Genetic Diversity Underlying the Envelope Glycoproteins of Hepatitis C Virus: Structural and Functional Consequences and the Implications for Vaccine Design

Tarr, Alexander W.; Khera, Tanvi; Hueging, Kathrin; Sheldon, Julie; Steinmann, Eike; Pietschmann, Thomas; Brown, Richard J. P.

doi:10.3390/v7072809

Cited by 42 publications

(37 citation statements)

References 315 publications

(492 reference statements)

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“…Notably, within infected individuals, the virus actively evades the immune system [19] and evolves into a large number of quasispecies through error-prone replication [20]. This presents a major challenge for vaccine design, requiring the identification of functionally important, conserved portions of the virus to target immunologically.…”

Section: Hcv Immune Evasion and Sequence Variabilitymentioning

confidence: 99%

Viral evasion and challenges of hepatitis C virus vaccine development

Pierce

Keck

Foung

2016

Current Opinion in Virology

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Hepatitis C virus (HCV) is a major global disease burden, often leading to chronic liver diseases, cirrhosis, cancer, and death in those infected. Despite the recent approval of antiviral therapeutics, a preventative vaccine is recognized as the most effective means to control HCV globally, particularly in at-risk and developing country populations. Here we describe the efforts and challenges related to the development of an HCV vaccine, which after decades of research have not been successful. Viral sequence variability poses a major challenge, yet recent research has provided unprecedented views of the atomic structure of HCV epitopes and immune recognition by antibodies and T cell receptors. This, coupled with insights from deep sequencing, robust neutralization assays, and other technological advances, is spurring research toward rationally HCV designed vaccines that preferentially elicit responses toward conserved epitopes of interest that are associated with viral neutralization and clearance.

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Section: Hcv Immune Evasion and Sequence Variabilitymentioning

confidence: 99%

Viral evasion and challenges of hepatitis C virus vaccine development

Pierce

Keck

Foung

2016

Current Opinion in Virology

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“…In patients, HCV circulates as a pool of quasispecies, viral variants which are genetically distinct and continually evolving due to a high viral mutation rate. [59] HCV variants reinfecting the liver graft are characterized by both enhanced entry in hepatocytes and escape from nAbs. [60] HCV has developed numerous strategies to avoid recognition by host humoral responses.…”

Section: Viral Evasion From Neutralizing Antibodiesmentioning

confidence: 99%

Hepatitis C virus vaccine candidates inducing protective neutralizing antibodies

Fauvelle

Colpitts

Keck

et al. 2016

Expert Review of Vaccines

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Introduction With more than 150 million chronically infected people, hepatitis C virus (HCV) remains a substantial global health burden. Direct-acting antivirals have dramatically improved viral cure. However, limited access to therapy, late stage detection of infection and re-infection following cure illustrate the need for a vaccine for global control of infection. Vaccines with induction of neutralizing antibodies (nAbs) have been shown to protect successfully against infections by multiple viruses and are currently developed for HCV. Areas covered Here we review the progress towards the development of vaccines aiming to confer protection against chronic HCV infection by inducing broadly nAbs. The understanding or viral immune evasion in infected patients, the development of novel model systems and the recent structural characterization of viral envelope glycoprotein E2 has markedly advanced our understanding of the molecular mechanisms of virus neutralization with the concomitant development of several vaccine candidates. Expert commentary While HCV vaccine development remains challenged by the high viral diversity and immune evasion, marked progress in HCV research has advanced vaccine development. Several vaccine candidates have shown robust induction of nAbs in animal models and humans. Randomized clinical trials are the next step to assess their clinical efficacy for protection against chronic infection.

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“…HCV is a small-enveloped, single-stranded RNA virus [4]. The envelope glycoproteins E1 and E2 are structural proteins located on the surface of HCV and responsible for binding to cells and entry.…”

Section: Introductionmentioning

confidence: 99%

“…However, it was previously shown that these receptors individually are not sufficient to allow viral entry into hepatocytes [17,18]. Neutralizing epitopes have also been described that are different from the CD81 binding region [4]. The recently reported crystal structure of E2 has confirmed that a broadly conserved neutralizing epitopic stretch exists around the discontinuous CD81 binding site encompassing residues 412-424, 436-442 and 520-535 that harbour contact residues for many neutralizing antibodies [18].…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel epitope in the C terminus of hepatitis C virus-E2 protein that induces potent and cross-reactive neutralizing antibodies

Das

Mullick

Kumar

et al. 2017

Journal of General Virology

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Hepatitis C virus (HCV) is a leading cause of chronic viral hepatitis, but an effective vaccine is still not available to prevent infection. Use of neutralizing antibodies could be a potential therapeutic option. In this study, the presence of anti-HCV antibodies in HCV-infected patients was assessed from 50 patients and the presence of neutralizing antibodies was examined using 'hepatitis C virus-like particles'. Antibodies from two samples exhibited significant inhibitory activity, suggesting that these may neutralize viral infection. Antigenic determinants generating the neutralizing antibodies from these two samples were delineated by epitope mapping using the core, E1 and E2 regions and a stretch of 45 amino acid peptide (E2C45) derived from the C-terminal region of HCV-E2 protein (aa 634-679) was designed. Results suggest that this hitherto uncharacterized region has the potential to generate neutralizing antibodies against HCV and thus be effective in preventing virus entry into liver cells. Computational analysis of the structure of the modelled peptide (E2C45) suggested high conformational entropy for this region. Furthermore, E2C45 peptide-generated antibodies could block virus entry and monoclonal antibodies generated against this peptide could also significantly reduce virus replication in a cell culture system. It is possible that the inhibition could be partly due to a conformational alteration of the CD81-binding region, preventing virus attachment to liver cells. In conclusion, this work focused on the discovery of a novel epitope at the C terminus of E2 that induces potent neutralizing antibodies in HCV-infected patients.

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Genetic Diversity Underlying the Envelope Glycoproteins of Hepatitis C Virus: Structural and Functional Consequences and the Implications for Vaccine Design

Cited by 42 publications

References 315 publications

Viral evasion and challenges of hepatitis C virus vaccine development

Viral evasion and challenges of hepatitis C virus vaccine development

Hepatitis C virus vaccine candidates inducing protective neutralizing antibodies

Identification of a novel epitope in the C terminus of hepatitis C virus-E2 protein that induces potent and cross-reactive neutralizing antibodies

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