An activated innate immune response is thought to contribute to chronic intrahepatic inflammation in the HCV and HBV infection. In the past year we have completed studies to characterize this immune response in HCV and HBV infection. Project 1: HCV infection We had previously demonstrated an activated status of innate immune cells in chronic HCV infection. Natural killer (NK) cells are the most frequent innate immune cells in the liver, representing about 40% of the intrahepatic lymphocytic infiltrate. NK cells display increased pSTAT1mediated cytotoxicity and decreased pSTAT4-dependent IFN-γ production in patients with chronic HCV infection in comparison to those of uninfected control persons. This functional dichotomy is thought to be driven by chronic exposure to low levels of HCVinduced IFN-α, which increases STAT1/pSTAT1 levels in NK cells. The development of highly effective interferon-free regimens against HCV infection has provided the unique opportunity to analyze whether and how fast NK cell activation and liver inflammation resolve when HCV replication is blocked. A normalization of NK cell effector functions would also be of interest in the context of adaptive immune responses because HCV-specific T cells are dysfunctional due to chronic antigen stimulation in HCV infection. In this project we used multicolor flow cytometry to analyze NK cells from liver and blood of 13 HCV-infected patients who did not respond to treatment with pegylated interferon and ribavirin. Samples were collected before and during IFN-free treatment with the antivirals daclatasvir and asunaprevir. Serum levels of CXCL10 and CXCL11 were measured by ELISA. Prior to initiation of treatment all patients had increased levels of CXCL10 or CXCL11 and a different NK cell phenotype from uninfected controls, as demonstrated by increased expression of HLA-DR, NKp46, NKG2A, CD85j, pSTAT1, STAT1, and TNF-related apoptosis-inducing ligand (TRAIL) on NK cells. NK cells from patients also had increased degranulation and decreased production of IFNγ and TNFα compared with NK cells from controls. Nine patients had an end-of-treatment response (undetectable virus) and 4 had virologic breakthrough between weeks 4 and 12 of therapy. A rapid decrease in viremia and level of inflammatory cytokines in all patients was associated with decreased activation of intrahepatic NK cells within 24 hours of therapy; it was followed by restoration of a normal NK cell phenotype and function by week 8 in patients with undetectable viremia. This normalized NK cell phenotype was maintained until the end of treatment at week 24. Thus, treatment induced clearance of HCV is associated with loss of intrahepatic immune activation by IFNα, indicated by decreased levels of CXCL10 and CXCL11 and normalization of NK cell phenotype and function. Project 2: HBV infection We completed a characterization of the immune response of HBV/HDV coinfected patients in comparison to HBV monoinfected patients. Superinfection of chronic hepatitis B with hepatitis delta virus (HDV) severely enhances inflammatory liver injury and progression to liver cirrhosis. HDV is a small defective RNA virus that depends on HBV surface antigen to envelope its genome. The adaptive and innate cellular immune response to HDV is poorly characterized and the reason for the enhanced disease pathogenesis in HBV/HCV coinfected patients remains unknown. To study T cell responses we used IFN-gamma Elispot assays with overlapping HDV peptides. While strong HDV-specific CD4 and CD8 T cell responses were present in the peripheral blood of a patient with acute HDV/HBV infection and a patient who spontaneously cleared chronic HDV infection HDV-specific T cell responses were barely detectable in chronic HDV/HBV co-infection, They were not unmasked by depletion of regulatory T cells or generation of T cell lines. Likewise, HBcore and HBsurface-specific CD4 and CD8 T cell responses were weak in HDV/HBV co-infected patients and did not differ from those of HBV-infected patients. Interestingly, the serum levels of the two CXCR3-ligands CXCL9 and CXCL10, but not the chemokines CCL2, CCL3, CCL4 and CCL5 were significantly higher in HDV/HBV co-infected patients than in HBV-mono-infected patients. Serum CXCL9 and CXL10 levels correlated with ALT levels and histological activity score. Furthermore, intrahepatic CXCL9 and CXCL10 expression was greater in HDV/HBV co-infected patients than in HBV-mono-infected patients. To investigate whether HDV specifically induced these T cell-recruiting chemokines, we infected hepatoma cells with recombinant HDV and demonstrated the production of CXCL9 and CXCL10 at both RNA and protein level in a type I IFN-dependent manner. In summary, differences in the disease severity of HDV/HBV co-infection and HBV-infection were not attributed to the strength of the HDV and HBV-specific T cell response, but to HDVs capacity to specifically induce T-cell recruiting chemokines such as CXCL9 and CXCL10.

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Park, Heiyoung; O'Brien, Thomas R; Rehermann, Barbara (2018) The role of genetics in hepatic fibrosis among hepatitis C virus patients. Hepatology 67:2043-2045
Rehermann, Barbara; Thimme, Robert (2018) Insights From Antiviral Therapy into Immune Responses to HBV and HCV Infection. Gastroenterology :
Block, Timothy M; Locarnini, Stephen; McMahon, Brian J et al. (2017) Use of Current and New Endpoints in the Evaluation of Experimental Hepatitis B Therapeutics. Clin Infect Dis 64:1283-1288
Bolte, Fabian J; Rehermann, Barbara (2017) Tissue-resident T cells in hepatitis B: A new target for cure? J Exp Med 214:1564-1566
Bolte, Fabian J; O'Keefe, Ashley C; Webb, Lauren M et al. (2017) Intra-Hepatic Depletion of Mucosal-Associated Invariant T Cells in Hepatitis C Virus-Induced Liver Inflammation. Gastroenterology 153:1392-1403.e2
Cheng, Xiaoming; Xia, Yuchen; Serti, Elisavet et al. (2017) Hepatitis B virus evades innate immunity of hepatocytes but activates cytokine production by macrophages. Hepatology 66:1779-1793
Rehermann, Barbara (2017) Mature peritoneal macrophages take an avascular route into the injured liver and promote tissue repair. Hepatology 65:376-379
Rehermann, Barbara (2016) HCV in 2015: Advances in hepatitis C research and treatment. Nat Rev Gastroenterol Hepatol 13:70-2
Rehermann, Barbara (2016) Peptide-dependent HLA-KIR-mediated regulation of NK cell function. J Hepatol 65:237-9
Gara, Naveen; Abdalla, Adil; Rivera, Elenita et al. (2015) Durability of antibody response against hepatitis B virus in healthcare workers vaccinated as adults. Clin Infect Dis 60:505-13

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