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A Protocol for Analyzing Hepatitis C Virus Replication
Published on: June 26, 2014
A Hepatitis C Virus Envelope Polymorphism Confers Resistance to Neutralization by Polyclonal Sera and Broadly
Lisa N Wasilewski1, Ramy El-Diwany1, Supriya Munshaw2
1Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Insights
A newly discovered Hepatitis C virus (HCV) mutation can make the virus resistant to neutralizing antibodies. This finding in an ancestral HCV strain may guide the development of effective HCV vaccines.
Area of Science:
- Virology
- Immunology
- Vaccinology
Background:
- Hepatitis C virus (HCV) infection affects millions globally, posing risks for cirrhosis and liver cancer.
- Developing an HCV vaccine is crucial for disease control, necessitating a deeper understanding of antibody resistance mechanisms.
Purpose of the Study:
- To identify specific viral genetic variations that confer resistance to broadly neutralizing antibodies (bNAbs).
- To understand the impact of these variations on viral neutralization and fitness, informing HCV vaccine design.
Main Methods:
- Phylogenetic analysis of HCV sequences to identify variable codons.
- Introduction of a specific polymorphism into an ancestral HCV strain (Bole1a) to assess its effect on neutralization sensitivity.
Main Results:
- A single codon polymorphism was identified that confers resistance to neutralization by polyclonal plasma and multiple bNAbs.
- This resistance-conferring mutation was found to reduce the virus's replicative fitness.
Conclusions:
- The identified polymorphism is a key determinant of bNAb resistance in HCV.
- Understanding these resistance mechanisms is vital for developing a broadly effective HCV vaccine.
Unlabelled:
Hepatitis C virus (HCV) infection is a global health problem, with millions of chronically infected individuals at risk for cirrhosis and hepatocellular carcinoma. HCV vaccine development is vital in the effort toward disease control and eradication, an undertaking aided by an increased understanding of the mechanisms of resistance to broadly neutralizing antibodies (bNAbs). In this study, we identified HCV codons that vary deep in a phylogenetic tree of HCV sequences and showed that a polymorphism at one of these positions renders Bole1a, a computationally derived, ancestral genotype 1a HCV strain, resistant to neutralization by both polyclonal-HCV-infected plasma and multiple broadly neutralizing monoclonal antibodies with unique binding epitopes. This bNAb resistance mutation reduces replicative fitness, which may explain the persistence of both neutralization-sensitive and neutralization-resistant variants in circulating viral strains. This work identifies an important determinant of bNAb resistance in an ancestral, representative HCV genome, which may inform HCV vaccine development.
Importance:
Worldwide, more than 170 million people are infected with hepatitis C virus (HCV), the leading cause of hepatocellular carcinoma and liver transplantation in the United States. Despite recent significant advances in HCV treatment, a vaccine is needed. Control of the HCV pandemic with drug treatment alone is likely to fail due to limited access to treatment, reinfections in high-risk individuals, and the potential for resistance to direct-acting antivirals (DAAs). Broadly neutralizing antibodies (bNAbs) block infection by diverse HCV variants and therefore serve as a useful guide for vaccine development, but our understanding of resistance to bNAbs is incomplete. In this report, we identify a viral polymorphism conferring resistance to neutralization by both polyclonal plasma and broadly neutralizing monoclonal antibodies, which may inform HCV vaccine development.
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