U.S. Department of Health and Human Services

Liver Diseases Virology Section

T. Jake Liang, M.D., Chief

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Systems Biology of Host Factors in HCV Life Cycle

Using the complete HCV replication cycle (from entry to secretion) as a framework, all verified HCV host dependencies from this study were placed based on their predominant subcellular localization and relevance to particular stages of the viral life cycle. In addition, multiple datasets from other HCV siRNA screens and existing publications were mined, explored and integrated into a comprehensive up-to-date dataset of HCV interacting host factors. Computational mapping was performed to reconstitute the map that was further refined manually. HPFs (host proviral factors) are shown in red square, HAFs (host antiviral factors) are shown in green circle. Previously published HCV host dependencies that were also identified in this study are shown in yellow, and other known HCV host factors that were not identified in this study are shown in orange (HPF in circle and HAF in square).

Systems Biology of Host Factors in HCV Life CycleEnlarge
HCV Infection, Interferon Response and Lipid Droplet Biogenesis

A proposed model of innate antiviral response and HCV-induced lipogenesis and LD formation in HCV assembly. HCV can activate two distinct pathways. One is the induction of interferon pathway by interaction of HCV PAMP with RIG-I helicase like receptor (pattern recognition receptor) and the other is activation of lipogenic pathway via stress granule, DDX3X and Ikkα, that facilitates HCV assembly.

HCV Infection, Interferon Response and Lipid Droplet BiogenesisEnlarge
HCV Infection, I-SMAD and Lipid Metabolism

A proposed model for I-SMAD-regulated signaling that enhances HSPG expression, cholesterol uptake and HCV entry. HCV entry is mediated by viral binding to HSPGs, LDLR and SR-BI (and other entry factors, not shown) on the host cell surface, thereby triggering a cassette of signaling to facilitate the internalization of HCV virions. HCV infection also induces the expression of SMAD6 and SMAD7, two I-SMADs of the TGF-β signaling pathway via NF-κB regulation. The I-SMADs translocate to the nucleus and transcriptionally activate the expression HSPG core protein and other cholesterol uptake receptors. Increased expression level of heparin sulfate on the cell surface in turn enhances HCV binding. Additionally, the I-SMADs and HSPGs can be induced by BMP6 and BMP7, the ligands in the BMP/TGF-β pathway. 

HCV Infection, I-SMAD and Lipid MetabolismEnlarge
Schematic of HBV replication and drug targetsThe virus enters the hepatocyte using the sodium taurocholate cotransporting polypeptide as a receptor. cccDNA is generated by repairing the partially double stranded genome in the nucleus, whereupon viral transcription occurs. Encapsidation of the pregenomic RNA occurs in the cytoplasm via a complex interaction of viral and host proteins. Reverse transcription leading to negative and then positive strand synthesis occurs within the viral nucleocapsid. Viral assembly takes place in the ER. “Mature” nucleocapsids undergo assembly and coating with envelope proteins followed by budding and virion secretion into the blood. Potential targets for drug development are highlighted.Schematic of HBV replication and drug targetsEnlarge
3-D structure of HCVThe three-dimensional structure of HCV is visualized and simulated by using electron cryomicroscopy of recombinant HCV-like viral particles.3-D structure of HCVEnlarge
iPSC-derived human hepatocytesHuman hepatocytes, generated from induced pluripotent stem cells derived from a patient, produce and exhibit hepatocyte-specific proteins (albumin) and functions (lipid and glycogen storage, organic anion transport). This regenerative medicine technology can be a valuable strategy for cell-based therapy of liver diseases.iPSC-derived human hepatocytesEnlarge
Induction of steatosis by HCVHCV infection of human hepatocyte-derived cells induces a lipogenic program that results in massive accumulation of lipid droplets (green and yellow structures). This is known as steatosis and is essential for HCV propagation.Induction of steatosis by HCVEnlarge
Hepatitis C Electromicrograph 1Hepatitis C Electromicrograph 1Enlarge
Hepatitis C Electromicrograph 2Hepatitis C Electromicrograph 2Enlarge
Hepatitis C Viral LifecycleHepatitis C Viral LifecycleEnlarge