Hepatitis C Virus Continuously Escapes From Neutralizing Antibody and T-Cell Responses During Chronic Infection In Vivo

Hahn, Thomas von; Yoon, Jae-Cheol; Alter, Harvey J.; Rice, Charles M.; Rehermann, Barbara; Balfe, Peter; McKeating, Jane A.

doi:10.1053/j.gastro.2006.12.008

Cited by 367 publications

(325 citation statements)

References 57 publications

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“…Indeed, the host immune system lags behind the continuous evolution of HCV, allowing the virus to evade humoral immunity. 3,4 However, the escape mechanisms from nAbs during chronic HCV infection are only partially understood. Clearly, the development of an effective vaccine requires a detailed understanding of viral evasion from host immune responses, including nAbs.…”

Section: H Epatitis C Virus (Hcv) Is a Major Health Problem Infectingmentioning

confidence: 99%

Apolipoprotein E Mediates Evasion From Hepatitis C Virus Neutralizing Antibodies

et al. 2016

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BACKGROUND & AIMS:Efforts to develop an effective vaccine against hepatitis C virus (HCV) have been hindered by the propensity of the virus to evade host immune responses. HCV particles in serum and in cell culture associate with lipoproteins, which contribute to viral entry. Lipoprotein association has also been proposed to mediate viral evasion of the humoral immune response, though the mechanisms are poorly defined. METHODS: We used small interfering RNAs to reduce levels of apolipoprotein E (apoE) in cell cultureÀderived HCVÀproducing Huh7.5-derived hepatoma cells and confirmed its depletion by immunoblot analyses of purified viral particles. Before infection of naïve hepatoma cells, we exposed cell cultureÀderived HCV strains of different genotypes, subtypes, and variants to serum and polyclonal and monoclonal antibodies isolated from patients with chronic HCV infection. We analyzed the interaction of apoE with viral envelope glycoprotein 2 and HCV virions by immunoprecipitation. RESULTS: Through loss-of-function studies on patient-derived HCV variants of several genotypes and subtypes, we found that the HCV particle apoE allows the virus to avoid neutralization by patient-derived antibodies. Functional studies with human monoclonal antiviral antibodies showed that conformational epitopes of envelope glycoprotein 2 domains B and C were exposed after depletion of apoE. The level and conformation of virion-associated apoE affected the ability of the virus to escape neutralization by antibodies. CONCLUSIONS: In cell-infection studies, we found that HCV-associated apoE helps the virus avoid neutralization by antibodies against HCV isolated from chronically infected patients. This method of immune evasion poses a challenge for the development of HCV vaccines.

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Section: H Epatitis C Virus (Hcv) Is a Major Health Problem Infectingmentioning

confidence: 99%

Apolipoprotein E Mediates Evasion From Hepatitis C Virus Neutralizing Antibodies

et al. 2016

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“…Hypervariable region 1 is a major decoy that elicits isolate-specific neutralizing antibodies from which the virus can readily escape (11)(12)(13). Antigenic domain A is associated with non-neutralizing antibodies and constitutes another major decoy (15,16,18).…”

Section: Hepatitis C Virus (Hcv)mentioning

confidence: 99%

Structural Basis for Penetration of the Glycan Shield of Hepatitis C Virus E2 Glycoprotein by a Broadly Neutralizing Human Antibody

Pierce

Wang

et al. 2015

Journal of Biological Chemistry

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Background: HCV uses glycan shielding to mask epitopes recognized by neutralizing antibodies. Results: The structure of a human antibody bound to an HCV E2 epitope revealed how it penetrates a shield created by glycosylation shifting. Conclusion: Antibody binding induces an epitope conformation that accommodates multiple glycans. Significance: The structure provides a template for engineering E2 to elicit protective antibodies able to overcome glycosylation shifting.

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“…Major obstacles to HCV vaccine development are the diversity of the virus, the ability of the virus to evade the immune response in infected individuals with high rates of mutation, and development of “quasispecies,” which are distinct but closely related HCV variants that can be present in a single individual 5, 137, 142. Additional immune‐evading strategies that have been identified include antibody avoidance, cytotoxic T lymphocyte escape, and a failure to initiate an appropriate T cell response during the beginning of infection, among others 143, 144, 145, 146, 147, 148. Despite these challenges, several investigations have demonstrated success in preclinical animal studies showing induction of both humoral and cellular immunity against HCV 149, 150.…”

Section: Future Directionsmentioning

confidence: 99%

Hepatitis C virus infection in children and adolescents

Squires

Balistreri

2017

Hepatology Communications

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Hepatitis C Virus Continuously Escapes From Neutralizing Antibody and T-Cell Responses During Chronic Infection In Vivo

Cited by 367 publications

References 57 publications

Apolipoprotein E Mediates Evasion From Hepatitis C Virus Neutralizing Antibodies

Apolipoprotein E Mediates Evasion From Hepatitis C Virus Neutralizing Antibodies

Structural Basis for Penetration of the Glycan Shield of Hepatitis C Virus E2 Glycoprotein by a Broadly Neutralizing Human Antibody

Hepatitis C virus infection in children and adolescents

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