PMID- 28600137
OWN - NLM
STAT- MEDLINE
DCOM- 20180605
LR  - 20220129
IS  - 1600-0641 (Electronic)
IS  - 0168-8278 (Print)
IS  - 0168-8278 (Linking)
VI  - 67
IP  - 4
DP  - 2017 Oct
TI  - Alternative splicing of hepatitis B virus: A novel virus/host interaction 
      altering liver immunity.
PG  - 687-699
LID - S0168-8278(17)32065-2 [pii]
LID - 10.1016/j.jhep.2017.05.025 [doi]
AB  - BACKGROUND & AIMS: Hepatitis B virus (HBV) RNA can undergo alternative splicing, 
      but the relevance of this post-transcriptional regulation remains elusive. The 
      mechanism of HBV alternative splicing regulation and its impact on liver 
      pathogenesis were investigated. METHODS: HBV RNA-interacting proteins were 
      identified by RNA pull-down, combined with mass spectrometry analysis. HBV 
      splicing regulation was investigated in chemically and surgically induced liver 
      damage, in whole HBV genome transgenic mice and in hepatoma cells. Viral and 
      endogenous gene expression were quantified by quantitative reverse transcription 
      polymerase chain reaction, Western blot and enzyme-linked immunosorbent assay. 
      Resident liver immune cells were studied by fluorescence-activated cell sorting. 
      RESULTS: HBV pregenomic RNA-interacting proteins were identified and 15% were 
      directly related to the splicing machinery. Expression of these splicing factors 
      was modulated in HBV transgenic mice with liver injuries and contributed to an 
      increase of the HBV spliced RNA encoding for HBV splicing-generated protein 
      (HBSP). HBSP transgenic mice with chemically induced liver fibrosis exhibited 
      attenuated hepatic damage. The protective effect of HBSP resulted from a decrease 
      of inflammatory monocyte/macrophage recruitment through downregulation of C-C 
      motif chemokine ligand 2 (CCL2) expression in hepatocytes. In human hepatoma 
      cells, the ability of HBSP to control CCL2 expression was confirmed and 
      maintained in a whole HBV context. Finally, viral spliced RNA detection related 
      to a decrease of CCL2 expression in the livers of HBV chronic carriers 
      underscored this mechanism. CONCLUSION: The microenvironment, modified by liver 
      injury, increased HBSP RNA expression through splicing factor regulation, which 
      in turn controlled hepatocyte chemokine synthesis. This feedback mechanism 
      provides a novel insight into liver immunopathogenesis during HBV infection. Lay 
      summary: Hepatitis B virus persists for decades in the liver of chronically 
      infected patients. Immune escape is one of the main mechanisms developed by this 
      virus to survive. Our study highlights how the crosstalk between virus and liver 
      infected cells may contribute to this immune escape.
CI  - Copyright (c) 2017 European Association for the Study of the Liver. All rights 
      reserved.
FAU - Duriez, Marion
AU  - Duriez M
AD  - INSERM U1135, Centre d'immunologie et de maladie infectieuse, Paris, France; 
      Universite Pierre et Marie Curie, Paris, France.
FAU - Mandouri, Yassmina
AU  - Mandouri Y
AD  - INSERM U1135, Centre d'immunologie et de maladie infectieuse, Paris, France; 
      Universite Pierre et Marie Curie, Paris, France; Universite Versailles Saint 
      Quentin en Yvelines, Versailles, France.
FAU - Lekbaby, Bouchra
AU  - Lekbaby B
AD  - INSERM U1135, Centre d'immunologie et de maladie infectieuse, Paris, France; 
      Universite Pierre et Marie Curie, Paris, France.
FAU - Wang, Hualin
AU  - Wang H
AD  - INSERM U1135, Centre d'immunologie et de maladie infectieuse, Paris, France; 
      Universite Pierre et Marie Curie, Paris, France.
FAU - Schnuriger, Aurelie
AU  - Schnuriger A
AD  - INSERM U1135, Centre d'immunologie et de maladie infectieuse, Paris, France; 
      Universite Pierre et Marie Curie, Paris, France; Service de Virologie, Hopital 
      Trousseau, Paris, France.
FAU - Redelsperger, Francois
AU  - Redelsperger F
AD  - INSERM U1135, Centre d'immunologie et de maladie infectieuse, Paris, France; 
      Universite Pierre et Marie Curie, Paris, France.
FAU - Guerrera, Chiara Ida
AU  - Guerrera CI
AD  - Universite Paris Descartes, Paris, France.
FAU - Lefevre, Marine
AU  - Lefevre M
AD  - Service d'Anatomopathologie, Hopital Tenon, Paris, France.
FAU - Fauveau, Veronique
AU  - Fauveau V
AD  - Universite Pierre et Marie Curie, Paris, France; Universite Paris Descartes, 
      Paris, France.
FAU - Ahodantin, James
AU  - Ahodantin J
AD  - INSERM U1135, Centre d'immunologie et de maladie infectieuse, Paris, France; 
      Universite Pierre et Marie Curie, Paris, France.
FAU - Quetier, Ivan
AU  - Quetier I
AD  - INSERM U1135, Centre d'immunologie et de maladie infectieuse, Paris, France; 
      Universite Pierre et Marie Curie, Paris, France.
FAU - Chhuon, Cerina
AU  - Chhuon C
AD  - Universite Paris Descartes, Paris, France.
FAU - Gourari, Samir
AU  - Gourari S
AD  - Service de microbiologie CHU Mustapha Bacha, Alger, Algeria.
FAU - Boissonnas, Alexandre
AU  - Boissonnas A
AD  - INSERM U1135, Centre d'immunologie et de maladie infectieuse, Paris, France; 
      Universite Pierre et Marie Curie, Paris, France.
FAU - Gill, Upkar
AU  - Gill U
AD  - Division of Infection and Immunity, UCL, London, UK; Centre for Immunobiology, 
      Blizard Institute, Barts and The London School of Medicine & Dentistry, QMUL, 
      London, UK.
FAU - Kennedy, Patrick
AU  - Kennedy P
AD  - Division of Infection and Immunity, UCL, London, UK; Centre for Immunobiology, 
      Blizard Institute, Barts and The London School of Medicine & Dentistry, QMUL, 
      London, UK.
FAU - Debzi, Nabil
AU  - Debzi N
AD  - Service d'Hepatologie, CHU Mustapha Bacha, Alger, Algeria.
FAU - Sitterlin, Delphine
AU  - Sitterlin D
AD  - Universite Versailles Saint Quentin en Yvelines, Versailles, France; Laboratoire 
      de Genetique et Biologie Cellulaire, EA 4589/EPHE, Montigny le Bretonneux, 
      France.
FAU - Maini, Mala K
AU  - Maini MK
AD  - Division of Infection and Immunity, UCL, London, UK.
FAU - Kremsdorf, Dina
AU  - Kremsdorf D
AD  - INSERM U1135, Centre d'immunologie et de maladie infectieuse, Paris, France; 
      Universite Pierre et Marie Curie, Paris, France.
FAU - Soussan, Patrick
AU  - Soussan P
AD  - INSERM U1135, Centre d'immunologie et de maladie infectieuse, Paris, France; 
      Universite Pierre et Marie Curie, Paris, France; Service de Virologie, Hopital 
      Tenon, Paris, France. Electronic address: patrick.soussan@inserm.fr.
LA  - eng
GR  - MR/M020126/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170607
PL  - Netherlands
TA  - J Hepatol
JT  - Journal of hepatology
JID - 8503886
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (RNA Splicing Factors)
RN  - 0 (RNA, Viral)
SB  - IM
MH  - *Alternative Splicing/immunology
MH  - Animals
MH  - Chemokine CCL2/metabolism
MH  - Hepatitis B virus/*genetics/*immunology/pathogenicity
MH  - Hepatitis B, Chronic/immunology/virology
MH  - Host-Pathogen Interactions/*genetics/*immunology
MH  - Humans
MH  - Immune Evasion/genetics
MH  - Liver/immunology/injuries/virology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - RNA Splicing Factors/metabolism
MH  - RNA, Viral/genetics/metabolism
PMC - PMC6433284
MID - EMS82160
OTO - NOTNLM
OT  - Alternate splicing
OT  - CCL2
OT  - HBSP
OT  - HBV
OT  - Liver fibrosis
OT  - Macrophages
COIS- All authors have no conflict of interest.
EDAT- 2017/06/11 06:00
MHDA- 2018/06/06 06:00
PMCR- 2019/03/25
CRDT- 2017/06/11 06:00
PHST- 2016/07/10 00:00 [received]
PHST- 2017/05/24 00:00 [revised]
PHST- 2017/05/30 00:00 [accepted]
PHST- 2017/06/11 06:00 [pubmed]
PHST- 2018/06/06 06:00 [medline]
PHST- 2017/06/11 06:00 [entrez]
PHST- 2019/03/25 00:00 [pmc-release]
AID - S0168-8278(17)32065-2 [pii]
AID - 10.1016/j.jhep.2017.05.025 [doi]
PST - ppublish
SO  - J Hepatol. 2017 Oct;67(4):687-699. doi: 10.1016/j.jhep.2017.05.025. Epub 2017 Jun 
      7.