title: Impaired expression and function of TLR8 in chronic HBV infection and its association with treatment responses during peg-IFN-α-2a antiviral therapy.
abstract: OBJECTIVE
  Toll-like receptor 8 (TLR8) plays an important role in controlling chronic viral infections. However, the role of TLR8 in chronic hepatitis B virus (HBV) infection is poorly understood. In this study, we aimed to investigate the expression and function of TLR8 in peripheral blood mononuclear cells (PBMCs) of chronic hepatitis B (CHB) patients and its alteration during peg-IFN-α-2a therapy.
  
  
  METHODS
  We evaluated TLR8 expression and antiviral function in vitro by real-time RT-PCR and flow cytometry analysis using fresh PBMCs obtained from CHB patients compared to healthy controls. We also employed clinical cohorts to investigate TLR8 expression in response to peg-IFN-α-2a therapy.
  
  
  RESULTS
  TLR8 was mainly expressed in monocytes, and simulation with its ligand resulted in high levels of IFN-γ and TNF-α production. Compared with healthy controls, PBMCs obtained from CHB patients displayed reduced levels of TLR8 expression and IFN-γ, TNF-α and IL-12 induction. The exposure of HepG2.2.15 cells to conditioned medium from PBMCs stimulated by ssRNA40 strongly reduced the levels of HBV DNA, HBsAg and HBeAg, whereas the addition of IFN-γ or TNF-α neutralizing antibodies could block the antiviral effect. NK cells and T cells were the principal IFN-γ-producing lymphocytes after ssRNA40 stimulation, whereas monocytes were the primary source of TNF-α. Analysis of the temporal dynamics showed that patients who achieved a complete response sustained a significant higher level of TLR8 mRNA than those who did not achieve a complete response beginning at week 12 of peg-IFN-α-2a therapy.
  
  
  CONCLUSIONS
  TLR8 expression and function in PBMCs were impaired by chronic HBV infection. Higher TLR8 expression after treatment week 12 could potentially predict complete response to peg-IFN-α-2a therapy.
authors.affiliation: State key laboratory of organ failure research, Guangdong provincial key laboratory of viral hepatitis research, department of hepatology unit and infectious diseases, Nanfang hospital, Southern medical university, No. 1838, North Guangzhou avenue, 510515 Guangzhou, China.
authors.forename: Guangying
authors.initials: G
authors.lastname: Deng
authors.affiliation: State key laboratory of organ failure research, Guangdong provincial key laboratory of viral hepatitis research, department of hepatology unit and infectious diseases, Nanfang hospital, Southern medical university, No. 1838, North Guangzhou avenue, 510515 Guangzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ge
authors.affiliation: State key laboratory of organ failure research, Guangdong provincial key laboratory of viral hepatitis research, department of hepatology unit and infectious diseases, Nanfang hospital, Southern medical university, No. 1838, North Guangzhou avenue, 510515 Guangzhou, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: State key laboratory of organ failure research, Guangdong provincial key laboratory of viral hepatitis research, department of hepatology unit and infectious diseases, Nanfang hospital, Southern medical university, No. 1838, North Guangzhou avenue, 510515 Guangzhou, China.
authors.forename: Jinke
authors.initials: J
authors.lastname: Pang
authors.affiliation: State key laboratory of organ failure research, Guangdong provincial key laboratory of viral hepatitis research, department of hepatology unit and infectious diseases, Nanfang hospital, Southern medical university, No. 1838, North Guangzhou avenue, 510515 Guangzhou, China; Department of hepatology, affiliated infectious disease hospital, Fujian medical university, Fuzhou, China.
authors.forename: Zuxiong
authors.initials: Z
authors.lastname: Huang
authors.affiliation: State key laboratory of organ failure research, Guangdong provincial key laboratory of viral hepatitis research, department of hepatology unit and infectious diseases, Nanfang hospital, Southern medical university, No. 1838, North Guangzhou avenue, 510515 Guangzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Peng
authors.affiliation: State key laboratory of organ failure research, Guangdong provincial key laboratory of viral hepatitis research, department of hepatology unit and infectious diseases, Nanfang hospital, Southern medical university, No. 1838, North Guangzhou avenue, 510515 Guangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: State key laboratory of organ failure research, Guangdong provincial key laboratory of viral hepatitis research, department of hepatology unit and infectious diseases, Nanfang hospital, Southern medical university, No. 1838, North Guangzhou avenue, 510515 Guangzhou, China; Collaborative innovation center for diagnosis and treatment of infectious diseases, Zhejiang university, Hangzhou, China. Electronic address: jlhousmu@163.com.
authors.forename: Jinlin
authors.initials: J
authors.lastname: Hou
authors.affiliation: State key laboratory of organ failure research, Guangdong provincial key laboratory of viral hepatitis research, department of hepatology unit and infectious diseases, Nanfang hospital, Southern medical university, No. 1838, North Guangzhou avenue, 510515 Guangzhou, China; Collaborative innovation center for diagnosis and treatment of infectious diseases, Zhejiang university, Hangzhou, China. Electronic address: xiaoyzhang@smu.edu.cn.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D005260:Female; D019694:Hepatitis B, Chronic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000627:therapeutic use; D051200:Toll-Like Receptor 8 / Q000096:biosynthesis / Q000502:physiology*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D011994:Recombinant Proteins; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; D011092:Polyethylene Glycols; C100416:peginterferon alfa-2a