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1016A AASLD ABSTRACTS HEPATOLOGY, October, 2015 1655 A Novel Entecavir Resistance Mutation RtA186T Causes Viral Breakthrough in Chronic Hepatitis B Patients Sanae Hayashi 1 , Shuko Murakami 1 , Katsumi Omagari 1 , Takeshi Matsui 2 , Etsuko Iio 1 , Masanori Isogawa 1 , Tsunamasa Watanabe 1 , Yoshiyasu Karino 3 , Yuki Takamatsu 4 , Satoru Kohgo 5 , Kenji Maeda 5 , Hiroaki Mitsuya 4,5 , Yasuhito Tanaka 1 ; 1 Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; 2 Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan; 3 Department of Gastroenterology, Sapporo Kosei General Hospital, Hokkaido, Japan; 4 Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; 5 National Center for Global Health and Medicine, Tokyo, Japan Background & Aim: Entecavir (ETV) is approved for the first-line treatment of chronic hepatitis B virus (HBV) infections due to a high genetic barrier. The aim of this study is to characterize two novel reverse transcriptase (RT) mutations associated with viral breakthrough (VBT) in an ETV-refractory patient. Methods: Serum HBV from an ETV refractory patient was sequenced before ETV treatment and after VBT. The clones with candidate ETV resistance (ETVr) mutations (rtI163T and rtA186T) were analyzed for replication efficacy and susceptibility to ETV, Adefovir (ADV), Tenofovir Disoproxil Fumarate (TDF), and novel nucleoside analogues (NAs) (4’-C-cyano-2-amino-2’-deoxyadenosine (CAdA), 4’-C-cyano-2’-deoxyguanosine (CdG)) with similar efficacy to ETV in vitro. Moreover, chimeric mice with human hepatocytes were inoculated with the patient’s serum at VBT, and monitored for viral mutation pattern by next-generation sequencing. To confirm the prevalence of the novel mutations, 21 ETV-refractory patients were also examined. Results: The novel mutations, rtI163V and rtA186T, were detected together with LAMr at VBT, but not before ETV treatment. RtA186T significantly reduced viral replication efficacy, while rtI163V had no impact on it. RtA186T plus LAMr reduced susceptibility to ETV as strongly as previously reported ETVr mutations rtS202G plus LAMr, resulting in more than 111.1- fold resistance to ETV compared with the wild-type clone. In contrast, rtI163V plus LAMr resulted in a 20.4-fold resistance to ETV, suggesting that rt186T was mainly responsible for the VBT. The novel ETVr mutations did not confer cross-resistance to ADV, TDF, as well as novel NAs, CAdA and CdG. The viral mutation pattern in the chimeric mice indicated dominant proliferation of a clone containing rtI163V and rtA186T mutations plus LAMr under ETV treatment. In silico docking simulation indicated that rtA186T reduced the RT binding ability to ETV. In clinical practice, rtA186T, but not rtI163V, was detected in another ETV-refractory patient with VBT, suggesting that rtA186T could confer ETV resistance independently of rtI163V. Conclusion: A novel ETV resistance mutation rtA186T causes VBT, and should be closely monitored when chronic hepatitis B patients exhibit VBT during prolonged ETV treatment. Disclosures: Yoshiyasu Karino - Speaking and Teaching: BMS KK Yasuhito Tanaka - Grant/Research Support: Chugai Pharmaceutical CO., LTD., MSD, Bristol-Myers Squibb; Speaking and Teaching: janssen pharma, Bristol-Myers Squibb The following authors have nothing to disclose: Sanae Hayashi, Shuko Murakami, Katsumi Omagari, Takeshi Matsui, Etsuko Iio, Masanori Isogawa, Tsunamasa Watanabe, Yuki Takamatsu, Satoru Kohgo, Kenji Maeda, Hiroaki Mitsuya 1656 Hepatitis B Virus Surface Protein-induced hPIAS1 Transcription Requires TAL1, E47, MYOG, NFI, andMAPK Signal Pathways Hongyan Wang, Di Wu, Xiaofeng Wang, Guang Chen, Yuanya Zhang, Weiming Yan, Meifang Han, Qin Ning; Department and institute of Infectious Disease,, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China The protein inhibitor of activated STAT1 (PIAS1) is ubiquitous in mammals and fulfills key functions in cell proliferation and inflammation responses. Despite the importance of PIAS1 in regulating virus-induced or IFN-stimulated chronic hepatitis, little is known about the molecular mechanisms of activation in response to hepatic virus infection. Here, we report that the hepatitis B virus surface protein (HBs) enhancedhPIAS1 promoter activity in luciferase reporter assays. A strong regulatory region from −712 to −507 (relative to the transcriptional start site) was responsible forhPIAS1 gene transcription in response to HBs. TAL1, E47, myogenin (MYOG), and NFI were highly expressed and localized to the nucleus in response to HBs. Binding of TAL1, E47, MYOG, and NFI to a cis-regulatory element in the hPIAS1 promoter was confirmed by electrophoretic mobility shift assays and chromatin immunoprecipitation. siRNA knockdown of TAL1, E47, MYOG, and NFI expression inhibited hPIAS1transcription in response to HBs. Increased ERK and p38MAPK phosphorylation was observed in HBs-transfected HepG2 cells, and treatment with the ERK inhibitor PD098059 or p38MAPK inhibitor SB203580 abolished increase in nuclear TAL1, E47, MYOG, and NFI levels and hPIAS1 induction. Peripheral blood mononuclear cells from patients withhigh HBsAg levels (also withhigh levels of HBV DNA ) displayed increased ERK and p38MAPK phosphorylation and high levels of TAL1, E47, MYOG, and NFI, compared to those with low HBsAg levels or healthy controls. Increased hPIAS1 expression was detected in liver biopsies from CHB patients with high HBV replication compared to those of undetectable for HBV or healthy controls.These findings suggest that the HBs protein enhances hPIAS1transcription through activities of TAL1, E47, MYOG, and NFI that are dependent on MAPK signaling pathways. Disclosures: Qin Ning - Advisory Committees or Review Panels: ROCHE, NOVARTIS, BMS, MSD, GSK; Consulting: ROCHE, NOVARTIS, BMS, MSD, GSK; Grant/Research Support: ROCHE, NOVARTIS, BMS; Speaking and Teaching: ROCHE, NOVAR- TIS, BMS, MSD, GSK The following authors have nothing to disclose: Hongyan Wang, Di Wu, Xiaofeng Wang, Guang Chen, Yuanya Zhang, Weiming Yan, Meifang Han 1657 The activating receptor NKP46 is essential for the development of chronic hepatitis B Wanyu Li, Xiuzhu Gao, Ruqi Mei, Jinglan Jin, Junqi Niu; the first hospital of jilin university, Changchun, China BACKGROUND & AIMS: Our pervious study indicated that NKp46 expression regulated NK cell cytolytic function. NKp46 may moderate NK cell activity during HBV replication suppression and HBV-associated liver damage in peripheral blood. Here we studied the functions of NKP46 during hepatitis B virus (HBV) infection in vivo and in the liver of patients. METH- ODS: Intrahepatic NKP46 was investigated in chronic hepatitis B patients(n=25) and healthy controls(n=15) by immunohistochemistry.We examined the effects of blocking antibodies against NKP46(50ug) in immunocompetent mice that express HBV from a pAAV/HBV1.2 plasmid(10ug) and are positive
HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 1017A for serum hepatitis B surface antigen (a mouse model of HBV infection)(n=10).Goat IgG isotype control antibody was administered to control groups.Serum HBsAg titers and HBVDNA levels were tested at baseline and post-injection. RESULTS: Intrahepatic NKP46 expression is up-regulated in patients with CHB compared with healthy control(p=0.032).After injecting HBV plasmid,mice that remained HBsAg-positive were used to test whether anti-NKP46 mAb treatment affected HBsAg and HBVDNA levels during HBV infection.Serum different value of HBsAg levels(1508.57±1654.94vs 5597.50±4729.13 IU/ml;p
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