Adeno-Associated Viruses Can Induce Phosphorylation of eIF2α via PKR Activation, Which Can Be Overcome by Helper Adenovirus Type 5 Virus-Associated RNA

Nayak, Ramnath; Pintel, David J.

doi:10.1128/jvi.01132-07

Cited by 26 publications

(28 citation statements)

References 31 publications

(40 reference statements)

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“…*P < 0.01. 2α via dsRNA-induced protein kinase R activation (19)(20)(21). However, the roles played by VA-RNAs in the Ad vector-induced innate immune response have not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

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Induction of type I interferon by adenovirus-encoded small RNAs

Yamaguchi

Kono

Kouyama

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Transduction with replication-incompetent recombinant adenovirus (Ad) vectors results in a rapid activation of innate immune responses, such as inflammatory cytokine production and subsequent tissue damage. The precise mechanisms of the innate immune responses induced by Ad vectors remain to be clarified. Possible components of Ad vectors that activate innate immune responses are the capsid protein, the viral genome (DNA), and viral transcripts. In the present study, we demonstrate that virus-associated RNAs (VA-RNAs), which are small RNAs transcribed by RNA polymerase III, induce the production of type I IFN (IFN-α and IFN-β), but they do not induce the production of inflammatory cytokines (IL-6 and IL-12), in mouse embryonic fibroblasts (MEFs) and granulocyte-macrophage colony-stimulating factor–generated bone marrow-derived dendritic cells (GM-DCs). We also show that IFN-β promoter stimulator-1 is involved in VA-RNA–dependent IFN-β production in MEFs and is partially involved in type I IFN production in GM-DCs. This study provides important insight into the mechanisms of Ad vector-triggered innate immune responses, which may lead to more advanced and rational Ad vector designs for gene therapies and vaccine applications.

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“…*P < 0.01. 2α via dsRNA-induced protein kinase R activation (19)(20)(21). However, the roles played by VA-RNAs in the Ad vector-induced innate immune response have not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…VA-RNAs are synthesized by RNA polymerase III, are ≈160 nucleotides long, and are structurally highly conserved. Previous studies have demonstrated that VARNAs induce the phosphorylation of eukaryotic initiation factor-2α via dsRNA-induced protein kinase R activation (19)(20)(21).…”

mentioning

confidence: 99%

Induction of type I interferon by adenovirus-encoded small RNAs

Yamaguchi

Kono

Kouyama

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Similar studies conducted with adeno-associated viruses showed that E2a is the major contributor to the adenoviral helper effect on AAV-2, 23 whereas VA RNA sustains the AAV-5 replication by blocking double-stranded RNA-activated protein kinase activation and suppressing the antiviral cellular response. 20 This study shows that pXX6 significantly increases and accelerates viral DNA replication during the production of recPVs. In agreement with these results, adenovirus 2 facilitated DNA replication of the closely related parvovirus MVM, 27 whereas pXX6 adenoviral vector, enabled the erythrovirus B19 to replicate its DNA and produce infectious progeny particles in non-permissive HEK 293 cells.…”

Section: Discussionmentioning

confidence: 75%

“…19 VA RNA was also reported to support AAV-5 replication by physically interacting with the double-stranded RNA-activated protein kinase and impairing its ability to elicit an antiviral defense response through the inhibition of viral translation. 20 Studies with recombinant AAV-2 have confirmed that a small subset of adenoviral genes is sufficient for the helper effect. In HEK 293 cells, which provide the E1 gene in trans, the minimal set of genes for efficient recombinant AAV-2 production is E2a, E4(orf6) and the VA RNA gene.…”

Section: Introductionmentioning

confidence: 98%

Novel adenovirus-based helper system to support production of recombinant parvovirus

et al. 2010

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Preclinical studies using various cell culture and animal systems highlight the potential of recombinant rodent parvoviruses (recPVs) for cancer therapy. Production of these viruses is, however, not efficient and this hampers the clinical applications of these agents. In this study, we show that the adenovirus genes E2a, E4(orf6) and VA RNA increase the production of recPVs by more than 10-fold and reduce the time of production from 3 to 2 days in HEK293T cells. The helper effects of these genes can be observed with different recPVs, regardless of the nature and size of the inserted transgene. Furthermore, we generated a recombinant Adenovirus 5 carrying the parvovirus VP transcription unit. This helper, named Ad-VP, allows recPVs to be efficiently produced through a protocol based only on cell infection, making possible to use cell lines, such as NB324K, which are good producers of parvoviruses but are hardly transfectable. Hence, we could further improve viral titers and reduce time and costs of production. This Ad-VP helper-based protocol could be scaled up to a bioreactor format for the generation of the large amounts of recPVs needed for future clinical applications.

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“…In the Adeno-Associated Virus type 5 (AAV5), a member of the Dependovirus genus, viral replication and protein synthesis was highly enhanced by the co-expression of an adenovirus VA I RNA (Nayak and Pintel 2007a) that, by binding to PKR, prevents its otherwise activation by a short RNA sequence of AAV5 messengers (Nayak and Pintel 2007b). The infection of untransformed fibroblast cells by MVM of the Parvovirus genus, activated PKR and subsequently phosphorylated eIF2α (Ventoso et al 2010).…”

Section: Translational Control Of Parvovirus Gene Expression In Gliobmentioning

confidence: 99%