The Humoral Immune Response to HCV: Understanding is Key to Vaccine Development

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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“…A number of mechanisms have been identified through which HCV evades the immune response, as reviewed by others [9,10]. These include:…”

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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“…18 Although some patient studies suggest that the rapid induction of broadly reactive nAbs is associated with viral clearance, 19 20 the implications for immunotherapy and vaccine development remain unclear. Specifically, the envelope proteins of HCV could be immunologically distinct across genotypes, or even subtypes, resulting in limited antibody cross-reactivity.…”

Section: Significance Of This Studymentioning

confidence: 99%

“…The role of neutralising antibodies (nAbs) in resolving acute HCV infection remains incompletely understood 18. Although some patient studies suggest that the rapid induction of broadly reactive nAbs is associated with viral clearance,19 20 the implications for immunotherapy and vaccine development remain unclear.…”

Section: Introductionmentioning

confidence: 99%

HVR1-mediated antibody evasion of highly infectious in vivo adapted HCV in humanised mice

Prentoe

Verhoye

Velázquez-Moctezuma

et al. 2015

Gut

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ObjectiveHCV is a major cause of chronic liver disease worldwide, but the role of neutralising antibodies (nAbs) in its natural history remains poorly defined. We analysed the in vivo role of hypervariable region 1 (HVR1) for HCV virion properties, including nAb susceptibility.DesignAnalysis of HCV from human liver chimeric mice infected with cell-culture-derived prototype genotype 2a recombinant J6/JFH1 or HVR1-deleted variant J6/JFH1ΔHVR1 identified adaptive mutations, which were analysed by reverse genetics in Huh7.5 and CD81-deficient S29 cells. The increased in vivo genomic stability of the adapted viruses facilitated ex vivo density analysis by ultracentrifugation and in vivo neutralisation experiments addressing the role of HVR1.ResultsIn vivo, J6/JFH1 and J6/JFH1ΔHVR1 depended on single substitutions within amino acids 867–876 in non-structural protein, NS2. The identified A876P-substitution resulted in a 4.7-fold increase in genomic stability. In vitro, NS2 substitutions enhanced infectivity 5–10-fold by increasing virus assembly. Mouse-derived mJ6/JFH1A876P and mJ6/JFH1ΔHVR1/A876P viruses displayed similar heterogeneous densities of 1.02–1.1 g/mL. Human liver chimeric mice loaded with heterologous patient H (genotype 1a) immunoglobulin had partial protection against mJ6/JFH1A876P and complete protection against mJ6/JFH1ΔHVR1/A876P. Interestingly, we identified a putative escape mutation, D476G, in mJ6/JFH1A876P. This mutation in hypervariable region 2 conferred 6.6-fold resistance against H06 IgG in vitro.ConclusionsThe A876P-substitution bridges in vitro and in vivo studies using J6/JFH1-based recombinants. We provide the first in vivo evidence that HVR1 protects cross-genotype conserved HCV neutralisation epitopes, which advocates the possibility of using HVR1-deleted viruses as vaccine antigens to boost broadly reactive protective nAb responses.

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“…Significant progress toward understanding the molecular and structural basis for antibody-mediated neutralization has been made for several clinically important viruses through studies of monoclonal antibodies (MAbs) (4,(8)(9)(10)(11). How antibodies with different functional properties act in concert in human sera is poorly understood.…”

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confidence: 99%

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

VanBlargan

Goo

Pierson

2016

Microbiol Mol Biol Rev

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SUMMARY The antibody response plays a key role in protection against viral infections. While antiviral antibodies may reduce the viral burden via several mechanisms, the ability to directly inhibit (neutralize) infection of cells has been extensively studied. Eliciting a neutralizing-antibody response is a goal of many vaccine development programs and commonly correlates with protection from disease. Considerable insights into the mechanisms of neutralization have been gained from studies of monoclonal antibodies, yet the individual contributions and dynamics of the repertoire of circulating antibody specificities elicited by infection and vaccination are poorly understood on the functional and molecular levels. Neutralizing antibodies with the most protective functionalities may be a rare component of a polyclonal, pathogen-specific antibody response, further complicating efforts to identify the elements of a protective immune response. This review discusses advances in deconstructing polyclonal antibody responses to flavivirus infection or vaccination. Our discussions draw comparisons to HIV-1, a virus with a distinct structure and replication cycle for which the antibody response has been extensively investigated. Progress toward deconstructing and understanding the components of polyclonal antibody responses identifies new targets and challenges for vaccination strategies.

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The Humoral Immune Response to HCV: Understanding is Key to Vaccine Development

Cited by 69 publications

References 167 publications

Viral evasion and challenges of hepatitis C virus vaccine development

Viral evasion and challenges of hepatitis C virus vaccine development

HVR1-mediated antibody evasion of highly infectious in vivo adapted HCV in humanised mice

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

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