Hepatitis C Viral Proteins Affect Cell Viability and Membrane Permeability

Kalkeri, Gururaj; Khalap, Nutan; Akhter, Shamim; Garry, Robert F.; Fermin, César D.; Dash, Srikanta

doi:10.1006/exmp.2001.2392

Cited by 19 publications

(12 citation statements)

References 52 publications

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“…Such an effect is clearly ascribable to the R9 residue expressed by the chimeric virus, as the pseudorecombinant CMV-D/S produced only negligible variations of lymphocyte apoptosis. The R9-CMV-mediated apoptotic effect observed in cells from healthy subjects is in line with evidence relating hepatocyte apoptosis with a cytopathic effect of HCV proteins [31, 32]. This further suggests that the glycoprotein E2, from which the synthetic R9 mimotope is derived, might be the mediator of the liver damage directly induced by the virus.…”

Section: Discussionsupporting

confidence: 79%

Apoptotic Effects of a Chimeric Plant Virus Carrying a Mimotope of the Hepatitis C virus Hypervariable Region 1: Role of Caspases and Endoplasmic Reticulum-Stress

et al. 2012

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The role of apoptosis in the persistence of hepatitis C virus (HCV) infection is controversial. Moreover, conflicting data on the modulation of this process by HCV proteins have been provided. We evaluated the susceptibility of peripheral lymphocytes from patients with chronic hepatitis C to apoptosis both spontaneous and after incubation with a chimeric Cucumber mosaic virus (CMV) carrying 180 copies of the synthetic R9 mimotope obtained from more than 200 hypervariable region-1 sequences of HCV. Resting T lymphocytes were found to be sensitized to apoptosis as a result of chronic HCV infection. The plant virus-derived vector R9-CMV displayed a strong pro-apoptotic effect associated with activation of both caspase-8 and −9, indicating the involvement of both extrinsic and intrinsic apoptotic pathways. A parallel R9-CMV-mediated activation of endoplasmic reticulum-stress was suggested by the significant induction of BiP/GRP78, GADD153 and caspase-12. These data contribute to define the complex HCV/host interaction, and open new prospects for developing a plant-derived antigen-presenting system to strengthen host defences against persistent pathogens.

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Section: Discussionsupporting

confidence: 79%

Apoptotic Effects of a Chimeric Plant Virus Carrying a Mimotope of the Hepatitis C virus Hypervariable Region 1: Role of Caspases and Endoplasmic Reticulum-Stress

et al. 2012

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“…Several complementary strategies to investigate extrahepatic replication of HCV include DNA-based expression systems, 41,[49][50][51][52][53] lymphocyte cell lines that constitutively express HCV, 21,23,54 peripheral blood mononuclear cell (PBMC) cultures from HCV-infected persons, 21,55,56 direct viral infection of extrahepatic cell types with HCV-infected sera, 35,[57][58][59][60] in situ hybridization and immunohistochemistry, 38,[61][62][63][64] and laser capture microdissection. 37,65 The relevance of each of these strategies to extrahepatic replication of HCV is not currently known and can only be determined through extensive validation and cross-comparison amongst all available methodologies.…”

Section: Detection Of Extrahepatic Replicationmentioning

confidence: 99%

Extrahepatic replication of HCV: Insights into clinical manifestations and biological consequences

2006

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“…In particular, IRES activity can be main- tained during the early stages of apoptosis, when overall protein synthesis is strongly inhibited Holcik et al 2000aHolcik et al , 2000b. Because HCV infection can induce apoptosis in hepatocytes (Nasir et al 2000;Kalkeri et al 2001), it could be of advantage to the virus to prolong the synthesis of its own proteins under these conditions. Moreover, PKR has a marked pro-apoptotic effect (Gil and Esteban 2000;Barber 2001), and it was therefore of interest to determine whether the properties of the HCV IRES might play a role in protecting IRES-driven protein synthe- …”

Section: Regulation Of Pkr By the Hcv Iresmentioning

confidence: 99%

Inhibition of the protein kinase PKR by the internal ribosome entry site of hepatitis C virus genomic RNA

Vyas

Elia²,

Clemens³

2003

RNA

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Translation of the hepatitis C genome is mediated by internal ribosome entry on the structurally complex 5 untranslated region of the large viral RNA. Initiation of protein synthesis by this mechanism is independent of the cap-binding factor eIF4E, but activity of the initiator Met-tRNA f -binding factor eIF2 is still required. HCV protein synthesis is thus potentially sensitive to the inhibition of eIF2 activity that can result from the phosphorylation of the latter by the interferon-inducible, double-stranded RNA-activated protein kinase PKR. Two virally encoded proteins, NS5A and E2, have been shown to reduce this inhibitory effect of PKR by impairing the activation of the kinase. Here we present evidence for a third viral strategy for PKR inhibition. A region of the viral RNA comprising part of the internal ribosome entry site (IRES) is able to bind to PKR in competition with double-stranded RNA and can prevent autophosphorylation and activation of the kinase in vitro. The HCV IRES itself has no PKR-activating ability. Consistent with these findings, cotransfection experiments employing a bicistronic reporter construct and wild-type PKR indicate that expression of the protein kinase is less inhibitory towards HCV IRES-driven protein synthesis than towards cap-dependent protein synthesis. These data suggest a dual function for the viral IRES, with both a structural role in promoting initiation complex formation and a regulatory role in preventing inhibition of initiation by PKR.

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Hepatitis C Viral Proteins Affect Cell Viability and Membrane Permeability

Cited by 19 publications

References 52 publications

Apoptotic Effects of a Chimeric Plant Virus Carrying a Mimotope of the Hepatitis C virus Hypervariable Region 1: Role of Caspases and Endoplasmic Reticulum-Stress

Apoptotic Effects of a Chimeric Plant Virus Carrying a Mimotope of the Hepatitis C virus Hypervariable Region 1: Role of Caspases and Endoplasmic Reticulum-Stress

Extrahepatic replication of HCV: Insights into clinical manifestations and biological consequences

Inhibition of the protein kinase PKR by the internal ribosome entry site of hepatitis C virus genomic RNA

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