Apolipoprotein E Mediates Evasion From Hepatitis C Virus Neutralizing Antibodies

Fauvelle, Catherine; Felmlee, Daniel J.; Crouchet, Émilie; Lee, Ji-Young; Heydmann, Laura; Lefèvre, Mathieu; Magrì, Andrea; Hiet, Marie–Sophie; Fofana, Isabel; Habersetzer, François; Foung, Steven K. H.; Milne, Ross W.; Patel, Arvind H.; Vercauteren, Koen; Meuleman, Philip; Zeisel, Mirjam B.; Bartenschlager, Ralf; Schuster, Catherine; Baumert, Thomas F.

doi:10.1053/j.gastro.2015.09.014

Cited by 69 publications

(61 citation statements)

References 38 publications

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“…This quantitative difference in HCVpp and HCVcc neutralization may be explained by the recent demonstration by Fauvelle et al (2016) that ApoE increases HCVcc neutralization resistance.…”

Section: Agreement Between Hcvcc and Hcvpp Neutralizationmentioning

confidence: 99%

Hepatitis C virus resistance to broadly neutralizing antibodies measured using replication-competent virus and pseudoparticles

Wasilewski

Ray

Bailey

2016

Journal of General Virology

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A better understanding of natural variation in neutralization resistance and fitness of diverse hepatitis C virus (HCV) envelope (E1E2) variants will be critical to guide rational development of an HCV vaccine. This work has been hindered by inadequate genetic diversity in viral panels and by a lack of standardization of HCV entry assays. Neutralization assays generally use lentiviral pseudoparticles expressing HCV envelope proteins (HCVpp) or chimeric full-length viruses that are replication competent in cell culture (HCVcc). There have been few systematic comparisons of specific infectivities of E1E2-matched HCVcc and HCVpp, and to our knowledge, neutralization of E1E2-matched HCVpp and HCVcc has never been compared using a diverse panel of human broadly neutralizing monoclonal antibodies (bNAbs) targeting distinct epitopes. Here, we describe an efficient method for introduction of naturally occurring E1E2 genes into a full-length HCV genome, producing replication-competent chimeric HCVcc. We generated diverse panels of E1E2-matched HCVcc and HCVpp and measured the entry-mediating fitness of E1E2 variants using the two systems. We also compared neutralization of E1E2-matched HCVcc and HCVpp by a diverse panel of human bNAbs targeting epitopes across E1E2. We found no correlation between specific infectivities of E1E2-matched HCVcc versus HCVpp, but found a very strong positive correlation between relative neutralization resistance of these same E1E2-matched HCVcc and HCVpp variants. These results suggest that quantitative comparisons of neutralization resistance of E1E2 variants can be made with confidence using either HCVcc or HCVpp, allowing the use of either or both systems to maximize diversity of neutralization panels.

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“…This quantitative difference in HCVpp and HCVcc neutralization may be explained by the recent demonstration by Fauvelle et al (2016) that ApoE increases HCVcc neutralization resistance.…”

Section: Agreement Between Hcvcc and Hcvpp Neutralizationmentioning

confidence: 99%

Hepatitis C virus resistance to broadly neutralizing antibodies measured using replication-competent virus and pseudoparticles

Wasilewski

Ray

Bailey

2016

Journal of General Virology

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“…A recent study showed that binding of ApoE to HCV virions mediates viral evasion from neutralizing antibodies (51). Although the binding of HCV with ApoE intracellularly or extracellularly may have only a slight influence on the virus life cycle, the interaction of either pseudo-viral particles or…”

Section: Discussionmentioning

confidence: 99%

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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“…These include cell-to-cell transmission [150,284], interfering antibodies [279], apolipoprotein E [285], N-linked glycosylation [256,257,286], and a broad neutralization protection mechanism involving shielding by HVR1 [143,259,[287][288][289]. The latter research was spurred by the earlier finding that an HVR1 deleted genotype 1a recombinant was viable in vivo [290], an observation later expanded to different genotype recombinants in cell culture [288].…”

Section: Shielding Of Hcv From Neutralizationmentioning

confidence: 99%

The history of hepatitis C virus (HCV): Basic research reveals unique features in phylogeny, evolution and the viral life cycle with new perspectives for epidemic control

Bukh

2016

Journal of Hepatology

212

173

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The discovery of hepatitis C virus (HCV) in 1989 permitted basic research to unravel critical components of a complex life cycle for this important human pathogen. HCV is a highly divergent group of viruses classified in 7 major genotypes and a great number of subtypes, and circulating in infected individuals as a continuously evolving quasispecies destined to escape host immune responses and applied antivirals. Despite the inability to culture patient viruses directly in the laboratory, efforts to define the infectious genome of HCV resulted in development of experimental recombinant in vivo and in vitro systems, including replicons and infectious cultures in human hepatoma cell lines. And HCV has become a model virus defining new paradigms in virology, immunology and biology. For example, HCV research discovered that a virus could be completely dependent on microRNA for its replication since microRNA-122 is critical for the HCV life cycle. A number of other host molecules critical for HCV entry and replication have been identified. Thus, basic HCV research revealed important molecules for development of host targeting agents (HTA). The identification and characterization of HCV encoded proteins and their functional units contributed to the development of highly effective direct acting antivirals (DAA) against the NS3 protease, NS5A and the NS5B polymerase. In combination, these inhibitors have since 2014 permitted interferon-free therapy with cure rates above 90% among patients with chronic HCV infection; however, viral resistance represents a challenge. Worldwide control of HCV will most likely require the development of a prophylactic vaccine, and numerous candidates have been pursued. Research characterizing features critical for antibody-based virus neutralization and T cell based virus elimination from infected cells is essential for this effort. If the world community promotes an ambitious approach by applying current DAA broadly, continues to develop alternative viral- and host- targeted antivirals to combat resistant variants, and invests in the development of a vaccine, it would be possible to eradicate HCV. This would prevent about 500 thousand deaths annually. However, given the nature of HCV, the millions of new infections annually, a high chronicity rate, and with over 150 million individuals with chronic infection (which are frequently unidentified), this effort remains a major challenge for basic researchers, clinicians and communities.

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Apolipoprotein E Mediates Evasion From Hepatitis C Virus Neutralizing Antibodies

Cited by 69 publications

References 38 publications

Hepatitis C virus resistance to broadly neutralizing antibodies measured using replication-competent virus and pseudoparticles

Hepatitis C virus resistance to broadly neutralizing antibodies measured using replication-competent virus and pseudoparticles

Extracellular Interactions between Hepatitis C Virus and Secreted Apolipoprotein E

The history of hepatitis C virus (HCV): Basic research reveals unique features in phylogeny, evolution and the viral life cycle with new perspectives for epidemic control

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