PMID- 23796863
OWN - NLM
STAT- MEDLINE
DCOM- 20140228
LR  - 20130826
IS  - 1532-2742 (Electronic)
IS  - 0163-4453 (Linking)
VI  - 67
IP  - 4
DP  - 2013 Oct
TI  - Anti-HBV treatment induces novel reverse transcriptase mutations with reflective 
      effect on HBV S antigen.
PG  - 303-12
LID - S0163-4453(13)00155-2 [pii]
LID - 10.1016/j.jinf.2013.05.008 [doi]
AB  - 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.
CI  - Copyright (c) 2013 The British Infection Association. Published by Elsevier Ltd. 
      All rights reserved.
FAU - Cento, Valeria
AU  - Cento V
AD  - Department of Experimental Medicine and Surgery, University of Rome "Tor 
      Vergata", 00100 Rome, Italy.
FAU - Van Hemert, Formijn
AU  - Van Hemert F
FAU - Neumann-Fraune, Maria
AU  - Neumann-Fraune M
FAU - Mirabelli, Carmen
AU  - Mirabelli C
FAU - Di Maio, Velia-Chiara
AU  - Di Maio VC
FAU - Salpini, Romina
AU  - Salpini R
FAU - Bertoli, Ada
AU  - Bertoli A
FAU - Micheli, Valeria
AU  - Micheli V
FAU - Gubertini, Guido
AU  - Gubertini G
FAU - Romano, Sara
AU  - Romano S
FAU - Visca, Michela
AU  - Visca M
FAU - De Sanctis, Giuseppe-Maria
AU  - De Sanctis GM
FAU - Berkhout, Ben
AU  - Berkhout B
FAU - Marino, Nicoletta
AU  - Marino N
FAU - Mazzotta, Francesco
AU  - Mazzotta F
FAU - Cappiello, Giuseppina
AU  - Cappiello G
FAU - Spano, Alberto
AU  - Spano A
FAU - Sarrecchia, Cesare
AU  - Sarrecchia C
FAU - Ceccherini-Silberstein, Francesca
AU  - Ceccherini-Silberstein F
FAU - Andreoni, Massimo
AU  - Andreoni M
FAU - Angelico, Mario
AU  - Angelico M
FAU - Verheyen, Jens
AU  - Verheyen J
FAU - Perno, Carlo Federico
AU  - Perno CF
FAU - Svicher, Valentina
AU  - Svicher V
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130622
PL  - England
TA  - J Infect
JT  - The Journal of infection
JID - 7908424
RN  - 0 (Codon, Nonsense)
RN  - 0 (Hepatitis B Surface Antigens)
RN  - 0 (Organophosphonates)
RN  - 0 (Reverse Transcriptase Inhibitors)
RN  - 6GQP90I798 (adefovir)
RN  - EC 2.7.7.49 (RNA-Directed DNA Polymerase)
RN  - JAC85A2161 (Adenine)
SB  - IM
MH  - Adenine/administration & dosage/analogs & derivatives/pharmacology
MH  - Adult
MH  - Cell Line
MH  - Codon, Nonsense
MH  - Drug Resistance, Viral
MH  - Female
MH  - Gene Expression
MH  - Hepatitis B/*drug therapy
MH  - Hepatitis B Surface Antigens/*analysis/genetics
MH  - Hepatitis B virus/*drug effects
MH  - Hepatocytes/virology
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - *Mutation
MH  - Organophosphonates/administration & dosage/pharmacology
MH  - Protein Binding
MH  - RNA-Directed DNA Polymerase/*genetics/metabolism
MH  - Reverse Transcriptase Inhibitors/*administration & dosage/metabolism/pharmacology
MH  - Selection, Genetic
MH  - Treatment Failure
OTO - NOTNLM
OT  - HBV drug-resistance
OT  - HBsAg secretion
OT  - HBsAg stop codon
OT  - HBsAg structure
OT  - Treatment failure
EDAT- 2013/06/26 06:00
MHDA- 2014/03/01 06:00
CRDT- 2013/06/26 06:00
PHST- 2013/02/04 00:00 [received]
PHST- 2013/05/06 00:00 [revised]
PHST- 2013/05/24 00:00 [accepted]
PHST- 2013/06/26 06:00 [entrez]
PHST- 2013/06/26 06:00 [pubmed]
PHST- 2014/03/01 06:00 [medline]
AID - S0163-4453(13)00155-2 [pii]
AID - 10.1016/j.jinf.2013.05.008 [doi]
PST - ppublish
SO  - J Infect. 2013 Oct;67(4):303-12. doi: 10.1016/j.jinf.2013.05.008. Epub 2013 Jun 
      22.