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Neutralizing antibodies represent a key component of immune control in many viral infections. For a long time, these antibodies were thought to play a marginal role in hepatitis C virus (HCV) infection, and that cellular immune responses are more critical in immune control. The development of model systems to study HCV entry and significant advances in our understanding of viral entry and escape, have reenergized interest in the potential of protective neutralizing antibodies against HCV. Yet further investigations are needed to completely elucidate the role of neutralizing antibodies, recent data on their clinical impact during HCV infection and recent development of monoclonal antibodies capable of neutralizing autologous and heterologousHCVstrains, represent our best hope for the development of novel therapeutic or preventive vaccine.

Liver chronic infections by hepatotropic viruses remain a major health problem worldwide. Hepatitis B, C, and D viruses (HBV, HCV, HDV) are responsible for severe liver damages. In spite of different viral structures and life cycles, they all exclusively infect the liver, suggesting the presence of hepatocyte-specific factors allowing viral infection. If viral life cycles are already well described, the molecular interactions between liver host factors and viral structures remain elusive. Host factors represent promising targets for the development of new antiviral strategies. Recently, the bile acid transporter NTCP, mainly expressed at the cell surface of hepatocytes, was described as the first bona-fide receptor for both HBV and HDV. Moreover, this solute carrier was shown to be involved in the modulation of HCV entry, confirming its importance in liver infection by hepatic viruses. This review summarizes the interactions between NTCP and these three major viruses.

Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies. journal article review 2020 Apr 03 2020 04 03 imported

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The E2 envelope glycoprotein is the primary target of human neutralizing antibody response against hepatitis C virus (HCV), and is thus a major focus of vaccine and immunotherapeutics efforts. There is emerging evidence that E2 is a highly complex, dynamic protein with residues across the protein that are modulating antibody recognition, local and global E2 stability, and viral escape. To comprehensively map these determinants, we performed global E2 alanine scanning with a panel of 16 human monoclonal antibodies (hmAbs), resulting in an unprecedented dataset of the effects of individual alanine substitutions across the E2 protein (355 positions) on antibody recognition. Analysis of shared energetic effects across the antibody panel identified networks of E2 residues involved in antibody recognition and local and global E2 stability, as well as predicted contacts between residues across the entire E2 protein. Further analysis of antibody binding hotspot residues defined groups of residues essential for E2 conformation and recognition for all 14 conformationally dependent E2 antibodies and subsets thereof, as well as residues that enhance antibody recognition when mutated to alanine, providing a potential route to engineer E2 vaccine immunogens. By incorporating E2 sequence variability, we found a number of E2 polymorphic sites that are responsible for loss of neutralizing antibody binding. These data and analyses provide fundamental insights into antibody recognition of E2, highlighting the dynamic and complex nature of this viral envelope glycoprotein, and can serve as a reference for development and rational design of E2-targeting vaccines and immunotherapeutics.