Cento, Valeria ORCID: 0000-0002-3272-4252, Van Hemert, Formijn, Neumann-Fraune, Maria, Mirabelli, Carmen ORCID: 0000-0002-4785-5482, Di Maio, Velia-Chiara, Salpini, Romina ORCID: 0000-0002-2488-2082, Bertoli, Ada, Micheli, Valeria ORCID: 0000-0001-5629-3875, Gubertini, Guido, Romano, Sara, Visca, Michela, De Sanctis, Giuseppe-Maria, Berkhout, Ben, Marino, Nicoletta, Mazzotta, Francesco, Cappiello, Giuseppina, Spano, Alberto, Sarrecchia, Cesare, Ceccherini-Silberstein, Francesca, Andreoni, Massimo ORCID: 0000-0002-3205-9758, Angelico, Mario, Verheyen, Jens, Perno, Carlo Federico and Svicher, Valentina (2013). Anti-HBV treatment induces novel reverse transcriptase mutations with reflective effect on HBV S antigen. J. Infect., 67 (4). S. 303 - 313. LONDON: W B SAUNDERS CO LTD. ISSN 1532-2742

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Abstract

Introduction: The identification of novel reverse-transcriptase (RT) drug-resistance mutations is critical in predicting the probability of success to anti-HBV treatment. Furthermore, due to HBV-RT/HBsAg gene-overlap, they can have an impact on HBsAg-detection and quantification. Methods: 356 full-length HBV-RT sequences from 197 drug-naive patients and 159 patients experiencing virological-breakthrough to nucleoside/nucleotide-analogs (NUCs) were analyzed. Mutants and wild-type HBs-antigens were expressed in HuH7-hepatocytes and quantified in cell-supernatants and cell-lysates by Architect HBsAg-assay. Results: Ten novel RT-mutations (rtN53T-rtS78T-rtS85F-rtS135T-rtA181I-rtA200V-rtK212Q-rtL229V/F-rtM309K) correlated with specific NUC-treatments and classical drug-resistance mutations on divergent evolutionary pathways. Some of them reduced RT-binding affinity for anti-HBV drugs and altered S-antigen structure. Indeed, rtS78T (prevalence: 1.1% in drug-naive and 12.2% in adefovir-failing patients) decreased the RT-affinity for adefovir more than the classical adefovir-resistance mutations rtA181 T/V (WT: -9.63 kcal/mol, rtA181T: -9.30 kcal/mol, rtA181V: -7.96 kcal/mol, rtS78T: -7.37 kcal/mol). Moreover, rtS78T introduced a stop-codon at HBsAg-position 69, and completely abrogated HBsAg-quantification in both supernatants and cell-lysates, indicating an impaired HBsAg-secretion/production. Furthermore, the HBsAg-mutation sP217L, silent in RT, significantly correlated with M204V/I-related virological-breakthrough and increased HBsAg-quantification in cell-lysate. Conclusions: Mutations beyond those classically known can affect drug-binding affinity of mutated HBV-RT, and may have potential effects on HBsAg. Their cumulative effect on resistance and HBV-pathogenicity indicates the importance of preventing therapeutic failures. (C) 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Cento, ValeriaUNSPECIFIEDorcid.org/0000-0002-3272-4252UNSPECIFIED
Van Hemert, FormijnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neumann-Fraune, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mirabelli, CarmenUNSPECIFIEDorcid.org/0000-0002-4785-5482UNSPECIFIED
Di Maio, Velia-ChiaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Salpini, RominaUNSPECIFIEDorcid.org/0000-0002-2488-2082UNSPECIFIED
Bertoli, AdaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Micheli, ValeriaUNSPECIFIEDorcid.org/0000-0001-5629-3875UNSPECIFIED
Gubertini, GuidoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Romano, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Visca, MichelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Sanctis, Giuseppe-MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berkhout, BenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marino, NicolettaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mazzotta, FrancescoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cappiello, GiuseppinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spano, AlbertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sarrecchia, CesareUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ceccherini-Silberstein, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andreoni, MassimoUNSPECIFIEDorcid.org/0000-0002-3205-9758UNSPECIFIED
Angelico, MarioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Verheyen, JensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perno, Carlo FedericoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Svicher, ValentinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-475574
DOI: 10.1016/j.jinf.2013.05.008
Journal or Publication Title: J. Infect.
Volume: 67
Number: 4
Page Range: S. 303 - 313
Date: 2013
Publisher: W B SAUNDERS CO LTD
Place of Publication: LONDON
ISSN: 1532-2742
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HEPATITIS-B-VIRUS; ANTIVIRAL RESISTANCE; POLYMERASE GENE; ENVELOPE; PROTEIN; SECRETION; INFECTION; MUTANTS; REGIONMultiple languages
Infectious DiseasesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/47557

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