Inhibition of Vaccinia Virus Replication by Two Small Interfering RNAs Targeting B1R and G7L Genes and Their Synergistic Combination with Cidofovir

Vigne, Solenne; Duraffour, Sophie; Andrei, Gracíela; Snoeck, Robert; Garín, Daniel; Crance, Jean‐Marc

doi:10.1128/aac.01626-08

Cited by 25 publications

(19 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is unclear if these two activities are related, but the activity of this compound did not translate into animal models of infection (Smee et al, 2010). The inhibition of B1R and G7L expression by siRNA has also been reported that results in significant reductions in the replication of vaccinia virus (Vigne et al, 2009). …”

Section: Potential Molecular Targets In Orthopoxvirus Replication mentioning

confidence: 96%

Orthopoxvirus targets for the development of new antiviral agents

Prichard

Kern

2012

Antiviral Research

View full text Add to dashboard Cite

Investments in the development of new drugs for orthopoxvirus infections have fostered new avenues of research, provided an improved understanding of orthopoxvirus biology and yielded new therapies that are currently progressing through clinical trials. These broad-based efforts have also resulted in the identification of new inhibitors of orthopoxvirus replication that target many different stages of viral replication cycle. This review will discuss progress in the development of new anti-poxvirus drugs and the identification of new molecular targets that can be exploited for the development of new inhibitors. The prototype of the orthopoxvirus group is vaccinia virus and its replication cycle will be discussed in detail noting specific viral functions and their associated gene products that have the potential to serve as new targets for drug development. Progress that has been achieved in recent years should yield new drugs for the treatment of these infections and might also reveal new approaches for antiviral drug development with other viruses.

show abstract

Section: Potential Molecular Targets In Orthopoxvirus Replication mentioning

confidence: 96%

Orthopoxvirus targets for the development of new antiviral agents

Prichard

Kern

2012

Antiviral Research

View full text Add to dashboard Cite

show abstract

“…In this regard, however, it is worth noting that a single envelope trimer is sufficient for HIV entry (46). Several recent studies indicated that siRNAs can inhibit VACV replication, although they were not used to analyze the roles of the silenced genes (9,19,40,41). In a screen of siRNAs to 12 monkeypox virus ORFs, knockdown of the J5 homolog reduced the virus yield by approximately 60% (2).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Repression and RNA Silencing Act Synergistically To Demonstrate the Function of the Eleventh Component of the Vaccinia Virus Entry-Fusion Complex

Wolfe

Ojeda

Moss

2012

J Virol

View full text Add to dashboard Cite

Poxviruses have an elaborate system for infecting cells comprising several proteins for attachment and a larger number dedicated to membrane fusion and entry. Thus far, 11 proteins have been identified as components of the vaccinia virus (VACV) entry-fusion complex (EFC), and 10 of these proteins have been shown to be required for entry. J5, the remaining functionally uncharacterized component of the complex, is conserved in all poxviruses, has a predicted C-terminal transmembrane domain, and is an N-terminally truncated paralog of two other EFC proteins. To determine the role of J5, we constructed a mutant that inducibly regulates J5 transcription. Although the virus yield was reduced only about 80% without inducer, the inability to isolate a J5 deletion mutant suggested an essential function. To enhance stringency, we employed RNA silencing alone and together with transcriptional repression of the inducible mutant. The yield of infectious virus was reduced 4-to 5-fold by repression, 2-fold by silencing, and 60-fold by the combination of the two. Virus particles made under the latter conditions appeared to contain a full complement of proteins excluding J5 but had very low infectivity. Further studies indicated that after binding to cells, J5-deficient virions had a defect in core entry and an inability to induce syncytium formation. In addition, we confirmed that J5 is associated with the EFC by affinity purification. These data indicate that J5 is a functional component of the EFC and highlights the advantage of combining transcriptional repression and RNA silencing for stringent reduction of gene expression. The members of the virus family Poxviridae are linear doublestranded DNA viruses that replicate exclusively in the cytoplasm of the host cell (23). Vaccinia virus (VACV), the prototype poxvirus, has a 190-kbp genome predicted to encode nearly 200 proteins of which approximately 80 have been identified as components of the mature virion (MV) (8,29,48). MVs enter cells by neutral-and low-pH fusion with plasma and endosomal membranes, respectively (3, 38) utilizing macropinocytosis or fluid phase uptake (16,22). Four proteins have been reported to participate in attachment by binding to glycosaminoglycans and laminin (6,7,15,20). Analysis of conditional lethal mutants established roles in entry and membrane fusion for 11 viral proteins with homologs in all poxviruses: A16 (28), A21 (37), A28 (34), F9 (5), G3 (17), G9 (27), H2 (32), I2 (26), L1 (4), L5 (36), and O3 (30). Each of these proteins, except I2, has been shown to be associated in a stable complex that can be extracted from membranes and purified. However, the complex could not be isolated if either A16, A21, A28, G3, G9, H2, L5, or O3 was repressed even though the remaining entry proteins were still incorporated into virions, suggesting that the complex is held together by multiple protein interactions. L1 and F9 are not required for isolation of the complex, which suggests that they are peripherally associated with the EFC. On this basis, A16, A21...

show abstract

“…One example may be the B1 kinase, which is of critical importance in the poxvirus replication cycle. A first indication for the potential of B1 as a target for antiviral therapy was demonstrated, since interfering RNAs that target B1 effectively reduced vaccinia and monkeypox virus yields and plaques in in vitro assays, especially when administered together with the proven antiviral drug cidofovir (220).…”

Section: Concluding Thoughtsmentioning

confidence: 99%

Viral Serine/Threonine Protein Kinases

Jacob

Broeke

Favoreel

2011

J Virol

109

View full text Add to dashboard Cite

Phosphorylation represents one the most abundant and important posttranslational modifications of proteins, including viral proteins. Virus-encoded serine/threonine protein kinases appear to be a feature that is unique to large DNA viruses. Although the importance of these kinases for virus replication in cell culture is variable, they invariably play important roles in virus virulence. The current review provides an overview of the different viral serine/threonine protein kinases of several large DNA viruses and discusses their function, importance, and potential as antiviral drug targets.

show abstract

Inhibition of Vaccinia Virus Replication by Two Small Interfering RNAs Targeting B1R and G7L Genes and Their Synergistic Combination with Cidofovir

Cited by 25 publications

References 73 publications

Orthopoxvirus targets for the development of new antiviral agents

Orthopoxvirus targets for the development of new antiviral agents

Transcriptional Repression and RNA Silencing Act Synergistically To Demonstrate the Function of the Eleventh Component of the Vaccinia Virus Entry-Fusion Complex

Viral Serine/Threonine Protein Kinases

Contact Info

Product

Resources

About