Longterm Outcome of Therapeutic Vaccination with a Third Generation Pre-S/S HBV Vaccine (PreHevbrio) of Chronically HBV Infected Patients.

Several antiviral treatment regimens for chronic hepatitis B (CHB) virus infection have been shown to be effective in suppressing viral load and reducing the risk of hepatocellular injury and its complications. It has been hypothesized that high levels of circulating HBV surface antigen(s) may lead to immune tolerance against HBV and contribute to chronic carriership. Conversely, low-level HBsAg may create a window for the reconstitution of an HBV-specific immune response through vaccination and control of infection.

Early application of IFNγ mediated the persistence of HBV in an HBV mouse model.

The antiviral activity of interferon gamma (IFNγ) against hepatitis B virus (HBV) was demonstrated both in vivo and in vitro in a previous study. IFNγ can suppress HBV replication by accelerating the decay of replication-competent nucleocapsids of HBV. However, in this study, we found that the direct application of the mouse IFNγ (mIFNγ) expression plasmid to the liver of an HBV hydrodynamic injection (HI) mouse model led to the persistence of HBV, as indicated by sustained HBsAg and HBeAg levels in the serum as well as an increased percentage of the HBsAg positive mice, whereas the level of HBV DNA in the serum and the expression of HBcAg in the liver were inhibited at the early stage after HI.

Aborted infection of human sodium taurocholate cotransporting polypeptide (hNTCP) expressing woodchuck hepatocytes with hepatitis B virus (HBV).

Due to the limited host range of HBV, research progress has been hindered by the absence of a suitable animal model. The natural history of woodchuck hepatitis virus (WHV) infection in woodchuck closely mirrors that of HBV infection in human, making this species a promising candidate for establishing both in vivo and in vitro HBV infection models. Therefore, this animal may be a valuable species to evaluate HBV vaccines and anti-HBV drugs.

HAMdetector: a Bayesian regression model that integrates information to detect HLA-associated mutations.

Motivation: A key process in anti-viral adaptive immunity is that the human leukocyte antigen (HLA) system presents epitopes as major histocompatibility complex I (MHC I) protein-peptide complexes on cell surfaces and in this way alerts CD8+ cytotoxic T-lymphocytes (CTLs). This pathway exerts strong selection pressure on viruses, favoring viral mutants that escape recognition by the HLA/CTL system. Naturally, such immune escape mutations often emerge in highly variable viruses, e.

A Mathematical Analysis of HDV Genotypes: From Molecules to Cells.

Hepatitis D virus HDV) is classified according to eight genotypes. The various genotypes are included in the HDVdb database, where each HDV sequence is specified by its genotype. In this contribution, a mathematical analysis is performed on RNA sequences in HDVdb.

Reply to the Letter of Charre et al. "Mis-Genotyping of Some Hepatitis D Virus Genotype 2 and 5 Sequences Using HDVdb".

We thank Charre and colleagues for spotting the mis-annotation of sequences in our database, which was caused by human error [...

HDVdb: A Comprehensive Hepatitis D Virus Database.

Hepatitis D virus (HDV) causes the most severe form of viral hepatitis, which may rapidly progress to liver cirrhosis and hepatocellular carcinoma (HCC). It has been estimated that 15-20 million people worldwide are suffering from the chronic HDV infection. Currently, no effective therapies are available to treat acute or chronic HDV infection.

Kinetics of hepatitis B surface antigen quasispecies during REP 2139-Ca therapy in HBeAg-positive chronic HBV infection.

Chronic HBV infection results in various clinical manifestations due to different levels of immune response. In recent years, hepatitis B treatment has improved by long-term administration of nucleos(t)ide analogues (NUCs) and peg-interferon. Nucleic acid polymers (NAPs; REP 2139-Ca and REP 2139-Mg) are new antiviral drugs that block the assembly of subviral particles, thus preventing the release of HBsAg and allowing its clearance and restoration of functional control of infection when combined with various immunotherapies.

Genetic diversity of hepatitis D virus genotype-1 in Europe allows classification into subtypes.

Hepatitis delta virus (HDV) is an RNA virus which leads to both acute and chronic forms of hepatitis. At present, HDV isolates have been classified into eight major genotypes distributed over different geographical regions. Recent increase in HDV sequences in Europe and worldwide has enabled us to revisit the taxonomic classification of HDV.

Mutations in Hepatitis D Virus Allow It to Escape Detection by CD8 T Cells and Evolve at the Population Level.

Background & Aims: Hepatitis D virus (HDV) superinfection in patients with hepatitis B virus (HBV) is associated with rapid progression to liver cirrhosis and hepatocellular carcinoma. Treatment options are limited, and no vaccine is available. Although HDV-specific CD8 T cells are thought to control the virus, little is known about which HDV epitopes are targeted by virus-specific CD8 T cells or why these cells ultimately fail to control the infection.

Induction of herpes simplex virus type 1 cell-to-cell spread inhibiting antibodies by a calcium phosphate nanoparticle-based vaccine.

Herpes simplex viruses 1 and 2 are among the most ubiquitous human infections and persist lifelong in their host. Upon primary infection or reactivation from ganglia, the viruses spread by direct cell-cell contacts (cell-to-cell spread) and thus escape from the host immune response. We have developed a monoclonal antibody (mAb 2c), which inhibits the HSV cell-to-cell spread, thereby protecting from lethal genital infection and blindness in animal models.

Variants of hepatitis B virus surface antigen observed during therapy with nucleic acid polymer REP 2139-Ca have no influence on treatment outcome and its detection by diagnostic assays.

The treatment of patients suffering from HBeAg-positive chronic hepatitis B with REP 2139-Ca resulted in potent reductions in HBsAg and HBV DNA, seroconversion to anti-HBs and the establishment of functional control of infection. In this cohort of 12 patients, we investigated whether differences between HBsAg sequences might explain the lack of response to REP 2139-Ca observed in 3 of 12 patients. We also assessed if the reduction or complete loss of HBsAg in serum observed during therapy were caused by mutations in the "a" determinant preventing the detection of HBsAg by standard diagnostic assays.

Overcoming immune tolerance in chronic hepatitis B by therapeutic vaccination.

The currently used nucleoside analogs (i.e. entecavir and tenofovir) with high barrier-to-resistance efficiently suppress viral replication, limit inflammation and reduce the sequelae of chronic hepatitis B, but cannot cure the disease and thus have to be applied long-term.

Amino Acid Substitutions within HLA-B*27-Restricted T Cell Epitopes Prevent Recognition by Hepatitis Delta Virus-Specific CD8 T Cells.

Virus-specific CD8 T cell response seems to play a significant role in the outcome of hepatitis delta virus (HDV) infection. However, the HDV-specific T cell epitope repertoire and mechanisms of CD8 T cell failure in HDV infection have been poorly characterized. We therefore aimed to characterize HDV-specific CD8 T cell epitopes and the impacts of viral mutations on immune escape.

TLR2 Stimulation Strengthens Intrahepatic Myeloid-Derived Cell-Mediated T Cell Tolerance through Inducing Kupffer Cell Expansion and IL-10 Production.

Hepatic APCs play a critical role in promoting immune tolerance in the liver. Recently, we have demonstrated that TLR2 stimulation on liver sinusoidal endothelial cells reverted their suppressive properties to induce T cell immunity. However, there is a paucity of information about how TLR2 stimulation modulates the immunological function of other hepatic APCs.

A Therapeutic Antiviral Antibody Inhibits the Anterograde Directed Neuron-to-Cell Spread of Herpes Simplex Virus and Protects against Ocular Disease.

Herpes simplex virus (HSV) is a leading cause of blindness and viral encephalitis in the developed world. Upon reactivation from sensory neurons, HSV returns via axonal transport to peripheral tissues where it causes, e.g.

Activity of nucleic acid polymers in rodent models of HBV infection.

Nucleic acid polymers (NAPs) block the release of HBsAg from infected hepatocytes. These compounds have been previously shown to have the unique ability to eliminate serum surface antigen in DHBV-infected Pekin ducks and achieve multilog reduction of HBsAg or HBsAg loss in patients with chronic HBV infection and HBV/HDV coinfection. In ducks and humans, the blockage of HBsAg release by NAPs occurs by the selective targeting of the assembly and/or secretion of subviral particles (SVPs).

Antibody-based immunotherapy of aciclovir resistant ocular herpes simplex virus infections.

The increasing incidence of aciclovir- (ACV) resistant strains in patients with ocular herpes simplex virus (HSV) infections is a major health problem in industrialized countries. In the present study, the humanized monoclonal antibody (mAb) hu2c targeting the HSV-1/2 glycoprotein B was examined for its efficacy towards ACV-resistant infections of the eye in the mouse model of acute retinal necrosis (ARN). BALB/c mice were infected by microinjection of an ACV-resistant clinical isolate into the anterior eye chamber to induce ARN and systemically treated with mAb hu2c at 24h prior (pre-exposure prophylaxis) or at 24, 40, and 56h after infection (post-exposure immunotherapy).

Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase 2 trial.

Background: REP 2139 clears circulating hepatitis B virus (HBV) surface antigen (HBsAg), enhancing the restoration of functional control of HBV infection by immunotherapy. We assessed the safety and efficacy of REP 2139 and pegylated interferon alfa-2a in patients with chronic HBV and hepatitis D virus (HDV) co-infection.

Methods: In this open-label, non-randomised, phase 2 trial, patients aged 18-55 years, who were treatment naive, hepatitis B e antigen [HBeAg] negative, anti-hepatitis D antigen [HDAg] positive, and HDV RNA positive, with serum HBsAg concentrations of more than 1000 IU/mL, and a history of HDV infection for 6 months or more before treatment, were recruited at Toma Ciorbă Hospital of Infectious Diseases in Chișinău, Moldova.

Low hepatitis B virus-specific T-cell response in males correlates with high regulatory T-cell numbers in murine models.

Unlabelled: Hepatitis B virus (HBV) infection shows significant gender-related differences in pathogenesis, disease progression, and development of hepatocellular carcinoma. The gender-associated differences in HBV replication and viral protein levels may be associated with distinct HBV-specific immune responses in the host. In the present study, we examined the impact of gender on HBV-specific immune responses in two different mouse models representing transient and persistent hepadnaviral infection; hydrodynamic injection with the HBV genome mimicked acute HBV infection, whereas the efficacy of therapeutic vaccination was studied in the woodchuck hepatitis virus transgenic mouse model.

Molecular cloning, characterization and expression analysis of Tim-3 and Galectin-9 in the woodchuck model.

In recent years, a critical role for T cell immunoglobulin mucin domain 3 (Tim-3) and its ligand Galectin-9 (Gal-9) has emerged in infectious disease, autoimmunity and cancer. Manipulating this immune checkpoint may have immunotherapeutic potential and could represent an alternative approach for improving immune responses to viral infections and cancer. The woodchuck (Marmot monax) infected by woodchuck hepatitis virus (WHV) represents an informative animal model to study HBV infection and HCC.

Transcriptome Analysis and Comparison of Marmota monax and Marmota himalayana.

The Eastern woodchuck (Marmota monax) is a classical animal model for studying hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) in humans. Recently, we found that Marmota himalayana, an Asian animal species closely related to Marmota monax, is susceptible to woodchuck hepatitis virus (WHV) infection and can be used as a new mammalian model for HBV infection. However, the lack of genomic sequence information of both Marmota models strongly limited their application breadth and depth.

Molecular cloning, characterization and expression analysis of TGF-β and receptor genes in the woodchuck model.

Transforming growth factor beta (TGF-β) is an important cytokine with pleiotropic regulatory functions in the immune system and in the responses against viral infections. TGF-β acts on a variety of immune cells through the cell surface TGF-β receptor (University of Duisburg-EssenTGFBR). The woodchuck has been used as a biomedical model for studies of obesity and energy balance, endocrine and metabolic function, cardiovascular, cerebrovascular and neoplastic disease.