Mapping the genomic diversity of HCV subtypes 1a and 1b: Implications of structural and immunological constraints for vaccine and drug development

摘要

Despite significant progress in hepatitis C (HCV) treatment, global viral eradication remains a challenge. An in-depth map ofits genome diversity within the context of structural and immunological constraints could contribute to the design of pangenotypicantivirals and preventive vaccines. For such analyses, extensive information is only available for the highly prevalentHCV genotypes (GT) 1a and 1b. Using 647 GT1a and 408 GT1b full-genome sequences obtained from the Los Alamosdatabase, we found that respectively 3 per cent and 82 per cent of all codon positions are under positive and negative selectivepressure, suggesting variation mainly accumulates due to random genetic drift. An association between conservationand both structured RNA and secondary protein structures confirmed the important role of structural elements at nucleotideand at amino acid level. Remarkably, CD8þ T-cell epitopes in HCV GT1a were significantly more conserved, while at thesame time containing more sites under positive selection. Similarly, CD4þ T-cell epitopes were significantly more conservedin both HCV subtypes, but under less positive selective pressure in GT1b and more negative selective pressure in GT1a.In contrast, B-cell epitopes in both subtypes were less conserved and under less stringent negative selection. These findingsargue against immune selective pressure as the main force of between-host diversifying evolution. Despite its high variability, HCV is under strict evolutionary constraints, most probably to keep its genes and proteins functional during thereplication cycle. These are encouraging findings for vaccine and drug design, which could consider these newly establishedgenetic diversity profiles.