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Pangenomic antiviral effect of REP 2139 in CRISPR/Cas9 engineered cell lines expressing hepatitis B virus surface antigen

Chronic hepatitis B remains a global health problem with 296 million people living with chronic HBV infection and being at risk of developing cirrhosis and hepatocellular carcinoma. Non-infectious subviral particles (SVP) are produced in large excess over infectious Dane particles in patients and ar...

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Autores principales: Angelo, Léna, Vaillant, Andrew, Blanchet, Matthieu, Labonté, Patrick
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10619774/
https://www.ncbi.nlm.nih.gov/pubmed/37910550
http://dx.doi.org/10.1371/journal.pone.0293167
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author Angelo, Léna
Vaillant, Andrew
Blanchet, Matthieu
Labonté, Patrick
author_facet Angelo, Léna
Vaillant, Andrew
Blanchet, Matthieu
Labonté, Patrick
author_sort Angelo, Léna
collection PubMed
description Chronic hepatitis B remains a global health problem with 296 million people living with chronic HBV infection and being at risk of developing cirrhosis and hepatocellular carcinoma. Non-infectious subviral particles (SVP) are produced in large excess over infectious Dane particles in patients and are the major source of Hepatitis B surface antigen (HBsAg). They are thought to exhaust the immune system, and it is generally considered that functional cure requires the clearance of HBsAg from blood of patient. Nucleic acid polymers (NAPs) antiviral activity lead to the inhibition of HBsAg release, resulting in rapid clearance of HBsAg from circulation in vivo. However, their efficacy has only been demonstrated in limited genotypes in small scale clinical trials. HBV exists as nine main genotypes (A to I). In this study, the HBsAg ORFs from the most prevalent genotypes (A, B, C, D, E, G), which account for over 96% of human cases, were inserted into the AAVS1 safe-harbor of HepG2 cells using CRISPR/Cas9 knock-in. A cell line producing the D144A vaccine escape mutant was also engineered. The secretion of HBsAg was confirmed into these new genotype cell lines (GCLs) and the antiviral activity of the NAP REP 2139 was then assessed. The results demonstrate that REP 2139 exerts an antiviral effect in all genotypes and serotypes tested in this study, including the vaccine escape mutant, suggesting a pangenomic effect of the NAPs.
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spelling pubmed-106197742023-11-02 Pangenomic antiviral effect of REP 2139 in CRISPR/Cas9 engineered cell lines expressing hepatitis B virus surface antigen Angelo, Léna Vaillant, Andrew Blanchet, Matthieu Labonté, Patrick PLoS One Research Article Chronic hepatitis B remains a global health problem with 296 million people living with chronic HBV infection and being at risk of developing cirrhosis and hepatocellular carcinoma. Non-infectious subviral particles (SVP) are produced in large excess over infectious Dane particles in patients and are the major source of Hepatitis B surface antigen (HBsAg). They are thought to exhaust the immune system, and it is generally considered that functional cure requires the clearance of HBsAg from blood of patient. Nucleic acid polymers (NAPs) antiviral activity lead to the inhibition of HBsAg release, resulting in rapid clearance of HBsAg from circulation in vivo. However, their efficacy has only been demonstrated in limited genotypes in small scale clinical trials. HBV exists as nine main genotypes (A to I). In this study, the HBsAg ORFs from the most prevalent genotypes (A, B, C, D, E, G), which account for over 96% of human cases, were inserted into the AAVS1 safe-harbor of HepG2 cells using CRISPR/Cas9 knock-in. A cell line producing the D144A vaccine escape mutant was also engineered. The secretion of HBsAg was confirmed into these new genotype cell lines (GCLs) and the antiviral activity of the NAP REP 2139 was then assessed. The results demonstrate that REP 2139 exerts an antiviral effect in all genotypes and serotypes tested in this study, including the vaccine escape mutant, suggesting a pangenomic effect of the NAPs. Public Library of Science 2023-11-01 /pmc/articles/PMC10619774/ /pubmed/37910550 http://dx.doi.org/10.1371/journal.pone.0293167 Text en © 2023 Angelo et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Angelo, Léna
Vaillant, Andrew
Blanchet, Matthieu
Labonté, Patrick
Pangenomic antiviral effect of REP 2139 in CRISPR/Cas9 engineered cell lines expressing hepatitis B virus surface antigen
title Pangenomic antiviral effect of REP 2139 in CRISPR/Cas9 engineered cell lines expressing hepatitis B virus surface antigen
title_full Pangenomic antiviral effect of REP 2139 in CRISPR/Cas9 engineered cell lines expressing hepatitis B virus surface antigen
title_fullStr Pangenomic antiviral effect of REP 2139 in CRISPR/Cas9 engineered cell lines expressing hepatitis B virus surface antigen
title_full_unstemmed Pangenomic antiviral effect of REP 2139 in CRISPR/Cas9 engineered cell lines expressing hepatitis B virus surface antigen
title_short Pangenomic antiviral effect of REP 2139 in CRISPR/Cas9 engineered cell lines expressing hepatitis B virus surface antigen
title_sort pangenomic antiviral effect of rep 2139 in crispr/cas9 engineered cell lines expressing hepatitis b virus surface antigen
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10619774/
https://www.ncbi.nlm.nih.gov/pubmed/37910550
http://dx.doi.org/10.1371/journal.pone.0293167
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