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Sequence analysis of integrated hepatitis B virus DNA during HBeAg-seroconversion.

ABSTRACT: Hepatitis B virus (HBV) integration into the host cell genome occurs early on in infection and reportedly induces pro-oncogenic changes in hepatocytes that drive HCC initiation. However, it remains unclear when these changes occur during hepatocarcinogenesis. Extensive expansion of hepatocyte clones with a selective advantage was shown to occur prior to cancer formation during the HBeAg-seroconversion phase of chronic HBV infection. We hypothesized that since integrations occur during the early stages of infection, cell phenotype could be altered and induce a selection advantage (e.g., through insertional mutagenesis or cis-mediated activation of downstream genes). Here, we analyzed the enrichment of genomic and functional patterns in the cellular host sequence adjacent to HBV DNA integration events. We examined 717 unique integration events detected in patients who have and have not undergone HBeAg-seroconversion (n?=?41) or in an in vitro model system. We also used an in silico model to control for detection biases. We showed that the sites of HBV DNA integration were distributed throughout the entire host genome without obvious enrichment of specific structural or functional genomic features in the adjacent cellular genome during HBeAg-seroconversion. Currently, this is the most comprehensive characterization of HBV DNA integration events prior to hepatocarcinogenesis. Our results suggest no significant selection for (or against) specific cellular sites of HBV DNA integration occur during the clonal expansion phase of chronic HBV infection. Thus, HBV DNA integration events likely represent passenger events rather than active drivers of liver cancer, which was previously suggested.

SUBMITTER: Budzinska MA

PROVIDER: S-EPMC6081408 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Sequence analysis of integrated hepatitis B virus DNA during HBeAg-seroconversion.

Budzinska Magdalena Agnieszka MA Shackel Nicholas Adam NA Urban Stephan S Tu Thomas T

Emerging microbes & infections 20180808 1

Hepatitis B virus (HBV) integration into the host cell genome occurs early on in infection and reportedly induces pro-oncogenic changes in hepatocytes that drive HCC initiation. However, it remains unclear when these changes occur during hepatocarcinogenesis. Extensive expansion of hepatocyte clones with a selective advantage was shown to occur prior to cancer formation during the HBeAg-seroconversion phase of chronic HBV infection. We hypothesized that since integrations occur during the early ...[more]

PMID: 30087321

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Project description:Background & aimsCurrent therapies for chronic hepatitis B virus (HBV) infection control viral replication but do not eliminate the risk of progression to hepatocellular carcinoma. HBV-specific CD8 T cells are necessary for viral control, but they are rare and exhausted during chronic infection. Preclinical studies have shown that blockade of the PD-1:PD-L1 axis can restore HBV-specific T cell functionality. The aim of this study was to analyze how the clinical and treatment status of patients impacts the ability of HBV-specific T cells to respond to PD-L1 blockade.MethodsExpression patterns of the PD-1:PD-L1/PD-L2 axis were analyzed in healthy donors and chronically infected patients in different clinical phases of disease. A functional assay was performed to quantify baseline HBV-specific T cell responses in chronically infected patients. Baseline responses were then compared to those attained in the presence of an anti-PD-L1 monoclonal antibody (MEDI2790).ResultsChronically infected patients were characterized by the upregulation of PD-1 within the T cell compartment and a concomitant upregulation of PD-L1 on myeloid dendritic cells. The upregulation was maximal in HBV e antigen (HBeAg)-positive patients but persisted after HBeAg negativization and was not restored by long-term treatment. HBV reactivity, measured as frequency of HBV-specific T cells, was significantly higher in HBeAg-negative patients with lower HBV DNA levels, independently of HBV surface antigen or alanine aminotransferase levels. Anti-PD-L1 blockade with MEDI2790 increased both the number of IFN-γ-producing T cells and the amount of IFN-γ produced per cell in 97% of patients with detectable HBV reactivity, independently of patients' clinical or treatment status.ConclusionPatients with lower levels of HBV DNA and the absence of HBeAg have more intact HBV-specific T cell immunity and may benefit the most from PD-L1 blockade as a monotherapy.Lay summaryHepatitis B virus (HBV)-specific T cell responses during chronic infection are weak due to the upregulation of inhibitor molecules on the immune cells. In this study we show that the inhibitory PD-1:PD-L1 axis is upregulated during chronic HBV infection and successful antiretroviral therapy does not restore normal levels of PD-1 and PD-L1 expression. However, in HBV e antigen-negative patients, treatment with an anti-PD-L1 antibody can increase the functionality of HBV-specific T cell responses by an average of 2-fold and is a promising new therapy for patients with chronic HBV infection.

Dataset Information

Sequence analysis of integrated hepatitis B virus DNA during HBeAg-seroconversion.

Publications

Sequence analysis of integrated hepatitis B virus DNA during HBeAg-seroconversion.

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