U.S. Department of Health and Human Services

Liver Diseases Branch

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
Color image depicting the process of iron homeostasis in yeastThis image depicts iron homeostasis in yeast. Proteins expressed as part of the Aft1 and 2 regulon are labeled in black text. The low affinity iron transporters Smf1 and Fet4 are also shown. Genes that are downregulated in iron deficiency are indicated in gray text.Color image depicting the process of iron homeostasis in yeastEnlarge
Color model depicting PCBP1 delivering iron to ferritinThis image depicts a model of PCBP1 delivering iron to ferritin. PCBP1 binds 3 Fe(II) ions and binds to ferritin, delivering the iron for mineralization of the ferritin core.Color model depicting PCBP1 delivering iron to ferritinEnlarge
Color image depicting PCBP iron chaperones in mammalian cellsThis image depicts circulating iron binds to transferrin (Tf), which binds to transferrin receptor (TfR) on the cell surface. Endocytosis internalizes ferric Tf/TfR complex and transferrin releases iron reduced to ferrous form. DMT1 transports ferrous iron to the cytosol. PCBP iron chaperones deliver it to cytosolic iron enzymes. Iron also transfers to mitochondria.Color image depicting PCBP iron chaperones in mammalian cellsEnlarge
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
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
Venopathy as a potential cause of nodular regenerative hyperplasiaVenopathy as a potential cause of nodular regenerative hyperplasia. Nodular regenerative hyperplasia: not all nodules are created equal. Reshamwala PA, Kleiner DE, Heller T. Hepatology. 2006 Jul;44(1):7-14 Venopathy as a potential cause of nodular regenerative hyperplasiaEnlarge
Gross photograph and magnification of a resected specimen showing NRHGross photograph and magnification of a resected specimen showing NRHEnlarge
Graphic representation of platelet slopes from representative patients in a CGD cohort who died or survived to end of followup in a cohort of CGD patientsThe image depicts platelet slopes from patients in a CGD cohort who (a) died and (b) survived to end of follow-up. Hepatic involvement and portal hypertension predict mortality in chronic granulomatous disease. Feld JJ, Hussain N, Wright EC, Kleiner DE, Hoofnagle JH, Ahlawat S, Anderson V, Hilligoss D, Gallin JI, Liang TJ, Malech HL, Holland SM, Heller T. Gastroenterology. 2008 Jun;134(7):1917-26Graphic representation of platelet slopes from representative patients in a CGD cohort who died or survived to end of followup in a cohort of CGD patientsEnlarge
Graph: Survival function estimate with cohort of CGD patients for each of the determinants of mortality based on the Cox proportional hazards modelEstimate of the survival function in a cohort of CGD patients for each of the determinants of mortality based on the Cox proportional hazards model. The curves compare the survival estimates for patients with and without a) declining platelet slope b) ALP elevations and c) a history of liver abscess. Each curve is adjusted for all factors in the multivariable Cox model. d) This figure compares the survival function for patients with all three determinants of mortality with that for patients with none of these factors. Hepatic involvement and portal hypertension predict mortality in chronic granulomatous disease. Feld JJ, Hussain N, Wright EC, Kleiner DE, Hoofnagle JH, Ahlawat S, Anderson V, Hilligoss D, Gallin JI, Liang TJ, Malech HL, Holland SM, Heller T. Gastroenterology. 2008 Jun;134(7):1917-26.Graph: Survival function estimate with cohort of CGD patients for each of the determinants of mortality based on the Cox proportional hazards modelEnlarge
Yeast as a tool to study heme transporters from other species.A yeast strain deficient in heme synthesis (hem1) can only grow when media are supplemented with heme precursor, 5-aminolevulinic acid (ALA), or a high concentration of heme. Expression of the heme transporter HRG4 from the worm C.elegans allows yeast to grow at low heme concentration.Yeast as a tool to study heme transporters from other species.Enlarge
Yeast heme oxygenase Hmx1 regulates heme homeostasisThis is an indirect Immunofluorescence image of Hmx1 in a yeast cell. Hmx1 is localized to the endoplasmic reticulum, a ring-like structure around the nucleus and periphery of the cell. Hmx1-HA was detected with (a) an anti-HA antibody, (b) a nucleus stained with DAPI, and (c) a merged image.Yeast heme oxygenase Hmx1 regulates heme homeostasisEnlarge
Heme homeostasis in the eukaryotic cell is a balance of synthesis, distribution, and degradation.This is a simplified scheme of heme homeostasis in the eukaryotic cell. The final step of heme biosynthesis, the ferrochelatase (FECH) reaction, takes place in the mitochondria. Newly synthesized heme is used for assembly of cytochomes (CytC) and other heme proteins located in the cytoplasm, endoplasmic reticulum (ER), lysosomes, and nucleus. The degradation of heme to the iron, biliverdin (BV), and carbon monoxide is catalyzed by heme oxygenase associated with the ER. Heme uptake and heme export are mediated by the function of the plasma membrane heme transporters. Question marks signal unexplored pathways of intracellular heme transfer.Heme homeostasis in the eukaryotic cell is a balance of synthesis, distribution, and degradation.Enlarge