The immune tolerant phase of chronic HBV infection: new perspectives on an old concept.
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ABSTRACT:
SUBMITTER: Bertoletti A
PROVIDER: S-EPMC4654319 | biostudies-other | 2015 May
REPOSITORIES: biostudies-other
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Project description:Hepatitis B virus (HBV) is the leading cause of liver disease and hepatic carcinoma (HCC). Approximately 350 million people worldwide are infected with HBV and at risk of chronicity. An efficient HBV-tolerant murine model that mimics HBV infection in humans is desirable for HBV-related research. In this study, we investigated and established a murine model by hydrodynamic injection (HDI) of pAAV/HBV into the tail vein of AAVS1 site element-transgenic mice. In 80% of the injected mice, the serum level of HBsAg reached 103-4 IU/ml and persisted for more than half a year. Next, the model was used to evaluate RNA interference (RNAi)-based antiviral therapy. Data obtained using the model demonstrated that this model will facilitate the elucidation of the mechanisms underlying chronic HBV infection and will also be useful for evaluating new antiviral drugs.
| S-EPMC5111840 | biostudies-other
Project description:Background & aimsChronic infection with hepatitis B virus (HBV) progresses through different phases. The first, called the immune-tolerant phase, has been associated with a lack of disease activity. We examined HBV-DNA integration, clonal hepatocyte expansion, HBV antigen expression, and HBV-specific immune responses in patients in the immune-tolerant phase to assess whether this designation is appropriate or if there is evidence of disease activity.MethodsWe studied HBV-DNA integration, clonal hepatocyte expansion, and expression of hepatitis B surface antigen and core antigen in liver tissues from 26 patients with chronic HBV infection (ages, 14-39 y); 9 patients were positive for hepatitis B e antigen (HBeAg) in the immune-tolerant phase and were matched for age with 10 HBeAg-positive patients with active disease and 7 HBeAg-negative patients with active disease. Peripheral blood samples were collected and HBV-specific T cells were quantified for each group.ResultsDetection of HBV antigens differed among groups. However, unexpectedly high numbers of HBV-DNA integrations, randomly distributed among chromosomes, were detected in all groups. Clonal hepatocyte expansion in patients considered immune tolerant also was greater than expected, potentially in response to hepatocyte turnover mediated by HBV-specific T cells, which were detected in peripheral blood cells from patients in all phases of infection.ConclusionsWe measured HBV-specific T cells, HBV-DNA integration, and clonal hepatocyte expansion in different disease phases of young patients with chronic hepatitis B, with emphasis on the so-called immune-tolerant phase. A high level of HBV-DNA integration and clonal hepatocyte expansion in patients considered immune tolerant indicated that hepatocarcinogenesis could be underway-even in patients with early stage chronic HBV infection. Our findings do not support the concepts that this phase is devoid of markers of disease progression or that an immune response has not been initiated. We propose that this early phase be called a high-replication, low-inflammation stage. The timing of therapeutic interventions to minimize further genetic damage to the hepatocyte population should be reconsidered.
| S-EPMC8406433 | biostudies-literature
Project description:Some patients with chronic hepatitis B virus (HBV) infection failed to clear HBV, even persistently continue to produce antibodies to HBV. Here we performed a two stage genome wide association study in a cohort of Chinese patients designed to discover single nucleotide variants that associate with HBV infection and clearance of HBV. The first stage involved genome wide exome sequencing of 101 cases (HBsAg plus anti-HBs positive) compared with 102 control patients (anti-HBs positive, HBsAg negative). Over 80% of individual sequences displayed 20 × sequence coverage. Adapters, uncertain bases > 10% or low-quality base calls (> 50%) were filtered and compared to the human reference genome hg19. In the second stage, 579 chronic HBV infected cases and 439 HBV clearance controls were sequenced with selected genes from the first stage. Although there were no significant associated gene variants in the first stage, two significant gene associations were discovered when the two stages were assessed in a combined analysis. One association showed rs506121-"T" allele [within the dedicator of cytokinesis 8 (DOCK8) gene] was higher in chronic HBV infection group than that in clearance group (P = 0.002, OR = 0.77, 95% CI [0.65, 0.91]). The second association involved rs2071676-A allele within the Carbonic anhydrase (CA9) gene that was significantly elevated in chronic HBV infection group compared to the clearance group (P = 0.0003, OR = 1.35, 95% CI [1.15, 1.58]). Upon replication these gene associations would suggest the influence of DOCK8 and CA9 as potential risk genetic factors in the persistence of HBV infection.
| S-EPMC7462954 | biostudies-literature
Project description:BACKGROUND:The restoration of host hepatitis B virus (HBV)-specific antiviral immunity is an effective strategy for hepatitis B recovery. Follicular dendritic cells (FDCs) play a crucial role in immune regulation. The goal of the present study was to investigate the characteristics and functions of FDCs in chronic HBV infection. METHODS:The frequencies of FDCs in peripheral blood, liver, and spleen were measured in patients with chronic HBV infection. Isolated FDCs from splenic tissues of HBV-related liver cirrhosis-induced hypersplenism patients were cultured with autologous intrasplenic CD4+ T cells and CD19+ B cells. RESULTS:We observed that patients with chronic HBV infection had a significantly increased frequency of circulating FDCs compared to that of healthy controls. Additionally, the frequency of circulating FDCs was positively correlated with that of intrahepatic and intrasplenic counterparts. Moreover, positive correlations were observed between the frequencies of circulating FDCs and plasmablast and memory B cells, as well as C-X-C motif chemokine receptor type 5 (CXCR5)+CD4+ T cells and CXCR5+CD8+ T cells. Notably, in vitro experimental results demonstrated that FDCs derived from splenic tissues of chronic HBV patients facilitated interferon-? and interleukin-21 production from autologous intrasplenic CD4+ T cells and promoted the proliferation of autologous intrasplenic CD19+ B cells. CONCLUSIONS:Expanded FDCs in patients with chronic HBV infection may favor host immune responses against HBV. The identification of this unique population of cell may contribute to a better understanding of the immune regulatory mechanisms associated with chronic HBV infection and provide a potential immunotherapeutic target for this disease.
| S-EPMC7648402 | biostudies-literature
Project description:Background & aimsFunctional cure of chronic HBV infection (CHB) without life-long treatment requires the restoration of defective HBV-specific humoral and cellular immunity. Therapeutic vaccines based on the major structural and non-structural proteins have been tested in patients with CHB but have shown scarce immunogenicity. BRII-179, also known as VBI-2601, is a novel formulation comprised of all 3 HBV surface envelope proteins (Pre-S1, Pre-S2, and S). Safety, antiviral activity, and immunogenicity of BRII-179 admixed with co-adjuvant interferon (IFN)-α were assessed in patients with CHB.MethodThis randomized, open-label, controlled phase Ib/IIa study included 2 dose levels, 20 μg BRII-179 (Part 1, n = 25) and 40 μg BRII-179 (Part 2, n = 24). Patients, virally suppressed under nucleos(t)ide analogue (NA) therapy were randomized 1:2:2 into 3 cohorts in Part 1 and 1:1 into 2 cohorts in Part 2 to receive 4 monthly intramuscular injections of BRII-179 admixed with/without 3 MIU IFN-α. Antibody and cellular responses to HBsAg, as well as evolution of circulating HBsAg were monitored.ResultsBoth 20 μg and 40 μg BRII-179 with/without IFN-α were well tolerated with no severe adverse events. BRII-179 induced anti-HBs responses in >30% patients in all treatment cohorts, however, moderate anti-Pre-S1 or anti-Pre-S2 antibody responses were only observed in patients receiving BRII-179 with IFN-α. BRII-179 also restored S-, Pre-S1-, Pre-S2-specific IFN-γ-producing T-cells in the majority of treated patients. Overall, no notable reduction of HBsAg was observed after BRII-179 treatment.ConclusionIn patients with CHB under NA therapy, BRII-179 with/without IFN-α exhibited a good safety profile and induced HBV-specific B- and T-cell immune responses. These data support further clinical evaluation of BRII-179 in combination with other therapies.Clinical trial numberACTRN12619001210167.Lay summaryBRII-179 is a therapeutic vaccine designed to improve the immune response in patients with chronic hepatitis B. In this study, BRII-179 alone or with a low dose of interferon-α was safe, well tolerated, and induced enhanced HBV-specific antibody and T-cell responses in patients with chronic hepatitis B. However, BRII-179 treatment alone had minimal effect on patient's virological status. The potential of BRII-179 to achieve a functional cure in conjunction with other agents is being evaluated in the clinic.
| S-EPMC8502773 | biostudies-literature
Project description:The autosomal dominant form of Caffey disease is a largely self-limiting infantile bone disorder characterized by acute inflammation of soft tissues and localized thickening of the underlying bone cortex. It is caused by a recurrent arginine-to-cysteine substitution (R836C) in the α1(I) chain of type I collagen. However, the functional link between this mutation and the underlying pathogenetic mechanisms still remains elusive. Importantly, it remains to be established as to how a point-mutation in type I collagen leads to a cascade of inflammatory events and spatio-temporally limited hyperostotic bone lesions, and how structural and inflammatory components contribute to the different organ-specific manifestations in Caffey disease. In this review we attempt to shed light on these questions based on the current understanding of other mutations in type I collagen, their role in perturbing collagen biogenesis, and consequent effects on cell-cell and cell-matrix interactions.
| S-EPMC3987944 | biostudies-literature
Project description:Background & aimsWe aim to describe the liver immune microenvironment by analyzing liver biopsies from patients with chronic HBV infection (CHB). Host immune cell signatures and their corresponding localization were characterized by analyzing the intrahepatic transcriptome in combination with a custom multiplex immunofluorescence panel.MethodMatching FFPE and fresh frozen liver biopsies were collected from immune active patients within the open-label phase IV study GS-US-174-0149. RNA-Seq was conducted on 53 CHB liver biopsies from 46 patients. Twenty-eight of the 53 samples had matched FFPE biopsies and were stained with a 12-plex panel including cell segmentation, immune and viral biomarkers. Corresponding serum samples were screened using the MSD Human V-plex Screen Service to identify peripheral correlates for the immune microenvironment.ResultsUsing unsupervised clustering of the transcriptome, we reveal two unique liver immune signatures classified as immune high and immune low based on the quantification of the liver infiltrate gene signatures. Multiplex immunofluorescence analysis demonstrated large periportal lymphoid aggregates in immune high samples consisting of CD4 and CD8 T cells, B cells and macrophages. Differentiation of the high and low immune microenvironments was independent of HBeAg status and peripheral viral antigen levels. In addition, longitudinal analysis indicates that treatment and normalization of ALT correlates with a decrease in liver immune infiltrate and inflammation. Finally, we screened a panel of peripheral biomarkers and identified ICAM-1 and CXCL10 as biomarkers that strongly correlate with these unique immune microenvironments.ConclusionThese data provide a description of immune phenotypes in patients with CHB and show that immune responses are downregulated in the liver following nucleotide analogue treatment. This may have important implications for both the safety and efficacy of immune modulator programs aimed at HBV cure.Lay summaryLiver biopsies from patients with chronic hepatitis B were submitted to RNA-Seq and multiplex immunofluorescence and identified two different liver immune microenvironments: immune high and immune low. Immune high patients showed elevated immune pathways, including interferon signaling pathways, and increase presence of immune cells. Longitudinal analysis of biopsies from treatment experienced patients showed that treatment correlates with a marked decrease in inflammation and these findings may have important implications for both safety and efficacy of immune modulator programs for HBV cure.
| S-EPMC8671126 | biostudies-literature
Project description:In spite of past controversies, the field of ancient DNA is now a reliable research area due to recent methodological improvements. A series of recent large-scale studies have revealed the true potential of ancient DNA samples to study the processes of evolution and to test models and assumptions commonly used to reconstruct patterns of evolution and to analyze population genetics and palaeoecological changes. Recent advances in DNA technologies, such as next-generation sequencing make it possible to recover DNA information from archaeological and paleontological remains allowing us to go back in time and study the genetic relationships between extinct organisms and their contemporary relatives. With the next-generation sequencing methodologies, DNA sequences can be retrieved even from samples (for example human remains) for which the technical pitfalls of classical methodologies required stringent criteria to guaranty the reliability of the results. In this paper, we review the methodologies applied to ancient DNA analysis and the perspectives that next-generation sequencing applications provide in this field.
| S-EPMC3390907 | biostudies-other
Project description:Background/aimsThe immune-tolerant (IT) phase of chronic hepatitis B (CHB) patients is not generally indicative of antiviral therapy (AVT). We assessed and compared the risk of hepatocellular carcinoma (HCC) during the IT-phase stringently defined by a low fibrosis-4 (FIB-4) index, compared to that in patients undergoing AVT.MethodsAmong 125 untreated patients that were hepatitis B e-antigen positive, hepatitis B virus-DNA >20,000 IU/mL, with normal alanine aminotransferase level from 2012 to 2018, those with a FIB-4 index of <1.45 were classified into the IT-group. The cumulative probability of HCC was estimated using Kaplan-Meier analysis. All patients were assessed until HCC development (intention-to-treat [ITT] analysis), whereas those suspected of experiencing CHB phase switch were assessed using the per-protocol (PP) and censored at the time of phase switch.ResultsThe cumulative probability of HCC at 1-, 3-, and 5-years among the IT-group was zero, compared to AVT-treated patients with FIB-4 indices <1.45 during the same period: 0.2%, 0.6%, and 1.4%, respectively (P=0.264 for ITT and P=0.533 for PP). Among the initially screened 125 untreated patients, those with a FIB-4 index of ≥1.45 had a higher risk of HCC compared to the IT-group (P=0.005). Furthermore, among AVT-treated patients, those with a FIB-4 index of ≥1.45 had a higher risk of HCC compared to their counterpart (P<0.001).ConclusionThe risk of HCC was negligible in the IT-group stringently defined by a low FIB-4 index. However, given that a higher HCC risk exists among untreated patients with higher FIB-4, appropriate criteria for AVT should be established.
| S-EPMC8046628 | biostudies-literature
Project description:Liver disease and gut dysbiosis are strictly associated, and the pathophysiology of this bidirectional relationship has recently been the subject of several investigations. Growing evidence highlights the link between gut microbiota composition, impairment of the gut-liver axis, and the development or progression of liver disease. Therefore, the modulation of gut microbiota to maintain homeostasis of the gut-liver axis could represent a potential instrument to halt liver damage, modify the course of liver disease, and improve clinical outcomes. Among all the methods available to achieve this purpose, fecal microbiota transplantation (FMT) is one of the most promising, being able to directly reshape the recipient's gut microbial communities. In this review, we report the main characteristics of gut dysbiosis and its pathogenetic consequences in cirrhotic patients, discussing the emerging data on the application of FMT for liver disease in different clinical settings.
| S-EPMC8231596 | biostudies-literature