Hepatitis C virus (HCV) genotype 1b displays higher genetic variability of hypervariable region 1 (HVR1) than genotype 3

ABSTRACT To study hepatitis C virus (HCV) genetic mutation during interferon (IFN) therapy, the temporal changes in HCV quasispecies heterogeneity were compared before and after treatment for nine patients infected with HCV genotype 1, including four nonresponders, four responders who relapsed after therapy, and one responder who experienced a breakthrough of viremia during therapy. Nine untreated patients with an average time between specimens of 8.4 years served as controls. Sequences from the second envelope glycoprotein gene hypervariable region 1 (HVR1) and the putative IFN sensitivity-determining region (ISDR) of the nonstructural NS5A gene were analyzed by heteroduplex mobility assays and nucleotide sequencing. A strong positive correlation was found between the percent change in a heteroduplex mobility ratio (HMR) and percent change in nucleotide sequence (r = 0.941,P < 0.001). The rate of fixation of mutations in the HVR1 was significantly higher for IFN-treated patients than for controls (6.97 versus 1.31% change in HMR/year; P = 0.02). Similarly, a higher rate of fixation of mutations was observed in the ISDR for IFN-treated patients than for untreated controls, although the result was not significant (1.45 versus 0.15 amino acid changes/year; P = 0.12). On an individual patient basis, IFN therapy was associated with measurable HVR1 and ISDR mutation in nine of nine (100%) and two of nine (22.2%) patients, respectively. Evolution to IFN-resistant ISDR sequences was observed in only one of nine IFN-treated patients. These data suggest that IFN therapy frequently exerts pressure on the HCV envelope region, while pressure on the ISDR was evident in only a subset of patients. Thus, the selection pressures evoked on HCV genotype 1 quasispecies during IFN therapy appear to differ among different patients.

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Safety, Pharmacokinetics, and Antiviral Activity of AT-527, a Novel Purine Nucleotide Prodrug, in Hepatitis C Virus-Infected Subjects with or without Cirrhosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01201-19 ◽

2019 ◽

Vol 63 (12) ◽

Cited By ~ 1

Author(s):

Elina Berliba ◽

Maxim Bogus ◽

Frédéric Vanhoutte ◽

Pieter-Jan Berghmans ◽

Steven S. Good ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Antiviral Activity ◽

Controlled Study ◽

Response Analysis ◽

Free Base ◽

Genotype 3 ◽

Once Daily ◽

Hcv Genotype ◽

Genotype 1B

ABSTRACT AT-527 is a novel modified guanosine nucleotide prodrug inhibitor of the hepatitis C virus (HCV) NS5B polymerase, with increased in vitro antiviral activity compared to sofosbuvir and a highly differentiated favorable preclinical profile compared to other anti-HCV nucleoside/nucleotide analogs. This was a multiple-part clinical study where multiple ascending doses of AT-527 up to 600 mg (expressed as AT-527 salt form; equivalent to 553 mg free base) once daily for 7 days were evaluated in a randomized, double-blind, placebo-controlled study of treatment-naive, noncirrhotic, genotype 1b, HCV-infected subjects. The highest dose of AT-527 for the same duration was then evaluated in two open-label cohorts of (i) noncirrhotic, genotype 3, HCV-infected subjects and (ii) HCV-infected subjects of any genotype with compensated (Child-Pugh A) cirrhosis. AT-527 was well tolerated for 7 days in all cohorts. At the highest dose tested, mean HCV RNA reductions of up to 2.4 log10 IU/ml occurred within the first 24 h of dosing. Mean maximum reductions observed with 7 days of dosing were 4.4, 4.5, and 4.6 log10 IU/ml in noncirrhotic subjects with HCV genotype 1b, noncirrhotic subjects with HCV genotype 3, and subjects with compensated cirrhosis, respectively. The systemic half-life of AT-273, the nucleoside metabolite considered a surrogate of intracellular phosphates including the active triphosphate, exceeded 20 h, supporting once-daily dosing. In summary, AT-527 demonstrated rapid, potent, dose/exposure-related, and pangenotypic antiviral activity with similar responses between subjects with and without cirrhosis. Exposure-antiviral response analysis identified 550 mg (free base equivalent) as the optimal dose of AT-527. Safety and antiviral activity data from this study warrant continued clinical development of AT-527 dosed once daily. (This study has been registered in the European Union Drug Regulating Authorities Clinical Trials Database [EudraCT] under number 2017-002148-34 and at ClinicalTrials.gov under identifier NCT03219957.)

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A Recombinant Hepatitis C Virus Genotype 1a E1/E2 Envelope Glycoprotein Vaccine Elicits Antibodies That Differentially Neutralize Closely Related 2a Strains through Interactions of the N-Terminal Hypervariable Region 1 of E2 with Scavenger Receptor B1

Journal of Virology ◽

10.1128/jvi.00810-19 ◽

2019 ◽

Vol 93 (22) ◽

Cited By ~ 4

Author(s):

Janelle Johnson ◽

Holly Freedman ◽

Michael Logan ◽

Jason Alexander Ji-Xhin Wong ◽

Darren Hockman ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Neutralizing Antibodies ◽

Scavenger Receptor ◽

Hypervariable Region ◽

Neutralization Sensitivity ◽

Hcv Genotype ◽

Hcv Genotypes ◽

E2 Glycoprotein ◽

Hypervariable Region 1

ABSTRACT The global health burden for hepatitis C virus (HCV) remains high, despite available effective treatments. To eliminate HCV, a prophylactic vaccine is needed. One major challenge in the development of a vaccine is the genetic diversity of the virus, with 7 major genotypes and many subtypes. A global vaccine must be effective against all HCV genotypes. Our previous data showed that the 1a E1/E2 glycoprotein vaccine component elicits broad cross-neutralizing antibodies in humans and animals. However, some variation is seen in the effectiveness of these antibodies to neutralize different HCV genotypes and isolates. Of interest was the differences in neutralizing activity against two closely related isolates of HCV genotype 2a, the J6 and JFH-1 strains. Using site-directed mutagenesis to generate chimeric viruses between the J6 and JFH-1 strains, we found that variant amino acids within the core E2 glycoprotein domain of these two HCV genotype 2a viruses do not influence isolate-specific neutralization. Further analysis revealed that the N-terminal hypervariable region 1 (HVR1) of the E2 protein determines the sensitivity of isolate-specific neutralization, and the HVR1 of the resistant J6 strain binds scavenger receptor class-B type-1 (SR-B1), while the sensitive JFH-1 strain does not. Our data provide new information on mechanisms of isolate-specific neutralization to facilitate the optimization of a much-needed HCV vaccine. IMPORTANCE A vaccine is still urgently needed to overcome the hepatitis C virus (HCV) epidemic. It is estimated that 1.75 million new HCV infections occur each year, many of which will go undiagnosed and untreated. Untreated HCV can lead to continued spread of the disease, progressive liver fibrosis, cirrhosis, and eventually, end-stage liver disease and/or hepatocellular carcinoma (HCC). Previously, our 1a E1/E2 glycoprotein vaccine was shown to elicit broadly cross-neutralizing antibodies; however, there remains variation in the effectiveness of these antibodies against different HCV genotypes. In this study, we investigated determinants of differential neutralization sensitivity between two highly related genotype 2a isolates, J6 and JFH-1. Our data indicate that the HVR1 region determines neutralization sensitivity to vaccine antisera through modulation of sensitivity to antibodies and interactions with SR-B1. Our results provide additional insight into optimizing a broadly neutralizing HCV vaccine.

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Humoral immune response to hypervariable region 1 of the putative envelope glycoprotein (gp70) of hepatitis C virus.

Journal of Virology ◽

10.1128/jvi.67.7.3923-3930.1993 ◽

1993 ◽

Vol 67 (7) ◽

pp. 3923-3930 ◽

Cited By ~ 234

Author(s):

N Kato ◽

H Sekiya ◽

Y Ootsuyama ◽

T Nakazawa ◽

M Hijikata ◽

...

Keyword(s):

Immune Response ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Humoral Immune Response ◽

Envelope Glycoprotein ◽

Hypervariable Region ◽

Humoral Immune ◽

Hypervariable Region 1

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Resistance Analysis of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00308-12 ◽

2012 ◽

Vol 56 (7) ◽

pp. 3670-3681 ◽

Cited By ~ 84

Author(s):

Fiona McPhee ◽

Jacques Friborg ◽

Steven Levine ◽

Chaoqun Chen ◽

Paul Falk ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Protease Inhibitor ◽

Clinical Studies ◽

Replication Capacity ◽

Replication Complex ◽

Hcv Genotype ◽

Genotype 1A ◽

Genotype 1B ◽

Ns3 Protease

ABSTRACTAsunaprevir (BMS-650032) is a potent hepatitis C virus (HCV) NS3 protease inhibitor demonstrating efficacy in alfa interferon-sparing, direct-acting antiviral dual-combination regimens (together with the NS5A replication complex inhibitor daclatasvir) in patients chronically infected with HCV genotype 1b. Here, we describe a comprehensivein vitrogenotypic and phenotypic analysis of asunaprevir-associated resistance against genotypes 1a and 1b using HCV replicons and patient samples obtained from clinical studies of short-term asunaprevir monotherapy. During genotype 1a resistance selection using HCV replicons, the primary NS3 protease substitutions identified were R155K, D168G, and I170T, which conferred low- to moderate-level asunaprevir resistance (5- to 21-fold) in transient-transfection susceptibility assays. For genotype 1b, a higher level of asunaprevir-associated resistance was observed at the same selection pressures, ranging from 170- to 400-fold relative to the wild-type control. The primary NS3 protease substitutions identified occurred predominantly at amino acid residue D168 (D168A/G/H/V/Y) and were associated with high-level asunaprevir resistance (16- to 280-fold) and impaired replication capacity. In asunaprevir single-ascending-dose and 3-day multiple-ascending-dose studies in HCV genotype 1a- or 1b-infected patients, the predominant pre-existing NS3 baseline polymorphism was NS3-Q80K. This substitution impacted initial virologic response rates in a single-ascending-dose study, but its effects after multiple doses were more ambiguous. Interestingly, for patient NS3 protease sequences containing Q80 and those containing K80, susceptibilities to asunaprevir were comparable when tested in an enzyme assay. No resistance-associated variants emerged in these clinical studies that significantly impacted susceptibility to asunaprevir. Importantly, asunaprevir-resistant replicons remained susceptible to an NS5A replication complex inhibitor, consistent with a role for asunaprevir in combination therapies.

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Hepatitis C virus envelope protein dynamics and the link to hypervariable region 1

Current Opinion in Virology ◽

10.1016/j.coviro.2021.07.006 ◽

2021 ◽

Vol 50 ◽

pp. 69-75

Author(s):

Elias H Augestad ◽

Jens Bukh ◽

Jannick Prentoe

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Protein Dynamics ◽

Envelope Protein ◽

Hypervariable Region ◽

Virus Envelope ◽

Hypervariable Region 1 ◽

Virus Envelope Protein

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Distribution of hepatitis C virus genotypes and subtypes in a group of patients with chronic hepatitis C from Canton Sarajevo, 2012-2018

Acta Medica Saliniana ◽

10.5457/ams.v49i0.524 ◽

2019 ◽

Vol 49 ◽

Author(s):

Irma Salimović- Bešić ◽

Adna Kahriman ◽

Suzana Arapčić ◽

Amela Dedeić- Ljubović

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Chronic Hepatitis C ◽

Hcv Rna ◽

Genotype 3 ◽

Hcv Genotype ◽

Hcv Genotypes ◽

Number Of Patients ◽

Subtype 1B

Background: Hepatitis C virus (HCV) genotypes and subtypes exhibit significant geographic variations.Aim: To analyse the distribution of genotypes/subtypes of HCV in a group of patients with chronic hepatitis C from Canton Sarajevo during 2012-2018.Material and methods:The study enrolled 247 human plasma samples of HCV-RNA positive patients with available results of HCV genotyping test.Results: During 2012-2018, the domination of subtypes 1a (34.01%), 1b (28.34%) and genotype 3 (23.89%) was registered. In 2012 and 2013, HCV subtype 1a was the most common (27/63; 42.86% and 17/40; 42.50%, respectively). In 2014, the leading HCV genotype/subtype were 3 and 1b (17/57; 29.82%). In 2015, the dominance of HCV genotype 3 (14/39; 35.90%) continued, while in 2016, the same number of HCV subtypes 1a and 1b (11/30; 36.67%) was recorded. Although in a small number of tested, during 2017, HCV subtype 1b was the most prevalent (7/14; 50.00%), and in 2018, it was replaced by a HCV subtype 1a (3/4; 75.00%). Distribution of HCV genotypes/subtypes by age group of patients varied significantly (p=0.000). The largest number of patients (71/247; 28.74%) belonged to the age category 30-39 years and HCV genotypes/subtypes 1, 3, 4, 1a and 1b were identified. Except in 2017, male gender significantly dominated (p=0.000). In males, HCV subtype 1a (68/170; 40.00%) was the most common, while in women it was HCV subtype 1b (44/77; 57.14%).Conclusion: This six-year retrospective study showed the time variations of the circulating HCV genotypes/subtypes among patients with chronic hepatitis C in Canton Sarajevo. Genotyping of the HCV has an important implications for diagnosis and treatment of the patients.

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