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1020A AASLD ABSTRACTS HEPATOLOGY, October, 2015 PlasmaBcells(4.1±3.8%Vs12.1±6.45%, p=0.03)&humoral immunity were also reduced in Gr A(Fig.B,C).RNA sequencing showed decreased expression (>2 fold) of TFH and B cell related genes;CD4, BCL6, ICOS, SLAMF1,CXCR5 and BAF- F,BATF,CD40, BAFFR in GrA than B(Fig1A).This was validated by qRT-PCR showing down-regulation of TFH related genes (Fig1D).ROC showed significance of CD4,TFH and B cells with cut-off values for prediction of transmission; with highest specificity&sensitivity with CD4+ICOS+ & CD4+CXCR5+cells as predictors for a transmitting mother(Table).Conclusions:Humoral Immunity is essential for viral neutralization.Decreased CD4 helper&TFH cells lead to impaired plasma B cell function&facilitate HBV transmission to the newborn. Plasma B cell can be used as a marker to predict HBV Transmission. beclin-1 (6 fold), SIRT-1 (4 fold), c-myc (4 fold), and PTEN with HA treatment (100 μg/ml). The expression of p-akt, p-erk-1/2 were also inhibited while the expression of the caspase-3 and β-catenin were found to be up-regulated. The autophagosome formation was inhibited significantly (p
HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 1021A 1666 Presence of naïve-like CD8+ T cells specific for subdominant hepatitis B virus epitopes in chronically infected patients Anita Schuch 1,2 , Muthamia Kiraithe 1,2 , Julia Lang 1 , Christoph Neumann-Haefelin 1 , Robert Thimme 1 ; 1 Department of Medicine II, University Hospital Freiburg, Freiburg, Germany; 2 Faculty of Biology, University of Freiburg, Freiburg, Germany In chronically HBV-infected patients, virus-specific CD8+ T cells are rarely detectable ex vivo by conventional tetramer stainings. We aimed to analyze whether his lack of HBV-specific CD8+ T-cell responses may be explained by insufficient priming or terminal deletion. To phenotypically characterize HBV-specific CD8+ T cells that are not detectable by conventional methods we used a combination of tetramer-associated magnetic bead enrichment and multiparametric flow cytometry and additionally performed viral sequence analyses. We analyzed CD8+ T-cell populations specific for 4 well-described HLA-A*02:01 restricted HBV epitopes (Core 18-27 , Env 183-191 , Env 335-343 and Pol 455-463 ) in a heterogeneous cohort of 34 chronically HBV-infected patients. We were able to detect 108 of 136 (79%) HBV-specific CD8+ T-cell populations. Of note, each patient had at least one detectable CD8+ T-cell population, suggesting that these cells are not completely deleted in chronic infection. Enriched CD8+ T cells specific for the immunodominant Core 18-27 epitope predominantly showed an antigen-experienced effector-memory phenotype (CD45RA - , CCR7 - , CD27 + , CD11a + ) which was also detectable in patients with resolved HBV infection. In contrast, CD8+ T cells specific for Env 183-191 , Env 335-343 and Pol 455-463 often displayed a naïvelike phenotype (15%, 44% and 19% respectively) defined by high expression of CD45RA, CCR7 and CD27. Absence of CD11a and CD95 expression additionally indicated a naïve status of these enriched HBV-specific CD8+ T cells. Importantly, the presence of wild type sequences in patients with naïve-like HBV-specific CD8+ T cells indicated that the presence of naïvelike cells is not due to infection with a variant HBV containing mismatched epitopes. It is also important to note that the presence of HBV-specific CD8+ T cells with naïve-like phenotype did not correlate with any clinical parameter such as viral load, transaminase levels or HBeAg status, and was independent of antiviral treatment. Taken together, our results indicate that HBV-specific CD8+ T cells are not completely deleted in chronically infected patients, but are rather maintained at a very low frequency. Furthermore, a substantial fraction of CD8+ T cells specific for subdominant HBV epitopes display a naïve-like phenotype despite ongoing viral replication. This suggests that insufficient priming and/or antigen ignorance of HBV-specific CD8+ T cells may also contribute to CD8+ T-cell failure in chronic HBV infection and that therapeutic vaccination may be a feasible approach in this patient cohort. Disclosures: Christoph Neumann-Haefelin - Advisory Committees or Review Panels: AbbVie; Speaking and Teaching: AbbVie, Gilead, Bristol-Myers Squibb The following authors have nothing to disclose: Anita Schuch, Muthamia Kiraithe, Julia Lang, Robert Thimme 1667 Precore and Basal Core Promoter mutations in HBeAg negative chronic hepatitis B virus infection in Cape Town, South Africa Mark W. Sonderup 1 , Heidi Smuts 2 , Ruud A. Roos 3,1 , Helen Wainwright 4 , Neliswa A. Gogela 1 , Mashiko Setshedi 1 , Henry N. Hairwadzi 1 , C. W. Spearman 1 ; 1 Department of Medicine and Division of Hepatology, University of Cape Town, Cape Town, South Africa; 2 Division of Medical Virology, University of Cape Town and NHLS, Cape Town, South Africa; 3 Vrije Universiteit, Amsterdam, Netherlands; 4 Department of Anatomical Pathology, University of Cape Town, Cape Town, South Africa Chronic HBeAg negative HBV represents the immune control or escape phase of infection. Precore (PC) and basal core promoter (BCP) mutations are associated with progressive liver disease or HCC although this is poorly studied in sub-Saharan Africa. Our aim was to characterize mutations in HBeAg negative patients. Methods: Prospectively, over 2 years, HBeAg negative patients were analysed by amplifying viral PC and BCP regions using nested primers. Amplicons were direct Sanger sequenced in the forward & reverse directions and compared to reference sequences. Relevant demographic, clinical, virological and histological data were captured. Results: 124 patients, median age 35.1 yrs (IQR 29-43.2), 60.5% (n=75) male, 3.2% (n=4) HIV co-infected, were analysed. Ethnically, 52% were mixed ancestry, 28% Black African, 16% White and 4% Asian. Genotype distribution - A 51%, B 2.3%, C 1.1%, D 42% and E 3.6%. Mutations were detected in 98.4% (n=122); 89% (n=109) with PC; 53.3% (n=65) BCP and 46% (n=56) both. Mutation frequencies are listed. Median ALT (U/L) was significantly higher when both PC/BCP than PC only mutations were present, [44 (IQR 41-47); 27 (19-52)] p=0.0007, but not with BCP only mutations [32 IQR (22-65)]; p=0.069. With dual A1762T G1764A BCP mutations, median ALT and HBV DNA (log 10 IU/ml) was significantly higher compared to the T1753C only BCP mutation, [52 (IQR 25-134); 24 (IQR21- 49)]; p=0.019 and [5.2 (IQR 4-7.6); 3.8 (3-5.3)]; p=0.02. In those biopsied (n=31), median Ishak necro-inflammatory stage and fibrosis grade scores were 5 (IQR 3-7) & 2 (IQR 1-3) respectively with no differences observed in PC, BCP or PC/ BCP groups. Six patients, 4.8%, developed HCC with 5 (83%) having both PC/BCP mutations, 3 (50%) the dual A1762T G1764A BCP mutation and 4 (66%) the G1896A PC mutation. Conclusion: In HBeAg negative, mostly A or D genotype CHB patients, PC were present more frequently than BCP mutations; almost half having both. Dual PC/BCP predicted for higher ALT and HBV DNA; a similar trend observed for the dual A1762T G1764A BCP mutation. Mutation analysis may have a role in guiding the need for antiviral therapy.
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1312A AUTHOR INDEX HEPATOLOGY, Octo
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1366A CATEGORY INDEX HEPATOLOGY, Oc
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