Immune-escape mutations and stop-codons in HBsAg develop in a large proportion of patients with chronic HBV infection exposed to anti-HBV drugs in Europe

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Abstract

Background

HBsAg immune-escape mutations can favor HBV-transmission also in vaccinated individuals, promote immunosuppression-driven HBV-reactivation, and increase fitness of drug-resistant strains. Stop-codons can enhance HBV oncogenic-properties. Furthermore, as a consequence of the overlapping structure of HBV genome, some immune-escape mutations or stop-codons in HBsAg can derive from drug-resistance mutations in RT. This study is aimed at gaining insight in prevalence and characteristics of immune-associated escape mutations, and stop-codons in HBsAg in chronically HBV-infected patients experiencing nucleos(t)ide analogues (NA) in Europe.

Methods

This study analyzed 828 chronically HBV-infected European patients exposed to ≥ 1 NA, with detectable HBV-DNA and with an available HBsAg-sequence.

The immune-associated escape mutations and the NA-induced immune-escape mutations sI195M, sI196S, and sE164D (resulting from drug-resistance mutation rtM204 V, rtM204I, and rtV173L) were retrieved from literature and examined. Mutations were defined as an aminoacid substitution with respect to a genotype A or D reference sequence.

Results

At least one immune-associated escape mutation was detected in 22.1% of patients with rising temporal-trend. By multivariable-analysis, genotype-D correlated with higher selection of ≥ 1 immune-associated escape mutation (OR[95%CI]:2.20[1.32–3.67], P = 0.002). In genotype-D, the presence of ≥ 1 immune-associated escape mutations was significantly higher in drug-exposed patients with drug-resistant strains than with wild-type virus (29.5% vs 20.3% P = 0.012). Result confirmed by analysing drug-naïve patients (29.5% vs 21.2%, P = 0.032). Strong correlation was observed between sP120T and rtM204I/V ( P < 0.001), and their co-presence determined an increased HBV-DNA.

At least one NA-induced immune-escape mutation occurred in 28.6% of patients, and their selection correlated with genotype-A (OR[95%CI]:2.03[1.32–3.10], P = 0.001).

Finally, stop-codons are present in 8.4% of patients also at HBsAg-positions 172 and 182, described to enhance viral oncogenic-properties.

Conclusions

Immune-escape mutations and stop-codons develop in a large fraction of NA-exposed patients from Europe. This may represent a potential threat for horizontal and vertical HBV transmission also to vaccinated persons, and fuel drug-resistance emergence.

Electronic supplementary material

The online version of this article (10.1186/s12879-018-3161-2) contains supplementary material, which is available to authorized users.

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Although hepatitis B virus (HBV) has been documented to cause hepatocellular carcinoma (HCC), the exact role of HBV in the development of HCC remains enigmatic. Several hypotheses have been proposed to explain the potential mechanism, including insertional mutagenesis of HBV genomes and transcriptional activators of HBV gene products such as hepatitis B x protein (HBx) and truncated middle S mutants. In the past few years, we have identified two types of large HBV surface antigens (LHBs) with deletions at the pre-S1 (DeltaS1-LHBs) and pre-S2 (DeltaS2-LHBs) regions in ground glass hepatocytes. The pre-S mutant LHBs are retained in the endoplasmic reticulum (ER) and escape from immune attack. The pre-S mutants, particularly DeltaS2-LHBs, are increasingly prevalent in patients with hepatitis B e antigen (HBeAg)-positive chronic HBV infection, ranging from 6% before the 3rd decade to 35% in the 6th decade. In HCC patients, the two pre-S mutants were detected in 60% of HCC patients, in the serum and in HCC tissues. Pre-S mutant LHBs can initiate ER stress to induce oxidative DNA damage and genomic instability. Furthermore, pre-S mutant LHBs can upregulate cyclooxygenase-2 and cyclin A to induce cell cycle progression and proliferation of hepatocytes. In transgenic mice, the pre-S mutants can induce dysplasia of hepatocytes and development of HCC. In a nested control study, the presence of pre-S mutants carried a high risk of developing HCC in HBV carriers. In summary, the findings we describe in this review suggest a potential role for HBV pre-S mutants in HBV-related hepatocarcinogenesis, providing a model of viral carcinogenesis associated with ER stress.

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Author and article information

Contributors

Luna Colagrossi: luna_colagrossi@yahoo.it

Lucas E. Hermans: L.E.Hermans-3@umcutrecht.nl

Romina Salpini: rsalpini@yahoo.it

Domenico Di Carlo: pvt.math82@gmail.com

Suzan D. Pas: s.pas@erasmusmc.nl

Marta Alvarez: martaalvest@yahoo.es

Ziv Ben-Ari: Ziv.Ben-Ari@sheba.health.gov.il

Greet Boland: G.J.Boland@umcutrecht.nl

Bianca Bruzzone: bianca.bruzzone@hsanmartino.it

Nicola Coppola: Nicola.COPPOLA@unina2.it

Carole Seguin-Devaux: Carole.Devaux@lih.lu

Tomasz Dyda: tdyda@zakazny.pl

Federico Garcia: fegarcia@ugr.es

Rolf Kaiser: rolf.kaiser@uk-koeln.de

Sukran Köse: sukrankose@yahoo.com

Henrik Krarup: h.krarup@rn.dk

Ivana Lazarevic: ilazarevic@med.bg.ac.rs

Maja M. Lunar: maja.lunar@mf.uni-lj.si

Sarah Maylin: sarah.maylin@sls.aphp.fr

Valeria Micheli: micheli.valeria@hsacco.it

Orna Mor: Orna.Mor@sheba.health.gov.il

Simona Paraschiv: mona@mateibals.ro

Dimitros Paraskevis: dparask@med.uoa.gr

Mario Poljak: mario.poljak@mf.uni-lj.si

Elisabeth Puchhammer-Stöckl: elisabeth.puchhammer@meduniwien.ac.at

François Simon: francois.simon@sls.aphp.fr

Maja Stanojevic: mstanojevic@med.bg.ac.rs

Kathrine Stene-Johansen: Kathrine.Stene-Johansen@fhi.no

Nijaz Tihic: nijazt@yahoo.com

Pascale Trimoulet: pascale.trimoulet@chu-bordeaux.fr

Jens Verheyen: jens.verheyen@uk-essen.de

Adriana Vince: avince@bfm.hr

Snjezana Zidovec Lepej: snjezana.zidovec.lepej@bfm.hr

Nina Weis: ninaweis@dadlnet.dk

Tülay Yalcinkaya: tulay.yalcinkaya@thsk.gov.tr

Charles A. B. Boucher: c.boucher@erasmusmc.nl

Annemarie M. J. Wensing: A.M.J.Wensing@umcutrecht.nl

Carlo F. Perno: 0039 06 72596566 , 0039 06 72596551 , cf.perno@uniroma2.it

Valentina Svicher:

ORCID: http://orcid.org/0000-0002-2377-504X

0039 06 72596564 , valentina.svicher@uniroma2.it

Journal

Journal ID (nlm-ta): BMC Infect Dis

Journal ID (iso-abbrev): BMC Infect. Dis

Title: BMC Infectious Diseases

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2334

Publication date (Electronic): 1 June 2018

Publication date PMC-release: 1 June 2018

Publication date Collection: 2018

Volume: 18

Electronic Location Identifier: 251

Affiliations

[1 ]ISNI 0000 0001 2300 0941, GRID grid.6530.0, Department of Experimental Medicine and Surgery, , University of Rome Tor Vergata, ; Via Montpellier, 1, 00133 Rome, Italy

[2 ]ISNI 0000000090126352, GRID grid.7692.a, Virology, Department of Medical Microbiology, , University Medical Centre Utrecht, ; Utrecht, The Netherlands

[3 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Viroscience, , Erasmus Medical Centre, ; Rotterdam, The Netherlands

[4 ]ISNI 0000000121678994, GRID grid.4489.1, Servicio de Microbiología, Hospital San Cecilio, Instituto de Investigación Biosanitaria ibs.GRANADA, , Hospitales Universitarios de Granada, ; Granada, Spain

[5 ]ISNI 0000 0004 1756 7871, GRID grid.410345.7, Hygiene Unit, , IRCCS AOU San Martino – IST, ; Genoa, Italy

[6 ]ISNI 0000 0001 2200 8888, GRID grid.9841.4, Malattie Infettive, , Seconda Università degli studi di Napoli, ; Naples, Italy

[7 ]ISNI 0000 0004 0621 531X, GRID grid.451012.3, Laboratory of Retrovirology, , CRP-Santé, ; Luxembourg, Luxembourg

[8 ]Molecular Diagnostics Laboratory, Hospital of Infectious Diseases, Warsaw, Poland

[9 ]ISNI 0000 0000 8580 3777, GRID grid.6190.e, Institute of Virology, , University of Cologne, ; Cologne, Germany

[10 ]Izmir Tepecik Education and Research Hospital, Clinic of Infectious Diseases and Clinical Microbiology, Izmir, Turkey

[11 ]ISNI 0000 0004 0646 7349, GRID grid.27530.33, Section of Molecular Diagnostics, Clinical Biochemistry, , Aalborg University Hospital, ; Aalborg, Denmark

[12 ]ISNI 0000 0001 2166 9385, GRID grid.7149.b, Institute of Microbiology and Immunology, Faculty of Medicine, , University of Belgrade, ; Belgrade, Serbia

[13 ]ISNI 0000 0001 0721 6013, GRID grid.8954.0, Institute of Microbiology and Immunology, Faculty of Medicine, , University of Ljubljana, ; Ljubljana, Slovenia

[14 ]Service de Microbiologie, University Paris Diderot, Hôpital Saint Louis, Paris, France

[15 ]ISNI 0000 0004 4682 2907, GRID grid.144767.7, L. Sacco Hospital, ; Milan, Italy

[16 ]ISNI 0000 0001 2107 2845, GRID grid.413795.d, National HIV Reference Laboratory, Central Virology Laboratory, Ministry of Health, , Tel Hashomer, ; Ramat Gan, Israel

[17 ]Molecular Diagnostics Laboratory, National Institute for Infectious Diseases “Matei Bals”, Bucharest, Romania

[18 ]ISNI 0000 0001 2155 0800, GRID grid.5216.0, National Retrovirus Reference Centre, Department of Hygiene, Epidemiology and Medical Statistics, Faculty of Medicine, , National and Kapodistrian University of Athens, ; Athens, Greece

[19 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Department for Virology, , Medical University of Vienna, ; Vienna, Austria

[20 ]Liver Disease Centre, Sheba Medical Centre, Ramat Gan, Israel

[21 ]ISNI 0000 0001 1541 4204, GRID grid.418193.6, Department of Virology, , Norwegian Institute of Public Health, ; Oslo, Norway

[22 ]ISNI 0000 0001 0682 9061, GRID grid.412410.2, Institute of Microbiology, Polyclinic for Laboratory Diagnostics, , University Clinical Centre Tuzla, ; Tuzla, Bosnia and Herzegovina

[23 ]ISNI 0000 0001 2106 639X, GRID grid.412041.2, Virology Laboratory, , Centre Hospitalier Régional et Université “Victor Segalen”, ; Bordeaux, France

[24 ]ISNI 0000 0001 2187 5445, GRID grid.5718.b, Institute of Virology, , University-Hospital, University Duisburg-Essen, ; Essen, Germany

[25 ]ISNI 0000 0001 0657 4636, GRID grid.4808.4, University of Zagreb School of Medicine and University Hospital for Infectious Diseases, ; Zagreb, Croatia

[26 ]ISNI 0000 0004 0646 7373, GRID grid.4973.9, Department of Infectious Diseases, , Copenhagen University Hospital, ; Hvidovre, Copenhagen, Denmark

[27 ]Refik Saydam National Public Health Agency, Ankara, Turkey

Author information

Valentina Svicher http://orcid.org/0000-0002-2377-504X

Article

Publisher ID: 3161

DOI: 10.1186/s12879-018-3161-2

PMC ID: 5984771

PubMed ID: 29859062

SO-VID: 6e66f6a8-70c2-4434-a3f4-837fae256063

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 4 August 2017

Date accepted : 23 May 2018

Funding

Funded by: FIRB project

Award ID: RBAP11YS7K_001

Award Recipient : Carlo F. Perno

Funded by: InterOmics

Award ID: PB05

Award Recipient : Carlo F. Perno

Custom metadata

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: hbv,hbsag,immune-escape,stop-codons,drug-resistance

Data availability: