Extracellular Interactions between Hepatitis C Virus and Secreted Apolipoprotein E

Abstract

Interactions between hepatitis C virus (HCV) and lipoproteins in humans play an important role in the efficient establishment of chronic infection. Apolipoprotein E (ApoE) on the HCV envelope mediates virus attachment to host cells as well as immune evasion. This interaction is thought to occur in hepatocytes, as ApoE plays dual functions in HCV assembly and maturation as well as cell attachment. In the present study, we found that secreted ApoE (sApoE) can also bind to viral particles via its C-terminal domain after HCV is released from the cell. Furthermore, the binding affinity of interactions between the sApoE N terminus and cell surface receptors affected HCV infectivity in a dose-dependent manner. The extracellular binding of sApoE to HCV is dependent on HCV envelope proteins, and recombinant HCV envelope proteins are also able to bind to sApoE. These results suggest that extracellular interactions between HCV and sApoE may potentially complicate vaccine development and studies of viral pathogenesis.IMPORTANCE End-stage liver disease caused by chronic HCV infection remains a clinical challenge, and there is an urgent need for a prophylactic method of controlling HCV infection. Because host immunity against HCV is poorly understood, additional investigations of host-virus interactions in the context of HCV are important. HCV is primarily transmitted through blood, which is rich in lipoproteins. Therefore, it is of interest to further determine how HCV interacts with lipoproteins in human blood. In this study, we found that secreted ApoE (sApoE), an exchangeable component found in lipoproteins, participates in extracellular interactions with HCV virions. More significantly, different variants of sApoE differentially affect HCV infection efficiency in a dose-dependent manner. These findings provide greater insight into HCV infection and host immunity and could help propel the development of new strategies for preventing HCV infection.KEYWORDS CRISPR-Cas9, hepatitis C virus, infectivity, secreted apolipoprotein E, envelope protein A pproximately 170 million people are chronically infected with hepatitis C virus (HCV) worldwide (1). Most HCV infections become chronic in humans and can progress to hepatic fibrosis, cirrhosis, or even hepatocellular carcinoma (2). This process is normally accompanied by high morbidity due to extrahepatic manifestations, including mixed cryoglobulinemia, diabetes mellitus, and atherosclerosis (3). In most developing countries, the current standard treatment for chronic hepatitis C is a combination of pegylated interferon with ribavirin (4), although unfortunately, the effects are unsatisfactory. Recently, highly efficacious directacting antiviral drugs (DAAs) have been approved; however, their clinical benefits

Delayed by Design: Role of Suboptimal Signal Peptidase Processing of Viral Structural Protein Precursors in Flaviviridae Virus Assembly

“…The physical proximity between the compartments for HCV RNA replication and assembly should facilitate nucleocapsid-containing virion assembly, preceding infectious HCV lipoviroparticle (LVP) formation by acquiring lipoprotein components including the lipids and apolipoproteins, such as ApoB and ApoE [ 76 , 77 , 78 , 79 ]. Interestingly, acquiring ApoE and lipids in the HCV virions could occur intracellularly during HCV egress following nucleocapsid formation and envelopment [ 80 ] or after viral secretion to the extracellular space [ 81 , 82 , 83 ]. For additional insight regarding HCV assembly and maturation, readers should refer to previous reviews [ 8 , 58 , 84 ].…”

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

“…Finally, it was shown that extracellular ApoE play a role in LVP maturation. Mature LVP are highly enriched in ApoE compared with normal VLDL ( 18 , 57 ). Recent studies related that ApoE exchange occurs between LVP and circulating lipoproteins.…”

“…Recent studies related that ApoE exchange occurs between LVP and circulating lipoproteins. This process is important to maintain a high ApoE level on the LVP surface that is required for an efficient infectivity and facilitates escape host immunity ( 57 – 59 ). Indeed, a study performed in our lab demonstrated that association of ApoE with E2 helps the virus to escape from patient neutralizing antibodies ( 60 ).…”

Inhibition Mechanisms of Hepatitis C Virus Infection by Caffeic Acid and Tannic Acid

“…It is well known that formation of a complex of HCV particles and ApoE is critical for viral infectivity. [27][28][29] These complexes, named lipoviroparticles (LVPs), enhance the interaction between HCV particles and cellular receptors, including heparan sulfate proteoglycans 34) such as syndecan 4, 35) low density lipoprotein (LDL) receptors, 36) and scavenger receptors class B type I, 37) resulting in efficient viral attachment to and entry into host cells. 28,38) We demonstrated that CA interrupted the association between ApoE and HCV particles ( Fig.…”

“…CA Prevented the Interaction Between HCV Particles and ApoE It is well known that the formation of a complex between HCV particles and ApoE is critical for the infectivity of HCV particles. [27][28][29][30][31][32] Therefore, we explored the possibility that CA interrupts the interaction between HCV particles and ApoE. The amounts of HCV particles bound to ApoE in the presence or absence of CA or TA were determined by im- munoprecipitation assays using anti-ApoE antibody (Fig.…”