Apolipoprotein E-ε4 protects against severe liver disease caused by hepatitis C virus

Wozniak, Matthew A.; Itzhaki, Ruth F.; Faragher, E. B.; James, Martin; Ryder, Stephen; Irving, William L.

doi:10.1053/jhep.2002.34745

Cited by 170 publications

(149 citation statements)

References 30 publications

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“…The advantage for HCV to use a host protein for its cell entry is to mask the host immune response so that it can establish a persistent infection. This concept is supported by recent findings derived from genetic studies that the outcome of HCV infection correlated with apoE polymorphism (44,60). The apoE3 allele was found to correlate with persistent HCV infection (44), whereas the apoE2 and apoE4 alleles were associated with a reduced likelihood of chronic HCV infection (44,60).…”

Section: Vol 81 2007 Requirement Of Apoe For Hcv Infectivity and Prsupporting

confidence: 57%

Human Apolipoprotein E Is Required for Infectivity and Production of Hepatitis C Virus in Cell Culture

Chang

Jiang

Cai

et al. 2007

J Virol

381

392

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Recent advances in reverse genetics of hepatitis C virus (HCV) made it possible to determine the properties and biochemical compositions of HCV virions. Sedimentation analysis and characterization of HCV RNAcontaining particles produced in the cultured cells revealed that HCV virions cover a large range of heterogeneous densities in sucrose gradient. The fractions of low densities are infectious, while the higher-density fractions containing the majority of HCV virion RNA are not. HCV core protein and apolipoprotein B and apolipoprotein E (apoE) were detected in the infectious HCV virions. The level of apoE correlates very well with HCV infectivity. Both apoE-and HCV E2-specific monoclonal antibodies precipitated HCV, demonstrating that HCV virions contain apoE and E2 proteins. apoE-specific monoclonal antibodies efficiently neutralized HCV infectivity in a dose-dependent manner, resulting in a reduction of infectious HCV by nearly 4 orders of magnitude. The knockdown of apoE expression by specific small interfering RNAs (siRNAs) remarkably reduced the levels of intracellular as well as secreted HCV virions. The apoE siRNA suppressed HCV production by more than 100-fold at 50 nM. These findings demonstrate that apoE is required for HCV virion infectivity and production, suggesting that HCV virions are assembled as apoE-enriched lipoprotein particles. Our findings also identified apoE as a novel target for discovery and development of antiviral drugs and monoclonal antibodies to suppress HCV virion formation and infection.Hepatitis C virus (HCV) is a major cause of liver diseases, affecting approximately 170 million people worldwide (59). Most (ϳ85%) acutely HCV-infected individuals become chronic carriers that can develop cirrhosis and hepatocellular carcinoma (50). HCV is an enveloped RNA virus with a singlestrand and positive-sense RNA genome and is classified as Hepacivirus in the Flaviviridae family (47). The genomic RNA consists of a long open reading frame and relatively short untranslated regions (UTR) at the 5Ј and 3Ј ends (11,32,36,46,53). The 5Ј and 3Ј UTR contain cis-acting RNA elements important for HCV polyprotein translation and RNA replication (16-18, 38, 39, 61, 62). The translation of HCV polyprotein is mediated by the internal ribosomal entry site within the 5Ј UTR (46, 58). Upon translation, the HCV polyprotein is cleaved by cellular peptidases and viral proteases into different viral proteins in the order of C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B (36, 38). A number of studies demonstrated that the NS3 to NS5B proteins are sufficient for HCV RNA replication (4, 6, 37), which occurs in the membranebound replication complex consisting of HCV RNA and proteins as well as cellular proteins (13,14,42,57). The core and NS5B coding regions also contain cis-acting RNA elements important for HCV RNA replication and regulation (40,63). Last, the newly synthesized HCV proteins and genomic RNA are packaged to form progeny virus particles. However, the molecular aspects underlying HCV virion assembly, matur...

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Section: Vol 81 2007 Requirement Of Apoe For Hcv Infectivity and Prsupporting

confidence: 57%

Human Apolipoprotein E Is Required for Infectivity and Production of Hepatitis C Virus in Cell Culture

Chang

Jiang

Cai

et al. 2007

J Virol

381

392

View full text Add to dashboard Cite

show abstract

“…We reported that HCV also binds to extracellular sApoE and found that both sApoE protein concentration and variant type affect virus infectivity. For example, sApoE4 caused a reduction in HCV infectivity, a finding that is consistent with clinical data indicating that the ApoE4 genotype is associated with a degree of resistance against HCV infection (48,49). During the preparation of the manuscript, another similar result was also reported (50).…”

Section: Discussionsupporting

confidence: 83%

Extracellular Interactions between Hepatitis C Virus and Secreted Apolipoprotein E

et al. 2017

J Virol

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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

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“…NO is critical for synapses [100][101][102][103] (b) Increasing cholesterol availability to the developing brain, cholesterol as a glial synaptogenic factor and indirect trigger for myelination in the brain [34,104,28,105,27] Infection (a) ApoE4 by downregulating LDL receptors may starve enteric pathogens from cholesterol and block proliferation. The LDL-receptor pathway is also highly conserved across the animal kingdom [106][107][108][109][110] (b) ApoE is secreted in a polarized manner by enterocytes, increased by 25-OHcholesterol and decreased by LPS through an LXR α /RXR independent signaling pathway [47].…”

Section: Boxmentioning

confidence: 99%

Role of apolipoprotein E4 in protecting children against early childhood diarrhea outcomes and implications for later development

et al. 2007

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SummaryOur group and others have reported a series of studies showing that heavy burdens of diarrheal diseases in the formative first two years of life in children in urban shantytowns have profound consequences of impaired physical and cognitive development lasting into later childhood and schooling. Based on these previous studies showing that apolipoprotein E4 (APOE4) is relatively common in favela children, we review recent data suggesting a protective role for the APOE4 allele in the cognitive and physical development of children with heavy burdens of diarrhea in early childhood. Despite being a marker for cognitive decline with Alzheimer's and cardiovascular diseases later in life, APOE4 appears to be important for cognitive development under the stress of heavy diarrhea. The reviewed findings provide a potential explanation for the survival advantage in evolution of the thrifty APOE4 allele and raise questions about its implications for human development under life-style changes and environmental challenges.

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Apolipoprotein E-ε4 protects against severe liver disease caused by hepatitis C virus

Cited by 170 publications

References 30 publications

Human Apolipoprotein E Is Required for Infectivity and Production of Hepatitis C Virus in Cell Culture

Human Apolipoprotein E Is Required for Infectivity and Production of Hepatitis C Virus in Cell Culture

Extracellular Interactions between Hepatitis C Virus and Secreted Apolipoprotein E

Role of apolipoprotein E4 in protecting children against early childhood diarrhea outcomes and implications for later development

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