scholarly journals Genetic heterogeneity of hepatitis C virus cell entry receptors seems to have no influence on selection of virus variants

2014 ◽  
Vol 11 (1) ◽  
pp. 50 ◽  
Author(s):  
Maren Lipskoch ◽  
Manfred Wiese ◽  
Joerg Timm ◽  
Michael Roggendorf ◽  
Sergei Viazov
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Genetic Heterogeneity ◽  
Cell Entry ◽  
Selection Of

scholarly journals Characterization of Resistance to the Nonnucleoside NS5B Inhibitor Filibuvir in Hepatitis C Virus-Infected Patients

2011 ◽  
Vol 56 (3) ◽  
pp. 1331-1341 ◽  
Author(s):  
Philip J. F. Troke ◽  
Marilyn Lewis ◽  
Paul Simpson ◽  
Katrina Gore ◽  
Jennifer Hammond ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Amino Acid ◽  
Site Directed Mutagenesis ◽  
Phenotypic Resistance ◽  
Number Of Patients ◽  
Chronic Hcv ◽  
Selection Of

ABSTRACTFilibuvir (PF-00868554) is an investigational nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural 5B (NS5B) RNA-dependent RNA polymerase currently in development for treating chronic HCV infection. The aim of this study was to characterize the selection of filibuvir-resistant variants in HCV-infected individuals receiving filibuvir as short (3- to 10-day) monotherapy. We identified amino acid M423 as the primary site of mutation arising upon filibuvir dosing. Through bulk cloning of clinical NS5B sequences into a transient-replicon system, and supported by site-directed mutagenesis of the Con1 replicon, we confirmed that mutations M423I/T/V mediate phenotypic resistance. Selection in patients of an NS5B mutation at M423 was associated with a reduced replicative capacityin vitrorelative to the pretherapy sequence; consistent with this, reversion to wild-type M423 was observed in the majority of patients following therapy cessation. Mutations at NS5B residues R422 and M426 were detected in a small number of patients at baseline or the end of therapy and also mediate reductions in filibuvir susceptibility, suggesting these are rare but clinically relevant alternative resistance pathways. Amino acid variants at position M423 in HCV NS5B polymerase are the preferred pathway for selection of viral resistance to filibuvirin vivo.

Winners of the Nobel Prize in Medicine in 2020

2021 ◽  
pp. 59-63
Author(s):  
Oksana Aleksandrovna Rybachok
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nobel Prize ◽  
The Body ◽  
Coronavirus Infection ◽  
First Time ◽  
Selection Of

Despite the height of the coronavirus infection, the Nobel Prize in Medicine was awarded in Stockholm in October 2020. This event was held online for the first time and was not accompanied by the traditional honoring of the laureates. In his will, Alfred Nobel entrusted the selection of the winner in this nomination to the Karolinska Medical and Surgical University of Stockholm, and the first award in this nomination took place in 1901. Since then, this event has been held 110 times, and 216 scientists have become laureates of the prize in the field of physiology and medicine, since the nominees are often not just one, but a group of researchers. This happened in 2020 - for research in the field of studying the hepatitis C virus, three scientists received the most prestigious award: the British Michael Houghton and the Americans Harvey Alter and Charles Rice. Due to the results of the research, which these three people conducted separately from each other, for the first time it became possible to completely eliminate the virus from the body.

scholarly journals Relevance of Baseline Viral Genetic Heterogeneity and Host Factors for Treatment Outcome Prediction in Hepatitis C Virus 1b-Infected Patients

PLoS ONE ◽  
2013 ◽  
Vol 8 (8) ◽  
pp. e72600 ◽  
Author(s):  
Verónica Saludes ◽  
Elisabet Bascuñana ◽  
Elena Jordana-Lluch ◽  
Sònia Casanovas ◽  
Mercè Ardèvol ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Genetic Heterogeneity ◽  
Outcome Prediction ◽  
Host Factors ◽  
Treatment Outcome Prediction

scholarly journals CD81 Is Required for Hepatitis C Virus Glycoprotein-Mediated Viral Infection

2004 ◽  
Vol 78 (3) ◽  
pp. 1448-1455 ◽  
Author(s):  
Jie Zhang ◽  
Glenn Randall ◽  
Adrian Higginbottom ◽  
Peter Monk ◽  
Charles M. Rice ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cell Lines ◽  
Viral Entry ◽  
Human Liver ◽  
Cell Entry ◽  
Target Cells ◽  
Small Interfering Rnas ◽  
Efficient Cell Culture System ◽  
Human Liver Cell

ABSTRACT CD81 has been described as a putative receptor for hepatitis C virus (HCV); however, its role in HCV cell entry has not been characterized due to the lack of an efficient cell culture system. We have examined the role of CD81 in HCV glycoprotein-dependent entry by using a recently developed retroviral pseudotyping system. Human immunodeficiency virus (HIV) pseudotypes bearing HCV E1E2 glycoproteins show a restricted tropism for human liver cell lines. Although all of the permissive cell lines express CD81, CD81 expression alone is not sufficient to allow viral entry. CD81 is required for HIV-HCV pseudotype infection since (i) a monoclonal antibody specific for CD81 inhibited infection of susceptible target cells and (ii) silencing of CD81 expression in Huh-7.5 hepatoma cells by small interfering RNAs inhibited HIV-HCV pseudotype infection. Furthermore, expression of CD81 in human liver cells that were previously resistant to infection, HepG2 and HH29, conferred permissivity of HCV pseudotype infection. The characterization of chimeric CD9/CD81 molecules confirmed that the large extracellular loop of CD81 is a determinant for viral entry. These data suggest a functional role for CD81 as a coreceptor for HCV glycoprotein-dependent viral cell entry.

scholarly journals Anti-HIV and Anti-Hepatitis C Virus Drugs Inhibit P-Glycoprotein Efflux Activity in Caco-2 Cells and Precision-Cut Rat and Human Intestinal Slices

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Ondrej Martinec ◽  
Martin Huliciak ◽  
Frantisek Staud ◽  
Filip Cecka ◽  
Ivan Vokral ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Molecular Mechanisms ◽  
Interindividual Variability ◽  
Ex Vivo ◽  
Efflux Transporter ◽  
P Glycoprotein ◽  
Bidirectional Transport ◽  
Anti Hiv ◽  
Selection Of

ABSTRACT P-glycoprotein (ABCB1), an ATP-binding-cassette efflux transporter, limits intestinal absorption of its substrates and is a common site of drug-drug interactions (DDIs). ABCB1 has been suggested to interact with many antivirals used to treat HIV and/or chronic hepatitis C virus (HCV) infections. Using bidirectional transport experiments in Caco-2 cells and a recently established ex vivo model of accumulation in precision-cut intestinal slices (PCIS) prepared from rat ileum or human jejunum, we evaluated the potential of anti-HIV and anti-HCV antivirals to inhibit intestinal ABCB1. Lopinavir, ritonavir, saquinavir, atazanavir, maraviroc, ledipasvir, and daclatasvir inhibited the efflux of a model ABCB1 substrate, rhodamine 123 (RHD123), in Caco-2 cells and rat-derived PCIS. Lopinavir, ritonavir, saquinavir, and atazanavir also significantly inhibited RHD123 efflux in human-derived PCIS, while possible interindividual variability was observed in the inhibition of intestinal ABCB1 by maraviroc, ledipasvir, and daclatasvir. Abacavir, zidovudine, tenofovir disoproxil fumarate, etravirine, and rilpivirine did not inhibit intestinal ABCB1. In conclusion, using recently established ex vivo methods for measuring drug accumulation in rat- and human-derived PCIS, we have demonstrated that some antivirals have a high potential for DDIs on intestinal ABCB1. Our data help clarify the molecular mechanisms responsible for reported increases in the bioavailability of ABCB1 substrates, including antivirals and drugs prescribed to treat comorbidity. These results could help guide the selection of combination pharmacotherapies and/or suitable dosing schemes for patients infected with HIV and/or HCV.

Genetic Heterogeneity of Hepatitis C Virus and Its Clinical Implications

1997 ◽  
Vol 15 (4-5) ◽  
pp. 192-206 ◽  
Author(s):  
Constantine G. Marousis ◽  
Johnson Y.N. Lau
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Genetic Heterogeneity ◽  
Clinical Implications

scholarly journals Positive Selection of Core 70Q Variant Genotype 1b Hepatitis C Virus Strains Induced by Pegylated Interferon and Ribavirin

2010 ◽  
Vol 201 (11) ◽  
pp. 1663-1671 ◽  
Author(s):  
Fuat Kurbanov ◽  
Yasuhito Tanaka ◽  
Kentaro Matsuura ◽  
Fuminaka Sugauchi ◽  
Abeer Elkady ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Positive Selection ◽  
Pegylated Interferon ◽  
Genotype 1B ◽  
Variant Genotype ◽  
Virus Strains ◽  
Selection Of

scholarly journals Barrier-Independent, Fitness-Associated Differences in Sofosbuvir Efficacy against Hepatitis C Virus

2016 ◽  
Vol 60 (6) ◽  
pp. 3786-3793 ◽  
Author(s):  
Isabel Gallego ◽  
Julie Sheldon ◽  
Elena Moreno ◽  
Josep Gregori ◽  
Josep Quer ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Drug Sensitivity ◽  
Specific Resistance ◽  
Antiviral Agents ◽  
Resistance Mutations ◽  
Coding Region ◽  
High Fitness ◽  
Selection Of

Sofosbuvir displays a high phenotypic barrier to resistance, and it is a component of several combination therapies for hepatitis C virus (HCV) infections. HCV fitness can be a determinant of decreased sensitivity to direct-acting antiviral agents such as telaprevir or daclatasvir, but fitness-dependent decreased drug sensitivity has not been established for drugs with a high phenotypic barrier to resistance. Low- and high-fitness HCV populations and biological clones derived from them were used to infect Huh-7.5 hepatoma cells. Sofosbuvir efficacy was analyzed by measuring virus progeny production during several passages and by selection of possible sofosbuvir resistance mutations determined by sequencing the NS5B-coding region of the resulting populations. Sofosbuvir exhibited reduced efficacy against high-fitness HCV populations, without the acquisition of sofosbuvir-specific resistance mutations. A reduced sofosbuvir efficacy, similar to that observed with the parental populations, was seen for high-fitness individual biological clones. In independently derived high-fitness HCV populations or clones passaged in the presence of sofosbuvir, M289L was selected as the only substitution in the viral polymerase NS5B. In no case was the sofosbuvir-specific resistance substitution S282T observed. High HCV fitness can lead to decreased sensitivity to sofosbuvir, without the acquisition of specific sofosbuvir resistance mutations. Thus, fitness-dependent drug sensitivity can operate with HCV inhibitors that display a high barrier to resistance. This mechanism may underlie treatment failures not associated with selection of sofosbuvir-specific resistance mutations, linked toin vivofitness of pretreatment viral populations.

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