1. Roles of Lipoproteins and Apolipoproteins in Particle Formation of Hepatitis C Virus 
Takasuke Fukuhara, Chikako Ono, Francesc Puig-Basagoiti, Yoshiharu Matsuura 
Trends in Microbiology 
Volume 23, Issue 10, Pages (October 2015)
DOI: /j.tim
Copyright © 2015 Elsevier Ltd Terms and Conditions

2. Figure 1
Entry, Replication, and Assembly of Hepatitis C Virus (HCV). HCV particles are trapped by heparan sulfate proteoglycans (HSPG) on the cell surface and internalized into the cytoplasm through an endocytosis upon interaction with various receptor candidates, including human CD81 (hCD81), dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN)/liver/lymph node-specific intercellular adhesion molecule-3-grabbing integrin (L-SIGN), low-density-lipoprotein receptor (LDLR), scavenger receptor class B type 1 (SR-B1), epidermal growth factor receptor (EGFR)/Ephrin receptor A2 (EphA2), claudin-1 (CLDN1), occludin (OCLN), and Niemann–Pick C1-like 1 (NPC1L1). After uncoating, viral RNA is translated into a precursor polyprotein which is cleaved by host and viral proteases to generate three structural and seven nonstructural proteins. A membrane-associated replication complex, composed of nonstructural proteins, host proteins, and viral RNA, is formed on the endoplasmic reticulum (ER) membrane. Replicated RNA and core proteins are recruited to the surface of the lipid droplet, and viral capsids are formed at the contact site with the ER membrane. Viral capsids acquire envelope proteins through budding into the ER lumen. Very-low-density lipoprotein (VLDL)-associated proteins, including apolipoprotein B (ApoB, in blue), Apolipoprotein E (ApoE, in red), and microsomal triglyceride transfer protein (MTP), participate in the maturation of infectious HCV particles in the ER lumen.
Trends in Microbiology  , DOI: ( /j.tim )
Copyright © 2015 Elsevier Ltd Terms and Conditions

3. Figure 2 Key Figure: Production of Lipoviroparticles (LVPs)
Two putative pathways might be involved in the formation of lipid-rich LVPs. In the first pathway, lipoproteins,including very-low-density lipoprotein (VLDL) are fused to viral particles to generate LVPs after the secretion of enveloped hepatitis C virus (HCV) particles into the endoplasmic reticulum (ER) lumen. In this model, exchangeable apolipoproteins are mainly supplied by the lipoproteins (red arrow). In the second pathway, cholesterol and triglyceride (TG) are incorporated into HCV particles as well as lipoproteins during their budding process. Binding of apolipoprotein B (ApoB) and exchangeable apolipoproteins confers stability and hydrophilicity to LVPs (blue arrow). Abbreviations: ApoA, apolipoprotein A; ApoB100, apolipoprotein B100; ApoC, apolipoprotein C; ApoE, apolipoprotein E.
Trends in Microbiology  , DOI: ( /j.tim )
Copyright © 2015 Elsevier Ltd Terms and Conditions

4. Figure 3
Apolipoproteins Containing Amphipathic α-Helices Facilitate the Formation of Infectious Hepatitis C Virus (HCV) Particles. The three-dimensional structures of apolipoprotein A1 (ApoA1) [Protein Data Bank (PDB) ID 3R2P; apolipoprotein C1 (ApoC1) (PDB ID 1IOJ; apolipoprotein D (ApoD) (PDB ID 2HZR; apolipoprotein E (ApoE) (PDB ID 2L7B; apolipoprotein H (ApoH) (PDB ID 1C1Z; and apolipoprotein M (ApoM) (PDB ID 2XKL; are also shown in a ribbon model. The helices and sheets in the apolipoproteins are colored red and cyan, respectively. Amphipathic α-helices are tandemly repeated in exchangeable apolipoproteins, including ApoA1, ApoC1, and ApoE, while the structures of ApoD, ApoH, and ApoM have no similarity to those of the exchangeable apolipoproteins. Apolipoproteins containing amphipathic α-helices facilitate efficient formation of infectious HCV particles. On the other hand, other apolipoproteins are not involved in the formation of HCV particles.
Trends in Microbiology  , DOI: ( /j.tim )
Copyright © 2015 Elsevier Ltd Terms and Conditions

5. Figure 4
In vivo Kinetics of Lipoproteins. Stored triglyceride (TG) in lipid droplets (LD) is incorporated into very-low-density lipoprotein (VLDL) by the action of microsomal triglyceride transfer protein (MTP). TG in VLDL and chylomicrons is hydrolysed by lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) to generate low-density lipoprotein (LDL). The apolipoprotein A (ApoA), apolipoprotein C (ApoC), and apolipoprotein E (ApoE) but not apolipoprotein B (ApoB) are exchanged among lipoproteins. For the entry into hepatocytes, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) utilize low-density lipoprotein receptor (LDLR) and scavenger receptor class B type 1 (SR-B1) as receptors, respectively. Abbreviation: CM, chylomicron.
Trends in Microbiology  , DOI: ( /j.tim )
Copyright © 2015 Elsevier Ltd Terms and Conditions

6. Figure 5
Hepato-tropism of Hepatitis C Virus (HCV) Infection and Pathogenesis. Chronic infection of HCV induces liver cirrhosis and hepatocellular carcinoma (HCC) at high rates. On the other hand, extrahepatic manifestations (EHM), including malignant lymphoma and autoimmune disease, are sometimes observed in chronic hepatitis C patients. In hepatocytes, several entry factors, miR-122 and exchangeable apolipoproteins are highly expressed and facilitate the efficient propagation of HCV. On the other hand, in nonhepatic cells, expression levels of scavenger receptor class B type 1 (SR-B1), Claudin 1 (CLDN1) and Niemann–Pick C1-like 1 (NPC1L1) are lower than those in hepatocytes. In addition, the deficiency of miR-122 inhibits the replication of HCV, and a low level of expression of exchangeable apolipoproteins impairs the formation of infectious HCV particles.
Trends in Microbiology  , DOI: ( /j.tim )
Copyright © 2015 Elsevier Ltd Terms and Conditions

7. Figure 6
Expression of Apolipoproteins in Tissues. The relative mRNA expression of the apolipoproteins in several tissues was determined using the NextBio Body Atlas application [86]. The median expression was calculated across all 128 human tissues from 1068 arrays using the Affymetrix GeneChip Human Genome U133 Plus 2.0 Array. Relative mRNA expression of each gene in each tissue was calculated dividing its expression by the median expression from all 128 human tissues.
Trends in Microbiology  , DOI: ( /j.tim )
Copyright © 2015 Elsevier Ltd Terms and Conditions