Contributions of vesicular stomatitis virus to the understanding of RNA virus evolution

2003 ◽  
Vol 6 (4) ◽  
pp. 399-405 ◽  
Author(s):  
Isabel S Novella
Keyword(s):  
Vesicular Stomatitis Virus ◽  
Rna Virus ◽  
Virus Evolution ◽  
Vesicular Stomatitis

scholarly journals Oligomerization of the Vesicular Stomatitis Virus Phosphoprotein Is Dispensable for mRNA Synthesis but Facilitates RNA Replication

2020 ◽  
Vol 94 (13) ◽  
Author(s):  
Louis-Marie Bloyet ◽  
Benjamin Morin ◽  
Vesna Brusic ◽  
Erica Gardner ◽  
Robin A. Ross ◽  
...  
Keyword(s):  
Vesicular Stomatitis Virus ◽  
Rna Viruses ◽  
Rna Virus ◽  
Rna Replication ◽  
Binding Domain ◽  
Genome Replication ◽  
Mrna Synthesis ◽  
Wild Type ◽  
Vesicular Stomatitis ◽  
Oligomerization Domain

ABSTRACT Nonsegmented negative-strand (NNS) RNA viruses possess a ribonucleoprotein template in which the genomic RNA is sequestered within a homopolymer of nucleocapsid protein (N). The viral RNA-dependent RNA polymerase (RdRP) resides within an approximately 250-kDa large protein (L), along with unconventional mRNA capping enzymes: a GDP:polyribonucleotidyltransferase (PRNT) and a dual-specificity mRNA cap methylase (MT). To gain access to the N-RNA template and orchestrate the LRdRP, LPRNT, and LMT, an oligomeric phosphoprotein (P) is required. Vesicular stomatitis virus (VSV) P is dimeric with an oligomerization domain (OD) separating two largely disordered regions followed by a globular C-terminal domain that binds the template. P is also responsible for bringing new N protomers onto the nascent RNA during genome replication. We show VSV P lacking the OD (PΔOD) is monomeric but is indistinguishable from wild-type P in supporting mRNA transcription in vitro. Recombinant virus VSV-PΔOD exhibits a pronounced kinetic delay in progeny virus production. Fluorescence recovery after photobleaching demonstrates that PΔOD diffuses 6-fold more rapidly than the wild type within viral replication compartments. A well-characterized defective interfering particle of VSV (DI-T) that is only competent for RNA replication requires significantly higher levels of N to drive RNA replication in the presence of PΔOD. We conclude P oligomerization is not required for mRNA synthesis but enhances genome replication by facilitating RNA encapsidation. IMPORTANCE All NNS RNA viruses, including the human pathogens rabies, measles, respiratory syncytial virus, Nipah, and Ebola, possess an essential L-protein cofactor, required to access the N-RNA template and coordinate the various enzymatic activities of L. The polymerase cofactors share a similar modular organization of a soluble N-binding domain and a template-binding domain separated by a central oligomerization domain. Using a prototype of NNS RNA virus gene expression, vesicular stomatitis virus (VSV), we determined the importance of P oligomerization. We find that oligomerization of VSV P is not required for any step of viral mRNA synthesis but is required for efficient RNA replication. We present evidence that this likely occurs through the stage of loading soluble N onto the nascent RNA strand as it exits the polymerase during RNA replication. Interfering with the oligomerization of P may represent a general strategy to interfere with NNS RNA virus replication.

scholarly journals TRIM24 facilitates antiviral immunity through mediating K63-linked TRAF3 ubiquitination

2020 ◽  
Vol 217 (7) ◽  
Author(s):  
Qingchen Zhu ◽  
Tao Yu ◽  
Shucheng Gan ◽  
Yan Wang ◽  
Yifei Pei ◽  
...  
Keyword(s):  
Virus Infection ◽  
Vesicular Stomatitis Virus ◽  
Rna Virus ◽  
Antiviral Immunity ◽  
Type I ◽  
Antiviral Signaling ◽  
Unknown Mechanism ◽  
Positive Regulator ◽  
Transcriptional Suppression ◽  
Vesicular Stomatitis

Ubiquitination is an essential mechanism in the control of antiviral immunity upon virus infection. Here, we identify a series of ubiquitination-modulating enzymes that are modulated by vesicular stomatitis virus (VSV). Notably, TRIM24 is down-regulated through direct transcriptional suppression induced by VSV-activated IRF3. Reducing or ablating TRIM24 compromises type I IFN (IFN-I) induction upon RNA virus infection and thus renders mice more sensitive to VSV infection. Mechanistically, VSV infection induces abundant TRIM24 translocation to mitochondria, where TRIM24 binds with TRAF3 and directly mediates K63-linked TRAF3 ubiquitination at K429/K436. This modification of TRAF3 enables its association with MAVS and TBK1, which consequently activates downstream antiviral signaling. Together, these findings establish TRIM24 as a critical positive regulator in controlling the activation of antiviral signaling and describe a previously unknown mechanism of TRIM24 function.

scholarly journals Vesicular stomatitis virus as a flexible platform for oncolytic virotherapy against cancer

2012 ◽  
Vol 93 (12) ◽  
pp. 2529-2545 ◽  
Author(s):  
Eric Hastie ◽  
Valery Z. Grdzelishvili
Keyword(s):  
Cancer Cells ◽  
Vesicular Stomatitis Virus ◽  
Reverse Genetics ◽  
Cell Transformation ◽  
Rna Virus ◽  
Type I ◽  
Delivery Methods ◽  
Recombinant Viruses ◽  
Antiviral Responses ◽  
Vesicular Stomatitis

Oncolytic virus (OV) therapy is an emerging anti-cancer approach that utilizes viruses to preferentially infect and kill cancer cells, while not harming healthy cells. Vesicular stomatitis virus (VSV) is a prototypic non-segmented, negative-strand RNA virus with inherent OV qualities. Antiviral responses induced by type I interferon pathways are believed to be impaired in most cancer cells, making them more susceptible to VSV than normal cells. Several other factors make VSV a promising OV candidate for clinical use, including its well-studied biology, a small, easily manipulated genome, relative independence of a receptor or cell cycle, cytoplasmic replication without risk of host-cell transformation, and lack of pre-existing immunity in humans. Moreover, various VSV-based recombinant viruses have been engineered via reverse genetics to improve oncoselectivity, safety, oncotoxicity and stimulation of tumour-specific immunity. Alternative delivery methods are also being studied to minimize premature immune clearance of VSV. OV treatment as a monotherapy is being explored, although many studies have employed VSV in combination with radiotherapy, chemotherapy or other OVs. Preclinical studies with various cancers have demonstrated that VSV is a promising OV; as a result, a human clinical trial using VSV is currently in progress.

scholarly journals Regulation of RNA Synthesis by the Genomic Termini of Vesicular Stomatitis Virus: Identification of Distinct Sequences Essential for Transcription but Not Replication

1999 ◽  
Vol 73 (1) ◽  
pp. 297-306 ◽  
Author(s):  
Sean P. J. Whelan ◽  
Gail W. Wertz
Keyword(s):  
Vesicular Stomatitis Virus ◽  
Rna Virus ◽  
N Gene ◽  
Specific Sequence ◽  
Virus Identification ◽  
Sequence Elements ◽  
Infected Cells ◽  
Vesicular Stomatitis ◽  
Sequence Requirements ◽  
Transcription And Replication

ABSTRACT The RNA-dependent RNA polymerase of vesicular stomatitis virus (VSV), a nonsegmented negative-strand RNA virus, directs two discrete RNA synthetic processes, transcription and replication. Available evidence suggests that the two short extragenic regions at the genomic termini, the 3′ leader (Le) and the complement of the 5′ trailer (TrC), contain essential signals for these processes. We examined the roles in transcription and replication of sequences in Le and TrC by monitoring the effects of alterations to the termini of subgenomic replicons, or infectious viruses, on these RNA synthetic processes. Distinct elements in Le were found to be required for transcription that were not required for replication. The promoter for mRNA transcription was shown to include specific sequence elements within Le at positions 19 to 29 and 34 to 46, a separate element at nucleotides 47 to 50, the nontranscribed leader-N gene junction. The sequence requirements for transcription within the Le region could not be supplied by sequences found at the equivalent positions in TrC. In contrast, sequences from either Le or TrC functioned well to signal replication, indicating that within the confines of the VSV termini, the sequence requirements for replication were less stringent. Deletions engineered at the termini showed that the terminal 15 nucleotides of either Le or TrC allowed a minimal level of replication. Within these confines, levels of replication were affected by both the extent of complementarity between the genomic termini and the involvement of the template in transcription. In agreement with our previous observations, increasing the extent of complementarity between the natural termini increased levels of replication, and this effect was most operative at the extreme genome ends. In addition, abolishing the use of Le as a promoter for transcription enhanced replication. These analyses (i) identified signals at the termini required for transcription and replication and (ii) showed that Le functions as a less efficient promoter for replication than TrC at least in part because of its essential role in transcription. Consequently, these observations help explain the asymmetry of VSV replication which results in the synthesis of more negative- than positive-sense replication products in infected cells.

scholarly journals A Polyamide Inhibits Replication of Vesicular Stomatitis Virus by Targeting RNA in the Nucleocapsid

2018 ◽  
Vol 92 (8) ◽  
pp. e00146-18 ◽  
Author(s):  
Ryan H. Gumpper ◽  
Weike Li ◽  
Carlos H. Castañeda ◽  
M. José Scuderi ◽  
James K. Bashkin ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Vesicular Stomatitis Virus ◽  
Ebola Virus ◽  
Rna Viruses ◽  
Rna Virus ◽  
Viral Rna ◽  
Negative Strand ◽  
Double Stranded Dna ◽  
Vesicular Stomatitis ◽  
Syncytial Virus

ABSTRACTPolyamides have been shown to bind double-stranded DNA by complementing the curvature of the minor groove and forming various hydrogen bonds with DNA. Several polyamide molecules have been found to have potent antiviral activities against papillomavirus, a double-stranded DNA virus. By analogy, we reason that polyamides may also interact with the structured RNA bound in the nucleocapsid of a negative-strand RNA virus. Vesicular stomatitis virus (VSV) was selected as a prototype virus to test this possibility since its genomic RNA encapsidated in the nucleocapsid forms a structure resembling one strand of an A-form RNA duplex. One polyamide molecule, UMSL1011, was found to inhibit infection of VSV. To confirm that the polyamide targeted the nucleocapsid, a nucleocapsid-like particle (NLP) was incubated with UMSL1011. The encapsidated RNA in the polyamide-treated NLP was protected from thermo-release and digestion by RNase A. UMSL1011 also inhibits viral RNA synthesis in the intracellular activity assay for the viral RNA-dependent RNA polymerase. The crystal structure revealed that UMSL1011 binds the structured RNA in the nucleocapsid. The conclusion of our studies is that the RNA in the nucleocapsid is a viable antiviral target of polyamides. Since the RNA structure in the nucleocapsid is similar in all negative-strand RNA viruses, polyamides may be optimized to target the specific RNA genome of a negative-strand RNA virus, such as respiratory syncytial virus and Ebola virus.IMPORTANCENegative-strand RNA viruses (NSVs) include several life-threatening pathogens, such as rabies virus, respiratory syncytial virus, and Ebola virus. There are no effective antiviral drugs against these viruses. Polyamides offer an exceptional opportunity because they may be optimized to target each NSV. Our studies on vesicular stomatitis virus, an NSV, demonstrated that a polyamide molecule could specifically target the viral RNA in the nucleocapsid and inhibit viral growth. The target specificity of the polyamide molecule was proved by its inhibition of thermo-release and RNA nuclease digestion of the RNA bound in a model nucleocapsid, and a crystal structure of the polyamide inside the nucleocapsid. This encouraging observation provided the proof-of-concept rationale for designing polyamides as antiviral drugs against NSVs.

scholarly journals Fibrinogen Gamma Chain Promotes Aggregation of Vesicular Stomatitis Virus in Saliva

Viruses ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 282 ◽  
Author(s):  
Valesca Anschau ◽  
Rafael Sanjuán
Keyword(s):  
Quantitative Analysis ◽  
Vesicular Stomatitis Virus ◽  
Rna Virus ◽  
Comparative Proteomics ◽  
Dependent Manner ◽  
Gamma Chain ◽  
Vesicular Stomatitis ◽  
Molecular Components ◽  
Dose Dependent ◽  
Infectious Unit

The spread of viruses among cells and hosts often involves multi-virion structures. For instance, virions can form aggregates that allow for the co-delivery of multiple genome copies to the same cell from a single infectious unit. Previously, we showed that vesicular stomatitis virus (VSV), an enveloped, negative-strand RNA virus, undergoes strong aggregation in the presence of saliva from certain individuals. However, the molecular components responsible for such aggregation remain unknown. Here we show that saliva-driven aggregation is protein dependent, and we use comparative proteomics to analyze the protein content of strongly versus poorly aggregating saliva. Quantitative analysis of over 300 proteins led to the identification of 18 upregulated proteins in strongly aggregating saliva. One of these proteins, the fibrinogen gamma chain, was verified experimentally as a factor promoting VSV aggregation in a dose-dependent manner. This study hence identifies a protein responsible for saliva-driven VSV aggregation. Yet, the possible involvement of additional proteins or factors cannot be discarded.

scholarly journals Exponential Fitness Gains of RNA Virus Populations Are Limited by Bottleneck Effects

1999 ◽  
Vol 73 (2) ◽  
pp. 1668-1671 ◽  
Author(s):  
Isabel S. Novella ◽  
Josep Quer ◽  
Esteban Domingo ◽  
John J. Holland
Keyword(s):  
Vesicular Stomatitis Virus ◽  
Rna Virus ◽  
Constant Environment ◽  
High Fitness ◽  
Large Populations ◽  
Vesicular Stomatitis ◽  
Very High

ABSTRACT Fitness is a parameter that quantitatively measures adaptation of a virus to a given environment. We have previously reported exponential fitness gains of large populations of vesicular stomatitis virus replicating in a constant environment (I. S. Novella et al., Proc. Natl. Acad. Sci. USA 92:5841–5844, 1995). In this paper, we report that during long-term passage of such large viral populations, fitness values reached a high-fitness plateau during which stochastic fitness variations were observed. This effect appears likely to be due to bottleneck effects on very high fitness populations.

scholarly journals Vesicular Stomatitis Virus: From Agricultural Pathogen to Vaccine Vector

Pathogens ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1092
Author(s):  
Guodong Liu ◽  
Wenguang Cao ◽  
Abdjeleel Salawudeen ◽  
Wenjun Zhu ◽  
Karla Emeterio ◽  
...  
Keyword(s):  
Vesicular Stomatitis Virus ◽  
Reverse Genetics ◽  
Ebola Virus ◽  
Rna Virus ◽  
Research Tool ◽  
Vaccine Vector ◽  
The Family ◽  
Vesicular Stomatitis ◽  
Negative Sense ◽  
Family Rhabdoviridae

Vesicular stomatitis virus (VSV), which belongs to the Vesiculovirus genus of the family Rhabdoviridae, is a well studied livestock pathogen and prototypic non-segmented, negative-sense RNA virus. Although VSV is responsible for causing economically significant outbreaks of vesicular stomatitis in cattle, horses, and swine, the virus also represents a valuable research tool for molecular biologists and virologists. Indeed, the establishment of a reverse genetics system for the recovery of infectious VSV from cDNA transformed the utility of this virus and paved the way for its use as a vaccine vector. A highly effective VSV-based vaccine against Ebola virus recently received clinical approval, and many other VSV-based vaccines have been developed, particularly for high-consequence viruses. This review seeks to provide a holistic but concise overview of VSV, covering the virus’s ascension from perennial agricultural scourge to promising medical countermeasure, with a particular focus on vaccines.

scholarly journals Structure and Function of the N-Terminal Domain of the Vesicular Stomatitis Virus RNA Polymerase

2015 ◽  
Vol 90 (2) ◽  
pp. 715-724 ◽  
Author(s):  
Shihong Qiu ◽  
Minako Ogino ◽  
Ming Luo ◽  
Tomoaki Ogino ◽  
Todd J. Green
Keyword(s):  
Vesicular Stomatitis Virus ◽  
Rna Viruses ◽  
Rna Virus ◽  
Three Dimensional ◽  
Viral Transcription ◽  
Content Type ◽  
Negative Strand ◽  
Terminal Domain ◽  
Vesicular Stomatitis ◽  
L Proteins

ABSTRACTViruses have various mechanisms to duplicate their genomes and produce virus-specific mRNAs. Negative-strand RNA viruses encode their own polymerases to perform each of these processes. For the nonsegmented negative-strand RNA viruses, the polymerase is comprised of the large polymerase subunit (L) and the phosphoprotein (P). L proteins from members of theRhabdoviridae,Paramyxoviridae, andFiloviridaeshare sequence and predicted secondary structure homology. Here, we present the structure of the N-terminal domain (conserved region I) of the L protein from a rhabdovirus, vesicular stomatitis virus, at 1.8-Å resolution. The strictly and strongly conserved residues in this domain cluster in a single area of the protein. Serial mutation of these residues shows that many of the amino acids are essential for viral transcription but not for mRNA capping. Three-dimensional alignments show that this domain shares structural homology with polymerases from other viral families, including segmented negative-strand RNA and double-stranded RNA (dsRNA) viruses.IMPORTANCENegative-strand RNA viruses include a diverse set of viral families that infect animals and plants, causing serious illness and economic impact. The members of this group of viruses share a set of functionally conserved proteins that are essential to their replication cycle. Among this set of proteins is the viral polymerase, which performs a unique set of reactions to produce genome- and subgenome-length RNA transcripts. In this article, we study the polymerase of vesicular stomatitis virus, a member of the rhabdoviruses, which has served in the past as a model to study negative-strand RNA virus replication. We have identified a site in the N-terminal domain of the polymerase that is essential to viral transcription and that shares sequence homology with members of the paramyxoviruses and the filoviruses. Newly identified sites such as that described here could prove to be useful targets in the design of new therapeutics against negative-strand RNA viruses.

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