Hepatitis C virus: life cycle in cells, infection and host response, and analysis of molecular markers influencing the outcome of infection and response to therapy

Dustin, Lynn B.; Bartolini, Barbara; Capobianchi, Maria Rosaria; Pistello, Mauro

doi:10.1016/j.cmi.2016.08.025

Cited by 79 publications

(66 citation statements)

References 90 publications

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“…SARS-CoV-2, the virus responsible for the COVID-19 pandemic, is a member of the Orthocoronavirinae subfamily. 9 Coronaviruses and hepatitis C virus (HCV) are both positive-sense single-strand RNA viruses, 10,11 with comparable mechanisms requiring an RNA-dependent RNA polymerase (RdRp) for its genome replication and transcription. Potential inhibitors have been investigated to target various steps in the Coronavirus infectious cycle, including the viral replication machinery.…”

Section: Introductionmentioning

confidence: 99%

Sofosbuvir Terminated RNA is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir

Jockusch

Tao

et al. 2020

Preprint

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SARS-CoV-2 is responsible for COVID-19, resulting in the largest pandemic in over a hundred years. After examining the molecular structures and activities of hepatitis C viral inhibitors and comparing hepatitis C virus and coronavirus replication, we previously postulated that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) might inhibit SARS-CoV-2. We subsequently demonstrated that Sofosbuvir triphosphate is incorporated by the relatively low fidelity SARS-CoV and SARS-CoV-2 RNA-dependent RNA polymerases (RdRps), serving as an immediate polymerase reaction terminator, but not by a host-like high fidelity DNA polymerase. Other investigators have since demonstrated the ability of Sofosbuvir to inhibit SARS-CoV-2 replication in lung and brain cells; additionally, COVID-19 clinical trials with EPCLUSA and with Sofosbuvir plus Daclatasvir have been initiated in several countries. SARS-CoV-2 has an exonuclease-based proofreader to maintain the viral genome integrity. Any effective antiviral targeting the SARS-CoV-2 RdRp must display a certain level of resistance to this proofreading activity. We report here that Sofosbuvir terminated RNA resists removal by the exonuclease to a substantially higher extent than RNA terminated by Remdesivir, another drug being used as a COVID-19 therapeutic. These results offer a molecular basis supporting the current use of Sofosbuvir in combination with other drugs in COVID-19 clinical trials.

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Section: Introductionmentioning

confidence: 99%

Sofosbuvir Terminated RNA is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir

Jockusch

Tao

et al. 2020

Preprint

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“…The viral genomic RNA is 9.6 kb long and codes for a single large protein (more than 3000 amino acids in length; Choo et al, 1991 ), which is co- and post-translationally cleaved by cellular and viral proteases into mature viral structural and non-structural proteins (for reviews, see Bartenschlager et al, 2013 ; Li et al, 2015 ; Bukh, 2016 ; Douam et al, 2016 ). Viral RNA is bordered by highly structured 5′ and 3′ untranslated regions (UTRs), which carry essential functions for virus replication, transcription, packaging of viral RNA into virions, and for the initiation of viral polyprotein synthesis (reviewed in, e.g., Dustin et al, 2016 ). Both UTRs assemble into complicated secondary and tertiary structures and interact with viral and cellular proteins and with each other ( Song et al, 2006 ; Niepmann, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Hepatitis C Virus IRES Quasispecies – From the Individual to the Pool

et al. 2018

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Hepatitis C virus (HCV) is a single-stranded positive-sense RNA virus from the genus Hepacivirus. The viral genomic +RNA is 9.6 kb long and contains highly structured 5′ and 3′ untranslated regions (UTRs) and codes for a single large polyprotein, which is co- and post-translationally processed by viral and cellular proteases into at least 11 different polypeptides. Most of the 5′ UTR and an initial part of the polyprotein gene are occupied by an internal ribosome entry site (IRES), which mediates cap-independent translation of the viral proteins and allows the virus to overcome cellular antiviral defense based on the overall reduction of the cap-dependent translation initiation. We reconsidered published results concerning a search for possible correlation between patient response to interferon-based antiviral therapy and accumulation of nucleotide changes within the HCV IRES. However, we were unable to identify any such correlation. Rather than searching for individual mutations, we suggest to focus on determination of individual and collective activities of the HCV IRESs found in patient specimens. We developed a combined, fast, and undemanding approach based on high-throughput cloning of the HCV IRES species to a bicistronic plasmid followed by determination of the HCV IRES activity by flow cytometry. This approach can be adjusted for measurement of the individual HCV IRES activity and for estimation of the aggregate ability of the whole HCV population present in the specimen to synthesize viral proteins. To detect nucleotide variations in the individual IRESs, we used denaturing gradient gel electrophoresis (DGGE) analysis that greatly improved identification and classification of HCV IRES variants in the sample. We suggest that determination of the collective activity of the majority of HCV IRES variants present in one patient specimen in a given time represents possible functional relations among variant sequences within the complex population of viral quasispecies better than bare information about their nucleotide sequences. A similar approach might be used for monitoring of sequence variations in quasispecies populations of other RNA viruses in all cases when changes in primary sequence represent changes in measurable and easily quantifiable phenotypes.

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“…Структурные белки включают гликопротеины оболочки Е1 и Е2, которые обеспечивают связывание вируса с клетками, и вирусный нуклеокапсидный белок Core, участвующий в формировании вирусной частицы. Неструктурные белки (NS2-NS5), обладающие ферментативной активностью, участвуют в процессах репликации вируса [25]. Все вирусные белки содержат эпитопы, распознаваемые В-клетками, хелперными CD4 + и цитотоксическими CD8 + Т-лимфоцитами.…”

Section: характеристика Hcvunclassified

Dendritic cells in the pathogenesis of viral hepatitis C

Черных

Олейник

Леплина

et al. 2019

Russian Journal of Infection and Immunity

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Резюме. Инфекция, вызванная вирусом гепатита С (HCV), является серьезной проблемой здравоохранения, поскольку в большинстве случаев (до 85%) приобретает хроническое течение и повышает риск развития цирроза печени, гепатоцеллюлярной карциномы и выраженных внепеченочных осложнений. Причины хронизации инфекции во многом связаны с недостаточностью противовирусного иммунного ответа. Эффективная элиминация вируса требует ранней активации врожденного иммунитета, индукции сильного HCV-специфического мультиэпитопного Т-клеточного ответа и формирования продолжительной иммунологической памяти. Дендритные клетки (DC), которые представляют гетерогенную популяцию антигенпрезентирующих клеток, являются продуцентами интерферонов первого типа, способны активировать натуральные киллерные клетки и индуцировать адаптивный иммунный ответ, выполняя, таким образом, важную роль в противовирусной защите. При этом нарушение функций DC при HCV-инфекции рассматривается в качестве одного из механизмов, позволяющих вирусу избежать иммунного надзора. Настоящий обзор включает современные данные, характеризующие роль DC в иммунном ответе при HCV-инфекции и освещает ряд ключевых вопросов, касающихся изменений фенотипа и функций различных субпопуляций DC у пациентов с вирусным гепатитом С, механизмов нарушения функциональной активности DC и перспектив лечения хронического гепатита С на основе использования генерированных ex vivo DC.

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Hepatitis C virus: life cycle in cells, infection and host response, and analysis of molecular markers influencing the outcome of infection and response to therapy

Cited by 79 publications

References 90 publications

Sofosbuvir Terminated RNA is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir

Sofosbuvir Terminated RNA is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir

Characterization of Hepatitis C Virus IRES Quasispecies – From the Individual to the Pool

Dendritic cells in the pathogenesis of viral hepatitis C

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