Innate Antiviral Immune Responses to Hepatitis B Virus

Hepatitis B virus (HBV) is a major cause of acute and chronic hepatitis in humans. As HBV itself is currently viewed as a non-cytopathic virus, the liver pathology associated with hepatitis B is mainly thought to be due to immune responses directed against HBV antigens. The outcome of HBV infection is the result of complex interactions between replicating HBV and the immune system. While the role of the adaptive immune response in the resolution of HBV infection is well understood, the contribution of innate immune mechanisms remains to be clearly defined. The innate immune system represents the first line of defense against viral infection, but its role has been difficult to analyze in humans due to late diagnosis of HBV infection. In this review, we discuss recent advances in the field of innate immunity to HBV infection

La danse du masque noir. Rites funéraires des Mossé du Kadiogo (Burkina Faso)

Les masques dont nous allons étudier l'intervention au cours des rites funéraires sont appelés en moré wan-sablassé, c'est-à-dire « Masques noirs », à cause de la longue « robe » de fibres végétales teintes en noir qui enveloppe et dissimule totalement le corps du danseur. Notre observation a porté sur un groupe d'une dizaine de villages, dans la région de Ziniaré, à quelques soixante kilomètres de Ouagadougou. Le wan-sablassé, chez les Mossé, est nécessairement sacré. Il ne s'exhibe ni « sur..

SPORT: A new sub-nanosecond time-resolved instrument to study swift heavy ion-beam induced luminescence - Application to luminescence degradation of a fast plastic scintillator

We developed a new sub-nanosecond time-resolved instrument to study the dynamics of UV-visible luminescence under high stopping power heavy ion irradiation. We applied our instrument, called SPORT, on a fast plastic scintillator (BC-400) irradiated with 27-MeV Ar ions having high mean electronic stopping power of 2.6 MeV/\mu m. As a consequence of increasing permanent radiation damages with increasing ion fluence, our investigations reveal a degradation of scintillation intensity together with, thanks to the time-resolved measurement, a decrease in the decay constant of the scintillator. This combination indicates that luminescence degradation processes by both dynamic and static quenching, the latter mechanism being predominant. Under such high density excitation, the scintillation deterioration of BC-400 is significantly enhanced compared to that observed in previous investigations, mainly performed using light ions. The observed non-linear behaviour implies that the dose at which luminescence starts deteriorating is not independent on particles' stopping power, thus illustrating that the radiation hardness of plastic scintillators can be strongly weakened under high excitation density in heavy ion environments.Comment: 5 figures, accepted in Nucl. Instrum. Methods

Targeting HCV Entry For Development of Therapeutics

Recent progress in defining the molecular mechanisms of Hepatitis C Virus (HCV) entry affords the opportunity to exploit new viral and host targets for therapeutic intervention. Entry inhibitors would limit the expansion of the infected cell reservoir, and would complement the many replication inhibitors now under development. The current model for the pathway of entry involves the initial docking of the virus onto the cell surface through interactions of virion envelope and associated low density lipoproteins (LDL) with cell surface glycosaminoglycans and lipoprotein receptors, followed by more specific utilization with other hepatocyte membrane proteins: Scavenger Receptor Class B type 1 (SR-BI), CD81, Claudin 1 (CLDN1) and Occludin (OCLN). The use of blockers of these interactions, e.g. specific antibodies, suggests that inhibition of any one step in the entry pathway can inhibit infection. Despite this knowledge base, the tools for compound screening, HCV pseudoparticles (HCVpp) and cell culture virus (HCVcc), and the ability to adapt them to industrial use are only recently available and as a result drug discovery initiatives are in their infancy. Several therapies aiming at modulating the virus envelope to prevent host cell binding are in early clinical testing. The first test case for blocking a cellular co-receptor is an SR-BI modulator. ITX 5061, an orally active small molecule, targets SR-BI and has shown potent antiviral activity against HCVpp and HCVcc. ITX 5061 has exhibited good safety in previous clinical studies, and is being evaluated in the clinic in chronic HCV patients and patients undergoing liver transplantation. Entry inhibitors promise to be valuable players in the future development of curative therapy against HCV

Production of multi-charged phosphorus ions with ecris 'SUPERSHyPIE' at GANIL

The Ganil's Ion Production Group tested the source SUPERSHyPIE123 for theproduction of phosphorus n+ ion beams. The SUPERSHyPIE ecris is used for many testsof multi-charged ion production and supply ion beams for LIMBE4 (low energie beamline). This ion source works with a 14.5ghz RF power injected by a circular waveguide inthe axis of the sourc

Antiviral Therapy for Hepatitis C Virus: Beyond the Standard of Care

Hepatitis C virus (HCV) represents a major health burden, with an estimated 180 million chronically infected individuals worldwide. These patients are at increased risk of developing liver cirrhosis and hepatocellular carcinoma. Infection with HCV is the leading cause of liver transplantation in the Western world. Currently, the standard of care (SoC) consists of pegylated interferon alpha (pegIFN-α) and ribavirin (RBV). However this therapy has a limited efficacy and is associated with serious side effects. Therefore more tolerable, highly potent inhibitors of HCV replication are urgently needed. Both Specifically Targeted Antiviral Therapy for HCV (STAT-C) and inhibitors that are believed to interfere with the host-viral interaction are discussed

Ion sources at GANIL

International audienceThe GANIL produces since many years heavy ion beams with Electron Cyclotron Resonance ion sources. Different facilities have been constructed during the last years in order to allow experiments in a large range of energy (from some tens of kV to 100 MeV/nucleon). The list of available ions has been greatly extended with the construction of the SPIRAL1 facility that produces and accelerates radioactives ions . An overview of the different developments made at GANIL for stable and radioactive ion beam production including the sources for the SPIRAL2 project is given in this paper

Hypoxia-inducible factor 1 alpha-mediated RelB/APOBEC3B down-regulation allows hepatitis B virus persistence

Background and Aims: Therapeutic strategies against HBV focus, among others, on the activation of the immune system to enable the infected host to eliminate HBV. Hypoxia‐inducible factor 1 alpha (HIF1α) stabilization has been associated with impaired immune responses. HBV pathogenesis triggers chronic hepatitis‐related scaring, leading inter alia to modulation of liver oxygenation and transient immune activation, both factors playing a role in HIF1α stabilization. Approach and Results: We addressed whether HIF1α interferes with immune‐mediated induction of the cytidine deaminase, apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B; A3B), and subsequent covalently closed circular DNA (cccDNA) decay. Liver biopsies of chronic HBV (CHB) patients were analyzed by immunohistochemistry and in situ hybridization. The effect of HIF1α induction/stabilization on differentiated HepaRG or mice ± HBV ± LTβR‐agonist (BS1) was assessed in vitro and in vivo. Induction of A3B and subsequent effects were analyzed by RT‐qPCR, immunoblotting, chromatin immunoprecipitation, immunocytochemistry, and mass spectrometry. Analyzing CHB highlighted that areas with high HIF1α levels and low A3B expression correlated with high HBcAg, potentially representing a reservoir for HBV survival in immune‐active patients. In vitro, HIF1α stabilization strongly impaired A3B expression and anti‐HBV effect. Interestingly, HIF1α knockdown was sufficient to rescue the inhibition of A3B up‐regulation and ‐mediated antiviral effects, whereas HIF2α knockdown had no effect. HIF1α stabilization decreased the level of v‐rel reticuloendotheliosis viral oncogene homolog B protein, but not its mRNA, which was confirmed in vivo. Noteworthy, this function of HIF1α was independent of its partner, aryl hydrocarbon receptor nuclear translocator. Conclusions: In conclusion, inhibiting HIF1α expression or stabilization represents an anti‐HBV strategy in the context of immune‐mediated A3B induction. High HIF1α, mediated by hypoxia or inflammation, offers a reservoir for HBV survival in vivo and should be considered as a restricting factor in the development of immune therapies