Inhibition of PKR by RNA and DNA viruses

Langland, Jeffrey; Cameron, J M; Heck, Michael; Jancovich, James K.; Jacobs, Bertram L.

doi:10.1016/j.virusres.2005.10.014

Cited by 192 publications

(173 citation statements)

References 127 publications

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“…Very few colonies of HT1080 cells survive reoviral exposure, whereas essentially all HTR1 and its virus-cured derivatives survive. In contrast, it appeared that PKR is constitutively activated in the persistently infected HTR1 cells (Figure 4c), and possibly this is a contributing factor to the moderately reduced efficiency of replication of exogenously added virus (Langland et al, 2006), as observed in Figure 3.…”

Section: Selection For Reoviral Resistance In Ras-transformed Cancer mentioning

confidence: 90%

Acquired resistance to reoviral oncolysis in Ras-transformed fibrosarcoma cells

et al. 2007

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Reovirus shows considerable potential as an oncolytic agent for Ras-activated tumors and is currently in clinical trials. Here we ask whether such tumor cell lines can acquire resistance to reoviral oncolysis. We challenged human HT1080 fibrosarcoma cells that carry a Ras mutation by prolonged exposure to reovirus, thereby yielding highly virus-resistant HTR1 cells. These cells are persistently infected with reovirus, exhibit high Ras activity and retain the original Ras gene mutation, showing that resistance to reovirus can be displayed in cells with active Ras. The HTR1 cells also exhibit reduced cellular cathepsin B activity, which normally contributes to viral entry and activation. Persistently infected HTR1 cells were not tumorigenic in vivo, whereas immunologically cured virus-free HTR1 cells were highly tumorigenic. Thus, acquisition of resistance to reovirus may constrain therapeutic strategies. To determine whether reoviral resistance is associated with a general reduction in apoptotic potential, we challenged the HTR1 cells with apoptotic inducers and E1B-defective adenovirus, resulting in significant apoptosis and cell death following both approaches. Therefore, even if resistance to reoviral oncolysis should arise in tumor cells in vivo, other therapeutic strategies may nevertheless remain effective.

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Section: Selection For Reoviral Resistance In Ras-transformed Cancer mentioning

confidence: 90%

Acquired resistance to reoviral oncolysis in Ras-transformed fibrosarcoma cells

et al. 2007

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“…Sensing of dsRNA via protein kinase R (PKR) has been recently described as a TLR-independent pathway for DC activation by viruses [43] and the importance of PKR in this process is emphasized by a large number of viruses that code for PKR inhibitors [44]. Based on our finding that APRIL is induced by viral products, via a PKR dependent pathway, and the importance of APRIL in IgA class switching, one might postulate that APRIL plays an important role in early IgA response against viruses.…”

Section: Discussionmentioning

confidence: 99%

Specific TLR ligands regulate APRIL secretion by dendritic cells in a PKR‐dependent manner

et al. 2007

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A proliferation inducing ligand (APRIL) and B cell activating factor belonging to the TNF family (BAFF/BLyS) have been implicated in IgA class switch recombination in thymus‐independent (TI) B cell responses. Dendritic cells (DC) are thought to regulate Ig class switching in TI B cell responses by providing B cells with cytokines, including APRIL and BAFF. We therefore set out to analyze the regulation of APRIL and BAFF expression by human monocyte‐derived DC (moDC). We observed that moDC produce and secrete APRIL, but could not detect expression of BAFF. Importantly, stimulation with the Toll‐like receptor ligands CpG and poly I:C specifically induced APRIL production, while other Toll‐like receptor ligands were ineffective. The increase in APRIL was dependent on translation, but surprisingly not transcription. Instead, enhanced APRIL production and secretion resulted from activation of protein kinase receptor (PKR), as it was completely inhibited by the specific inhibitor of PKR, 2‐aminopurine. This suggests that the specific induction of APRIL by CpG and poly I:C, and the signal integration by PKR, are regulated by translational modification and hint at a role for APRIL in the TI B cell response to viral infections.

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“…Dimerization of PKR molecules following the binding with dsRNA plays a crucial role in the mechanism of activation of PKR (60 -64). In the context of regular duplex RNA, a minimum of 30 -33 bp of dsRNA is required to activate PKR autophosphorylation, and the maximal level of activation increases with duplex length (60,63,65). Here, we asked whether exosomal TAR was able to activate PKR in recipient cells.…”

Section: Hiv-1 Tar Rna Released From Infected Cells Both In Vitro Andmentioning

confidence: 99%

Exosomes from HIV-1-infected Cells Stimulate Production of Pro-inflammatory Cytokines through Trans-activating Response (TAR) RNA

Sampey

Saifuddin

Schwab

et al. 2016

Journal of Biological Chemistry

181

273

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HIV-1 infection results in a chronic illness because longterm highly active antiretroviral therapy can lower viral titers to an undetectable level. However, discontinuation of therapy rapidly increases virus burden. Moreover, patients under highly active antiretroviral therapy frequently develop various metabolic disorders, neurocognitive abnormalities, and cardiovascular diseases. We have previously shown that exosomes containing trans-activating response (TAR) element RNA enhance susceptibility of undifferentiated naive cells to HIV-1 infection. This study indicates that exosomes from HIV-1-infected primary cells are highly abundant with TAR RNA as detected by RT-real time PCR. Interestingly, up to a million copies of TAR RNA/l were also detected in the serum from HIV-1-infected humanized mice suggesting that TAR RNA may be stable in vivo. Incubation of exosomes from HIV-1-infected cells with primary macrophages resulted in a dramatic increase of proinflammatory cytokines, IL-6 and TNF-␤, indicating that exosomes containing TAR RNA could play a direct role in control of cytokine gene expression. The intact TAR molecule was able to bind to PKR and TLR3 effectively, whereas the 5 and 3 stems (TAR microRNAs) bound best to TLR7 and -8 and none to PKR. Binding of TAR to PKR did not result in its phosphorylation, and therefore, TAR may be a dominant negative decoy molecule in cells. The TLR binding through either TAR RNA or TAR microRNA potentially can activate the NF-B pathway and regulate cytokine expression. Collectively, these results imply that exosomes containing TAR RNA could directly affect the proinflammatory cytokine gene expression and may explain a possible mechanism of inflammation observed in HIV-1-infected patients under cART.

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Inhibition of PKR by RNA and DNA viruses

Cited by 192 publications

References 127 publications

Acquired resistance to reoviral oncolysis in Ras-transformed fibrosarcoma cells

Acquired resistance to reoviral oncolysis in Ras-transformed fibrosarcoma cells

Specific TLR ligands regulate APRIL secretion by dendritic cells in a PKR‐dependent manner

Exosomes from HIV-1-infected Cells Stimulate Production of Pro-inflammatory Cytokines through Trans-activating Response (TAR) RNA

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