3 research outputs found
Hepatitis C Virus RNA-Dependent RNA Polymerase Interacts with the Akt/PKB Kinase and Induces Its Subcellular Relocalization
Hepatitis C virus (HCV) interacts with cellular components and modulates their activities for its own benefit. These interactions have been postulated as a target for antiviral treatment, and some candidate molecules are currently in clinical trials. The multifunctional cellular kinase Akt/protein kinase B (PKB) must be activated to increase the efficacy of HCV entry but is rapidly inactivated as the viral replication cycle progresses. Viral components have been postulated to be responsible for Akt/PKB inactivation, but the underlying mechanism remained elusive. In this study, we show that HCV polymerase NS5B interacts with Akt/ PKB. In the presence of transiently expressed NS5B or in replicon- or virus-infected cells, NS5B changes the cellular localization of Akt/PKB from the cytoplasm to the perinuclear region. Sequestration of Akt/PKB by NS5B could explain its exclusion from its participation in early Akt/PKB inactivation. The NS5B-Akt/PKB interaction represents a new regulatory step in the HCV infection cycle, opening possibilities for new therapeutic options.Fundación Ramón Areces. CIBERehd is funded by Instituto de Salud Carlos III. Celia Perales is supported by the Miguel Servet program (Instituto de Salud Carlos III).Peer Reviewe
Uso de la RNasa P como agente antiviral
Filing Date: (2009-11-11).-- Priority Data: ES P200803224 (2008-11-11).-- Titulares: Consejo Superior de Investigaciones Científicas (CSIC), Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Nacional de Investigaciones Agrarias (INIA), Universidad de Castilla La Mancha (UCLM).[EN] Use of the RNase P of Synechocysitis sp. to inhibit replication of RNA virus and for the production of medicaments for the treatment of diseases caused by RNA virus.[ES] Uso de la RNasa P de Synechocysitis sp. para inhibir la replicación de virus de RNA, y para la elaboración de medicamentos para el tratamiento de enfermedades provocadas por virus de RNA.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas, Instituto Nacional de Investigaciones Agrarias (INIA), Universidad de Castilla la ManchaA2 Solicitud de patentes sin informe sobre el estado de la técnic
Guanosine inhibits hepatitis C virus replication and increases indel frequencies, associated with altered intracellular nucleotide pools
In the course of experiments aimed at deciphering the inhibition mechanism of mycophenolic acid and ribavirin in hepatitis C virus (HCV) infection, we observed an inhibitory effect of the nucleoside guanosine (Gua). Here, we report that Gua and not the other standard nucleosides inhibits HCV replication in human hepatoma cells. Gua did not directly inhibit the in vitro polymerase activity of NS5B, but it modified the intracellular levels of nucleoside di- and tri-phosphate (NDPs and NTPs), leading to deficient HCV RNA replication and reduction of infectious progeny virus production. Changes in the concentrations of NTP or NDP modified NS5B RNA polymerase activity in vitro, in particular de novo RNA synthesis and template switching. Furthermore, the Gua-mediated changes were associated with a significant increase in the number of indels in viral RNA, which may account for the reduction of the specific infectivity of the viral progeny, suggesting the presence of defective genomes. Thus, a proper NTP:NDP balance appears to be critical to ensure HCV polymerase fidelity and minimal production of defective genomes.C.P. is supported by the Miguel Servet program of the Instituto de Salud Carlos III
(CP14/00121) cofinanced by the European Regional Development Fund (ERDF). CIBERehd
(Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas) is funded by Instituto
de Salud Carlos III. The work at CBMSO was supported by grants SAF2014-52400-R from
Ministerio de Economía y Competitividad (MINECO), SAF2017-87846-R, BFU2017-91384-EXP from Ministerio de Ciencia, Innovación y Universidades (MICIU), PI18/00210 from
Instituto de Salud Carlos III, S2013/ABI-2906, (PLATESA from Comunidad de
Madrid/FEDER) and S2018/BAA-4370 (PLATESA2 from Comunidad de Madrid/FEDER).
The team at CBMSO belongs to the Global Virus Network (GVN). The work in Albacete was supported by grants SAF2016-80451-P, EQC2018-004420-P, and EQC2018-004631-P from
MICIU, and by Plan Propio of the University of Castilla-La Mancha. The work in Malaga was
supported by Plan Propio of the University of Málaga. Institutional grants from the Fundación
Ramón Areces and Banco Santander to the CBMSO are also acknowledged.N