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Hepatitis C Virus (HCV)-Apolipoprotein Interactions and Immune Evasion and Their Impact on HCV Vaccine Design

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Review

Hepatitis C Virus (HCV)-Apolipoprotein Interactions and Immune Evasion and Their Impact on HCV Vaccine Design

Florian Wrensch et al. Front Immunol.

Abstract

With more than 71 million people chronically infected, hepatitis C virus (HCV) is one of the leading causes of liver disease and hepatocellular carcinoma. While efficient antiviral therapies have entered clinical standard of care, the development of a protective vaccine is still elusive. Recent studies have shown that the HCV life cycle is closely linked to lipid metabolism. HCV virions associate with hepatocyte-derived lipoproteins to form infectious hybrid particles that have been termed lipo-viro-particles. The close association with lipoproteins is not only critical for virus entry and assembly but also plays an important role during viral pathogenesis and for viral evasion from neutralizing antibodies. In this review, we summarize recent findings on the functional role of apolipoproteins for HCV entry and assembly. Furthermore, we highlight the impact of HCV-apolipoprotein interactions for evasion from neutralizing antibodies and discuss the consequences for antiviral therapy and vaccine design. Understanding these interactions offers novel strategies for the development of an urgently needed protective vaccine.

Keywords: ApoE; apolipoproteins; hepatitis C virus; lipo-viro-particle; neutralizing antibodies; viral evasion.

Figures

Figure 1
Figure 1
Model of the hepatitis C virus (HCV) lipo-viro-particle (LVP). The HCV particle consists of an icosahedral capsid, formed by the viral core protein, containing the positive-stranded viral RNA. The nucleocapsid is surrounded by an endoplasmic reticulum-derived envelop in which E1 and E2 glycoproteins are embedded. The highly infectious HCV particle corresponds to a hybrid particle composed of very-low-density lipoprotein (VLDL) components and viral components named LVP. The different apolipoproteins classically associated with VLDL and LVP are illustrated on this picture (ApoB-100 and the exchangeable apolipoproteins ApoE and ApoCs).
Figure 2
Figure 2
Role of apolipoproteins during early steps of hepatitis C virus (HCV) entry. The first step of HCV entry consists of the interaction between lipo-viro-particle (LVP)-associated ApoE, the heparan sulfate proteoglycans (HSPGs), and the low-density lipoprotein receptor (LDLR). Subsequently, the LVP interacts with the scavenger receptor class B type I (SR-BI) through ApoE and ApoB (not illustrated). The cholesterol transfer activity of SR-BI allows E2 exposure and binding of E2 to SR-BI and the tetraspanin CD81. Binding on CD81 activates the epithelial growth factor receptor (EGFR) signaling pathway and interaction between CD81 and claudin 1 (CLDN1) that triggers HCV entry.
Figure 3
Figure 3
Role of apolipoproteins in hepatitis C virus (HCV) morphogenesis. HCV assembly takes place at the surface of endoplasmic reticulum (ER)-derived membranes in close proximity to lipid droplets (LD). Core protein associates with viral RNA to form the nucleocapsid. The nucleocapsid buds at the ER membrane where E1 and E2 glycoproteins are anchored and afterward associate with nascent LD to acquire ApoE and ApoC. This step is facilitated by the interaction between ApoE and the non-structural (NS) viral protein NS5A as well as by the interaction between ApoE and the glycoproteins E1 and E2. In parallel, ApoB is lipidated by the microsomal triglyceride transfer protein (MTP) to generate very-low density lipoprotein (VLDL) precursors. The nascent HCV particle associates with these precursors by an unknown mechanism to generate mature lipo-viro-particles (LVPs).

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