part of the proposed structure cannot be formed when the genome is in its circularized conformation. Finally, we demonstrate that the CS-A elements can also mediate their function when the 5′-CS-A element is moved from its natural position to one corresponding to the mosquito-borne CS. The recognition of essential RNA elements and their differences between mosquito-borne and tick-borne flaviviruses has practical implications for the design of replicons in vaccine and vector development.
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Corver, Jeroen, Edith Lenches, Kayla Smith, R. Aaron Robison, Trisha Sando, Ellen G. Strauss i James H. Strauss. "Fine Mapping of a cis-Acting Sequence Element in Yellow Fever Virus RNA That Is Required for RNA Replication and Cyclization". Journal of Virology 77, nr 3 (1.02.2003): 2265–70. http://dx.doi.org/10.1128/jvi.77.3.2265-2270.2003.
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ABSTRACT We present fine mapping of a cis-acting nucleotide sequence found in the 5′ region of yellow fever virus genomic RNA that is required for RNA replication. There is evidence that this sequence interacts with a complementary sequence in the 3′ region of the genome to cyclize the RNA. Replicons were constructed that had various deletions in the 5′ region encoding the capsid protein and were tested for their ability to replicate. We found that a sequence of 18 nucleotides (residues 146 to 163 of the yellow fever virus genome, which encode amino acids 9 to 14 of the capsid protein) is essential for replication of the yellow fever virus replicon and that a slightly longer sequence of 21 nucleotides (residues 146 to 166, encoding amino acids 9 to 15) is required for full replication. This region is larger than the core sequence of 8 nucleotides conserved among all mosquito-borne flaviviruses and contains instead the entire sequence previously proposed to be involved in cyclization of yellow fever virus RNA.
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Tsetsarkin, Konstantin A., Guangping Liu, Kui Shen i Alexander G. Pletnev. "Kissing-loop interaction between 5′ and 3′ ends of tick-borne Langat virus genome ‘bridges the gap’ between mosquito- and tick-borne flaviviruses in mechanisms of viral RNA cyclization: applications for virus attenuation and vaccine development". Nucleic Acids Research 44, nr 7 (4.02.2016): 3330–50. http://dx.doi.org/10.1093/nar/gkw061.
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Liu, Zhong-Yu, Xiao-Feng Li, Tao Jiang, Yong-Qiang Deng, Qing Ye, Hui Zhao, Jiu-Yang Yu i Cheng-Feng Qin. "Viral RNA switch mediates the dynamic control of flavivirus replicase recruitment by genome cyclization". eLife 5 (1.10.2016). http://dx.doi.org/10.7554/elife.17636.
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Viral replicase recruitment and long-range RNA interactions are essential for RNA virus replication, yet the mechanism of their interplay remains elusive. Flaviviruses include numerous important human pathogens, e.g., dengue virus (DENV) and Zika virus (ZIKV). Here, we revealed a highly conserved, conformation-tunable cis-acting element named 5′-UAR-flanking stem (UFS) in the flavivirus genomic 5′ terminus. We demonstrated that the UFS was critical for efficient NS5 recruitment and viral RNA synthesis in different flaviviruses. Interestingly, stabilization of the DENV UFS impaired both genome cyclization and vRNA replication. Moreover, the UFS unwound in response to genome cyclization, leading to the decreased affinity of NS5 for the viral 5′ end. Thus, we propose that the UFS is switched by genome cyclization to regulate dynamic RdRp binding for vRNA replication. This study demonstrates that the UFS enables communication between flavivirus genome cyclization and RdRp recruitment, highlighting the presence of switch-like mechanisms among RNA viruses.
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Friedrich, Susann, Susanne Engelmann, Tobias Schmidt, Grit Szczepankiewicz, Sandra Bergs, Uwe G. Liebert, Beate M. Kümmerer, Ralph P. Golbik i Sven-Erik Behrens. "The Host Factor AUF1 p45 Supports Flavivirus Propagation by Triggering the RNA Switch Required for Viral Genome Cyclization". Journal of Virology 92, nr 6 (20.12.2017). http://dx.doi.org/10.1128/jvi.01647-17.
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ABSTRACTIn previous studies, we showed that the cellular RNA-binding protein AUF1 supports the replication process of the flavivirus West Nile virus. Here we demonstrate that the protein also enables effective proliferation of dengue virus and Zika virus, indicating that AUF1 is a general flavivirus host factor. Further studies demonstrated that the AUF1 isoform p45 significantly stimulates the initiation of viral RNA replication and that the protein's RNA chaperone activity enhances the interactions of the viral 5′UAR and 3′UAR genome cyclization sequences. Most interestingly, we observed that AUF1 p45 destabilizes not only the 3′-terminal stem-loop (3′SL) but also 5′-terminal stem-loop B (SLB) of the viral genome. RNA structure analyses revealed that AUF1 p45 increases the accessibility of defined nucleotides within the 3′SL and SLB and, in this way, exposes both UAR cyclization elements. Conversely, AUF1 p45 does not modulate the fold of stem-loop A (SLA) at the immediate genomic 5′ end, which is proposed to function as a promoter of the viral RNA-dependent RNA polymerase (RdRp). These findings suggest that AUF1 p45, by destabilizing specific stem-loop structures within the 5′ and 3′ ends of the flaviviral genome, assists genome cyclization and concurrently enables the RdRp to initiate RNA synthesis. Our study thus highlights the role of a cellular RNA-binding protein inducing a flaviviral RNA switch that is crucial for viral replication.IMPORTANCEThe genusFlaviviruswithin theFlaviviridaefamily includes important human pathogens, such as dengue, West Nile, and Zika viruses. The initiation of replication of the flaviviral RNA genome requires a transformation from a linear to a cyclized form. This involves considerable structural reorganization of several RNA motifs at the genomic 5′ and 3′ ends. Specifically, it needs a melting of stem structures to expose complementary 5′ and 3′ cyclization elements to enable their annealing during cyclization. Here we show that a cellular RNA chaperone, AUF1 p45, which supports the replication of all three aforementioned flaviviruses, specifically rearranges stem structures at both ends of the viral genome and in this way permits 5′-3′ interactions of cyclization elements. Thus, AUF1 p45 triggers the RNA switch in the flaviviral genome that is crucial for viral replication. These findings represent an important example of how cellular (host) factors promote the propagation of RNA viruses.
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Li, Xiao-Dan, Cheng-Lin Deng, Zhi-Ming Yuan, Han-Qing Ye i Bo Zhang. "Different Degrees of 5'-to-3' DAR Interactions Modulate Zika Virus Genome Cyclization and Host-Specific Replication". Journal of Virology 94, nr 5 (11.12.2019). http://dx.doi.org/10.1128/jvi.01602-19.
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ABSTRACT Mosquito-borne flaviviruses, which include many important human pathogens, such as West Nile virus (WNV), dengue virus (DENV), and Zika virus (ZIKV), have caused numerous emerging epidemics in recent years. Details of the viral genome functions necessary for effective viral replication in mosquito and vertebrate hosts remain obscure. Here, using ZIKV as a model, we found that the conserved “downstream of AUG region” (DAR), which is known to be an essential element for genome cyclization, is involved in viral replication in a host-specific manner. Mutational analysis of the DAR element showed that a single-nucleotide mismatch between the 5′ DAR and the 3′ DAR had little effect on ZIKV replication in mammalian cells but dramatically impaired viral propagation in mosquito cells. The revertant viruses passaged in mosquito cells generated compensatory mutations restoring the base pairing of the DAR, further confirming the importance of the complementarity of the DAR in mosquito cells. We demonstrate that a single-nucleotide mutation in the DAR is sufficient to destroy long-range RNA interaction of the ZIKV genome and affects de novo RNA synthesis at 28°C instead of 37°C, resulting in the different replication efficiencies of the mutant viruses in mosquito and mammalian cells. Our results reveal a novel function of the circular form of the flavivirus genome in host-specific viral replication, providing new ideas to further explore the functions of the viral genome during host adaptation. IMPORTANCE Flaviviruses naturally cycle between the mosquito vector and vertebrate hosts. The disparate hosts provide selective pressures that drive virus genome evolution to maintain efficient replication during host alteration. Host adaptation may occur at different stages of the viral life cycle, since host-specific viral protein processing and virion conformations have been reported in the individual hosts. However, the viral determinants and the underlying mechanisms associated with host-specific functions remain obscure. In this study, using Zika virus, we found that the DAR-mediated genome cyclization regulates viral replication differently and is under different selection pressures in mammalian and mosquito cells. A more constrained complementarity of the DAR is required in mosquito cells than in mammalian cells. Since the DAR element is stably maintained among mosquito-borne flaviviruses, our findings could provide new information for understanding the role of flavivirus genome cyclization in viral adaptation and RNA evolution in the two hosts.
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Li, Dan, Hai-Tao Lu, Yu-Zhen Ding, Hong-Jiang Wang, Jing-Long Ye, Cheng-Feng Qin i Zhong-Yu Liu. "Specialized cis -Acting RNA Elements Balance Genome Cyclization to Ensure Efficient Replication of Yellow Fever Virus". Journal of Virology, 5.04.2023. http://dx.doi.org/10.1128/jvi.01949-22.
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Yellow fever virus (YFV), the prototype of the Flavivirus genus, can cause devastating yellow fever disease. Although it is preventable by vaccination, there are still tens of thousands of yellow fever cases per year, and no approved antiviral medicine is available.