Interplay of Host and Viral Genetic Variations in Modulating Antibody Responses to Genotype 3a Hepatitis C Virus: Implications for Vaccine Design

Hepatitis C virus (HCV) exhibits significant genetic diversity and is a of cause severe liver complications, including liver failure and hepatocellular carcinoma. The envelope glycoproteins E1 and E2 of HCV are the primary targets for the humoral immune response and have the highest sequence diversity in the HCV genome. The humoral immune response to HCV infection may be modulated by host and virus genetic factors. Here, using virus sequencing and host genetic data, as well as antibody binding and neutralization assays from 54 patients infected with HCV subtype 3a virus, we investigated the factors associated with antibody binding and neutralization. Genetic variation in the host IFNL4 gene were associated with antibody binding response, with the IFNλ4-P70 variant associated with reduced binding relative to IFNλ4-Null variant. Testing for association between all variable amino acids in HCV E1 and E2 glycoproteins and antibody response, 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. By considering the complex factors that influence antibody binding and neutralization, future vaccine strategies can be designed to elicit a robust immune response against a diverse range of HCV strains, addressing the needs of a diverse population.