Interplay of Host and Viral Genetic Variations in Modulating Antibody Responses to Genotype 3a Hepatitis C Virus: Implications for Vaccine Design
Description
This study investigates the complex interplay between host and viral genetics that influence antibody responses to Hepatitis C Virus (HCV), with a focus on the understudied genotype 3a. By integrating viral whole-genome sequencing, robust binding and neutralization assays, and analysis of host factors for 54 patients with HCV gt3a infection, we identified novel viral polymorphisms and glycosylation motifs across HCV gt3a E1 and E2 associated with antibody responses. To be specific, we discovered two sites in or near the CD81 binding sites in E2 (sites 501 and 533) that were associated with neutralization sensitivity, along with an additional site in E2 (653) that was associated with binding. Additionally, motifs at two glycosylation sites (N476 and N234) were associated with binding and/or neutralisation. Furthermore, an increase in intra-patient hypervariable region 1 (HVR1) diversity was associated with stronger binding response. Our findings also highlight the importance of considering host factors, such as genetic variation in IFNL4 gene, in vaccine development and deployment strategies. Specifically, the IFNλ4-P70 variant, which exhibits reduced binding compared to the IFNλ4-Null variant, should be taken into account.