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At least 577 records · Page 32Linked to original sources
PubMed2006

Suppression of bovine viral diarrhea virus replication by small interfering RNA and short hairpin RNA-mediated RNA interference.

Bovine viral diarrhea virus (BVDV) is a ubiquitous viral pathogen that affects cattle herds' worldwide causing significant economic loss. The current strategies to control BVDV infection include vaccination (modified-live or killed) and control of virus spread by enhanced biosecurity management, however, the disease remains prevalent. With the discovery of the sequence-specific method of gene silencing known as RNA interference (RNAi), a new era in antiviral therapies has begun. Here we report the efficient inhibition of BVDV replication by small interfering (siRNA) and short hairpin RNA (shRNA)-mediated gene silencing. siRNAs were generated to target the 5' non-translated (NTR) region and the regions encoding the C, NS4B and NS5A proteins of the BVDV genome. The siRNAs were first validated using an EGFP/BVDV reporter system and were then shown to suppress BVDV-induced cytopathic effects and viral titers in cell culture with surprisingly different activities compared to the reporter system. Efficient viral suppression was then achieved by bovine 7SK-expressed BVDV-specific shRNAs. Overall, our results demonstrated the use of siRNA and shRNA-mediated gene silencing to achieve efficient inhibition of the replication of this virus in cell culture.

Animals↗
PubMed1981

A proteinless mutant of tobacco mosaic virus: evidence against the role of a viral coat protein for interference.

A coat-protein-free mutant of tobacco mosaic virus as well as mutants with a non-functional coat protein were found to interfere with the establishment and spread of challenging strains of TMV. The results do not support an earlier concept, according to which the genome of a related challenging virus could be captured by the coat protein of the virus introduced in advance. The presence of a viral coat protein is obviously not essential and a competition among the viral genomes for some specific site seems to be a more likely mechanism of cross protection.

Mutation↗
PubMed2002

RNA interference directed against viral and cellular targets inhibits human immunodeficiency Virus Type 1 replication.

Human immunodeficiency virus type 1 (HIV-1) gene expression is regulated by both cellular transcription factors and Tat. The ability of Tat to stimulate transcriptional elongation is dependent on its binding to TAR RNA in conjunction with cyclin T1 and CDK9. A variety of other cellular factors that bind to the HIV-1 long terminal repeat, including NF-kappaB, SP1, LBP, and LEF, are also important in the control of HIV-1 gene expression. Although these factors have been demonstrated to regulate HIV-1 gene expression by both genetic and biochemical analysis, in most cases a direct in vivo demonstration of their role on HIV-1 replication has not been established. Recently, the efficacy of RNA interference in mammalian cells has been shown utilizing small interfering RNAs (siRNAs) to result in the specific degradation of host mRNAs and decreases the levels of their corresponding proteins. In this study, we addressed whether siRNAs directed against either HIV-1 tat or reverse transcriptase or the NF-kappaB p65 subunit could specifically decrease the levels of these proteins and thus alter HIV-1 replication. Our results demonstrate the specificity of siRNAs for decreasing the expression of these viral and cellular proteins and inhibiting HIV-1 replication. These studies suggest that RNA interference is useful in exploring the biological role of cellular and viral regulatory factors involved in the control of HIV-1 gene expression.

Gene Products, tat↗
PubMed2006

Rabies viral mechanisms to escape the IFN system: the viral protein P interferes with IRF-3, Stat1, and PML nuclear bodies.

Interferons (IFNs) are a family of secreted proteins with antiviral, antiproliferative, and immunomodulatory activities. The different biologic actions of IFN are believed to be mediated by the products of specifically IFN-stimulated genes (ISG) in the target cells. The IFN response is the first line of defense against viral infections. Viruses, which require the cellular machinery for their replication, have evolved different ways to counteract the action of IFN by inhibiting IFN production or Jak-Stat signaling or by altering ISG products. This review focuses on the role of viral proteins from the RNA virus family, particularly rabies P protein. P protein mediates inhibition of the IFN system by different pathways: it inhibits IFN production by impairing IFN regulatory factor-3 (IRF-3) phosphorylation and IFN signaling by blocking nuclear transport of Stat1 and alters promyelocytic leukemia (PML) nuclear bodies by retaining PML in the cytoplasm.

Animals↗
PubMed2006

Viral suppressors of RNA interference impair RNA silencing induced by a Semliki Forest virus replicon in tick cells.

It was recently shown that infection of ISE6 tick cells by a recombinant Semliki Forest virus (SFV) expressing a heterologous gene induced small interfering RNAs (siRNAs) and silencing of the gene. To gain information on RNA interference (RNAi) in ticks, three known viral inhibitors that act in different ways, the NS1 protein of Influenza virus, NSs of Tospovirus Tomato spotted wilt virus and HC-Pro of Zucchini yellow mosaic virus were expressed and investigated to determine if they antagonize induced RNAi. Using the recombinant SFV replicon expressing firefly luciferase, silencing was induced and the suppressor activity of these inhibitors during or after initiation of siRNA synthesis was tested, to determine which step of the RNAi pathway is impaired. It was found that these proteins, identified in mammalian or plant systems, also display activity in tick cells. These data suggest that ticks utilize a mechanism similar to the one found in other eukaryotes.

Animals↗
PubMed2006

Oligonucleotide-based antiviral strategies.

In the age of extensive global traffic systems, the close neighborhood of man and livestock in some regions of the world, as well as inadequate prevention measures and medical care in poorer countries, greatly facilitates the emergence and dissemination of new virus strains. The appearance of avian influenza viruses that can infect humans, the spread of the severe acute respiratory syndrome (SARS) virus, and the unprecedented raging of human immunodeficiency virus (HIV) illustrate the threat of a global virus pandemic. In addition, viruses like hepatitis B and C claim more than one million lives every year for want of efficient therapy. Thus, new approaches to prevent virus propagation are urgently needed. Antisense strategies are considered a very attractive means of inhibiting viral replication, as oligonucleotides can be designed to interact with any viral RNA, provided its sequence is known. The ensuing targeted destruction of viral RNA should interfere with viral replication without entailing negative effects on ongoing cellular processes. In this review, we will give some examples of the employment of antisense oligonucleotides, ribozymes, and RNA interference strategies for antiviral purposes. Currently, in spite of encouraging results in preclinical studies, only a few antisense oligonucleotides and ribozymes have turned out to be efficient antiviral compounds in clinical trials. The advent of RNA interference now seems to be refueling hopes for decisive progress in the field of therapeutic employment of antisense strategies.

Animals↗
PubMed2005

Gene therapy for human small-cell lung carcinoma by inactivation of Skp-2 with virally mediated RNA interference.

Increase of Skp-2, which is involved in the degradation of cell cycle regulators including p27Kip1, p21 and c-myc, is one of the important mechanisms for dysregulation of cell cycles in various cancers. We applied RNA interference (RNAi) for Skp-2 by using HIV-lentiviral or adenoviral vectors for a human small-cell lung carcinoma cell line with increased Skp-2 to evaluate RNAi strategy for cancer gene therapy. HIV-lentivirus-mediated RNAi for Skp-2 resulted in efficient inhibition of the in vitro cell growth of cancer cells with increased Skp-2 through the increase of p27Kip1 and p21, but no significant effect on the growth of cells without high Skp-2 expression. Furthermore, intratumoral administration of adenovirus siRNA vector for Skp-2 efficiently inhibited growth of established subcutaneous tumor on NOD/SCID mice. These results indicate that the Skp-2 RNAi may be a useful strategy for gene therapy of cancers with high Skp-2 expression.

Adenoviridae↗
PubMed2005

Shutoff of RNA polymerase II transcription by poliovirus involves 3C protease-mediated cleavage of the TATA-binding protein at an alternative site: incomplete shutoff of transcription interferes with efficient viral replication.

The TATA-binding protein (TBP) plays a crucial role in cellular transcription catalyzed by all three DNA-dependent RNA polymerases. Previous studies have shown that TBP is targeted by the poliovirus (PV)-encoded protease 3C(pro) to bring about shutoff of cellular RNA polymerase II-mediated transcription in PV-infected cells. The processing of the majority of viral precursor proteins by 3C(pro) involves cleavages at glutamine-glycine (Q-G) sites. We present evidence that suggests that the transcriptional inactivation of TBP by 3C(pro) involves cleavage at the glutamine 104-serine 105 (Q104-S105) site of TBP and not at the Q18-G19 site as previously thought. The TBP Q104-S105 cleavage by 3C(pro) is greatly influenced by the presence of an aliphatic amino acid at the P4 position, a hallmark of 3C(pro)-mediated proteolysis. To examine the importance of host cell transcription shutoff in the PV life cycle, stable HeLa cell lines were created that express recombinant TBP resistant to cleavage by the viral proteases, called GG rTBP. Transcription shutoff was significantly impaired and delayed in GG rTBP cells upon infection with poliovirus compared with the cells that express wild-type recombinant TBP (wt rTBP). Infection of GG rTBP cells with poliovirus resulted in small plaques, significantly reduced viral RNA synthesis, and lower viral yields compared to the wt rTBP cell line. These results suggest that a defect in transcription shutoff can lead to inefficient replication of poliovirus in cultured cells.

3C Viral Proteases↗
PubMed1998

Apoptosis resulting from superinfection of Heliothis zea virus 1 is inhibited by p35 and is not required for virus interference.

Superinfection of Spodoptera frugiperda insect cells that are persistently infected with Heliothis zea 1 (Hz-1) virus induces general cellular apoptosis and subsequently results in homologous virus interference. Since apoptosis correlates closely with both a significant decrease in yield of virus progeny and expansion of virus infection among cells, further experiments were designed to verify the direct association of apoptosis with homologous interference. It was found that superinfection-induced apoptosis can be efficiently blocked by the stable transfection of p35 into cells before or after the establishment of persistent virus infection. However, persistently infected cells are still strongly resistant to the challenge of Hz-1 virus, indicating that the induction of apoptosis is not essential for the resulting homologous Hz-1 virus interference. Replication and transcription of viral genomes are greatly retarded upon Hz-1 virus superinfection of persistently infected cells, whether stably transfected with p35 or not, suggesting that upon superinfection, the decreasing yield of virus progeny in these persistently infected cells is caused by a blockage early after virus infection.

Animals↗
PubMed2006

Transgenically expressed viral RNA silencing suppressors interfere with microRNA methylation in Arabidopsis.

HEN1-dependent methylation of the 3'-terminal nucleotide is a crucial step in plant microRNA (miRNA) biogenesis. Here we report that several viral RNA silencing suppressors (P1/HC-Pro, p21 and p19) inhibit miRNA methylation. These suppressors have distinct effects on different miRNAs. We also show that miRNA* is methylated in vivo in a suppressor-sensitive manner, suggesting that the viral proteins interfere with miRNA/miRNA* duplexes. p19 and p21 bind both methylated and unmethylated miRNA/miRNA* duplexes in vivo. These findings suggest miRNA/miRNA* as the in vivo substrates for the HEN1 miRNA methyltransferase and raise intriguing possibilities regarding the cellular location of miRNA methylation.

Arabidopsis↗
PubMed1994

The envelopes of two ecotropic murine leukemia viruses display distinct efficiencies in retroviral vaccination by interference.

In cell cultures infected with a retrovirus, the expression of the viral envelope interferes with superinfection by retroviruses which recognize the same receptor. We have previously demonstrated that vaccination of susceptible strains of mice (of the Mus musculus species) with the attenuated ecotropic Friend murine leukemia virus (F-MuLV) B3 efficiently protects against the early hemolytic anemia and the erythroleukemia induced by a challenge with the virulent F-MuLV 57 through a similar in vivo mechanism of interference to superinfection (A. Corbin and M. Sitbon, J. Virol. 67, 5146-5152, 1993). Vaccination with the heterologous ecotropic Moloney-MuLV (M-MuLV) efficiently protects against the early hemolytic anemia but has a weak protective effect on the F-MuLV 57-induced erythroleukemia. Furthermore, vaccination with the attenuated F-MuLV B3 had only a transient protective effect on M-MuLV-induced thymomas. These different efficiencies of F- and M-MuLV to confer protection in this model of vaccination by interference were mostly due to envelope sequences, indicative of distinct in vivo interference properties of the two ecotropic envelopes.

Animals↗
PubMed1999

Cellular expression of bovine herpesvirus 1 gD inhibits cell-to-cell spread of two closely related viruses without blocking their primary infection.

Alphaherpesviral glycoprotein D (gD) is a critical component of the cell membrane penetration system. Cells that express gD of herpes simplex virus type 1 (HSV1), pseudorabies virus (PRV), or bovine herpesvirus type 1.1 (BHV1.1) resist infection by the homologous virus due to interference with viral entry at the level of penetration. BHV1.1 gD interferes with the distantly related viruses HSV1 and PRV despite only a 30-40% sequence similarity and the complete absence of antigenic cross-reactivity among the three gDs. The six cysteines that form three intrachain disulfide bonds in HSV1 are also present in PRV and BHV1.1 gD, suggesting structural similarities among the gD homologs. Functional similarities were postulated to be responsible for cross-interference. To test this hypothesis, we constructed a BHV1.1 gD-expressing cell line (MDBKgD) and assessed its resistance to the homologous BHV1.1 and two closely related viruses, BHV1.2 and BHV5. The gDs of these viruses share 98. 3% and 86% amino acid identity with BHV1.1 gD and bound monoclonal antibodies directed against all five neutralizing epitopes mapped on BHV1.1 gD. MDBKgD cells were resistant to BHV1.1 but fully susceptible to BHV1.2 and BHV5 infection as measured by plaque numbers and single cycle growth kinetics. However, all three viruses, but not vesicular stomatitis virus, made smaller plaques on MDBKgD cells than on control cells. These data suggest that gD-mediated interference is expressed both at the level of initial infection and at the level of cell-to-cell spread and that these two levels can be distinguished by using closely related viruses.

Amino Acid Sequence↗
PubMed1993

Cell fusion by the envelope glycoproteins of persistent measles viruses which caused lethal human brain disease.

Measles virus (MV) rarely induces lethal diseases of the human central nervous system characterized by reduced expression of the viral envelope proteins and by lack of viral budding. The MV envelope contains two integral membrane proteins, termed fusion (F) protein and hemagglutinin (H) protein, and a membrane-associated matrix (M) protein. Previously, analysis of MV genes from autopsy material indicated that the M protein and the F protein intracellular domain are often drastically altered by mutations. Here, we present evidence that truncation of the F protein intracellular domain does not impair fusion function, and we suggest that this alteration interferes with viral budding. Unexpectedly, certain combinations of functional F and H proteins were unable to induce syncytium formation, an observation suggesting that specific F-H protein interactions are required for cell fusion. We also found that three of four H proteins of persistent MVs are defective in intracellular transport, oligosaccharide modification, dimerization, and fusion helper function. Thus, MVs replicating in the brain at the terminal stage of infection are typically defective in M protein and in the two integral membrane proteins. Whereas the M protein appears dispensable altogether, partial preservation of F-protein function and H-protein function seems to be required, presumably to allow local cell fusion. Certain subtle alterations of the F and H proteins may be instrumental for disease development.

Autopsy↗