title: Intrahepatic innate immune response pathways are downregulated in untreated chronic hepatitis B.
abstract: Hepatitis B virus (HBV) persistence and the pathobiology of chronic HBV (CHB) infections result from the interplay between viral replication and host immune responses. We aimed to comprehensively analyse the expression of intrahepatic host genes as well as serum and liver HBV markers in a large cohort of untreated CHB patients.
  
  
  
  One-hundred and five CHB patients untreated at the time of liver biopsy (34 HBeAg[+] and 71 HBeAg[-]) were analysed for the intrahepatic expression profile of 67 genes belonging to multiple innate immunity pathways. Results were correlated to serological (quantification of HBsAg [qHBsAg] and HBV DNA) and intrahepatic viral markers (total HBV DNA, pre-genomic RNA and covalently closed circular HBV DNA).
  
  
  
  Intrahepatic gene expression profiling revealed a strong downregulation of antiviral effectors, interferon stimulated genes, Toll-like and pathogen recognition receptor pathways in CHB patients as compared to non-infected controls, which was not directly correlated to HBV replication. A subset of genes [CXCL10, GBP1, IFITM1, IFNB1, IL10, IL6, ISG15, TLR3, SOCS1, SOCS3] was more repressed in HBeAg(-) respect to HBeAg(+) patients (median of serum HBV DNA 7.9×103vs. 7.9×107IU/ml, respectively). Notably, HBeAg(-) patients with lower qHBsAg (<5×103IU/ml) showed a relief of repression of genes belonging to multiple pathways.
  
  
  
  Our results show a strong impairment of innate immune responses in the liver of CHB patients. The association of low levels of qHBsAg with gene repression, if confirmed, might prove useful for the identification of patients who would most benefit from immune-modulators and/or HBsAg targeting agents as strategies to restore immune responsiveness.
  
  
  
  Chronic hepatitis B virus (HBV) infections represent a major public health problem worldwide. Over 200 million people are chronically infected and at risk of developing chronic hepatitis, liver cirrhosis and cancer. Our work aimed to understand the molecular consequences of chronic hepatitis B in the infected liver. It was conducted in a large cohort of untreated chronically infected HBV patients and analysed the expression of immunity and liver disease-related genes in the liver, with respect to markers of viral replication and persistence. Our results indicate that chronic HBV infection has a suppressive effect on immune responses, which was more pronounced with high levels of hepatitis B virus surface antigen (HBsAg). These data provide novel insight into the mechanisms of HBV persistence in the liver and suggest that approaches aimed at reducing HBsAg levels, may restore immune responsiveness against the virus.
authors.affiliation: INSERM U1052-Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; Department of Hepatology, Croix Rousse Hospital, Hospices Civils de Lyon, France; University of Lyon, UMR_S1052, CRCL, 69008 Lyon, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Lebossé
authors.affiliation: INSERM U1052-Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, UMR_S1052, CRCL, 69008 Lyon, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Testoni
authors.affiliation: INSERM U1052-Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, UMR_S1052, CRCL, 69008 Lyon, France.
authors.forename: Judith
authors.initials: J
authors.lastname: Fresquet
authors.affiliation: Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
authors.forename: Floriana
authors.initials: F
authors.lastname: Facchetti
authors.affiliation: Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Galmozzi
authors.affiliation: INSERM U1052-Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, UMR_S1052, CRCL, 69008 Lyon, France.
authors.forename: Maëlenn
authors.initials: M
authors.lastname: Fournier
authors.affiliation: University of Lyon, UMR_S1052, CRCL, 69008 Lyon, France; Department of Pathology, Edouard Heriot Hospital, Hospices Civils de Lyon, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Hervieu
authors.affiliation: INSERM U1052-Cancer Research Center of Lyon (CRCL), 69008 Lyon, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Berthillon
authors.affiliation: INSERM U1052-Cancer Research Center of Lyon (CRCL), 69008 Lyon, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Berby
authors.affiliation: INSERM U1052-Cancer Research Center of Lyon (CRCL), 69008 Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bordes
authors.affiliation: INSERM U1052-Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, UMR_S1052, CRCL, 69008 Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Durantel
authors.affiliation: INSERM U1052-Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; Department of Hepatology, Croix Rousse Hospital, Hospices Civils de Lyon, France; Department of Internal Medicine - DMISM and the IIT Center for Life Nanoscience (CLNS), Sapienza University, Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Levrero
authors.affiliation: Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Lampertico
authors.affiliation: INSERM U1052-Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; Department of Hepatology, Croix Rousse Hospital, Hospices Civils de Lyon, France; University of Lyon, UMR_S1052, CRCL, 69008 Lyon, France. Electronic address: fabien.zoulim@inserm.fr.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
mesh_terms: D000328:Adult; D015536:Down-Regulation; D005260:Female; D006514:Hepatitis B Surface Antigens / Q000032:analysis; D006513:Hepatitis B e Antigens / Q000032:analysis; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate; D008099:Liver / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D059467:Transcriptome
chemical_list: D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens
keywords: HBV; HBsAg; Intrahepatic innate immune response; cccDNA