Human combinatorial libraries yield rare antibodies that broadly neutralize hepatitis C virus

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Investigating antibody responses is crucial for understanding microbial defense.
• Recent advances enable in vitro studies of neutralizing antibodies against hepatitis C virus (HCV).

Purpose of the Study:

• To characterize the neutralizing breadth and epitope targets of human monoclonal antibodies (mAbs) against diverse hepatitis C virus (HCV) genotypes.
• To confirm the potential for eliciting broadly neutralizing anti-HCV antibodies.

Main Methods:

• Isolated and characterized three human mAbs from an individual with HCV genotype 2b infection.
• Assessed antibody binding and neutralization of HCV pseudoparticles (HCVpp) and the infectious JFH-1 clone across multiple HCV genotypes.
• Mapped conformational epitopes of neutralizing mAbs to the E2 envelope glycoprotein, specifically the 523-535 amino acid region.

Main Results:

• Two mAbs, 1:7 and A8, demonstrated broad neutralization activity against HCV genotypes 1a, 1b, and others, including the infectious JFH-1 clone.
• These antibodies recognized the E2 envelope protein from all six major HCV genotypes.
• The neutralizing epitopes were mapped to overlapping but distinct regions within amino acids 523-535 of E2, crucial for CD81 interaction.

Conclusions:

• Broadly neutralizing human anti-HCV antibodies can be elicited.
• The 523-535 region of the HCV E2 envelope glycoprotein contains conserved neutralizing epitopes effective across all genotypes.
• These findings support the development of therapeutic strategies targeting conserved HCV epitopes.