Adaptation of hepatitis C virus to interferon lambda polymorphism across multiple viral genotypes

Abstract

Genetic polymorphism in the interferon lambda (IFN-λ) region is associated with spontaneous clearance of hepatitis C virus (HCV) infection and response to interferon-based treatment. Here, we evaluate associations between IFN-λ polymorphism and HCV variation in 8729 patients (Europeans 77%, Asians 13%, Africans 8%) infected with various viral genotypes, predominantly 1a (41%), 1b (22%) and 3a (21%). We searched for associations between rs12979860 genotype and variants in the NS3, NS4A, NS5A and NS5B HCV proteins. We report multiple associations in all tested proteins, including in the interferon-sensitivity determining region of NS5A. We also assessed the combined impact of human and HCV variation on pretreatment viral load and report amino acids associated with both IFN-λ polymorphism and HCV load across multiple viral genotypes. By demonstrating that IFN-λ variation leaves a large footprint on the viral proteome, we provide evidence of pervasive viral adaptation to innate immune pressure during chronic HCV infection.

Keywords: Hepatitis C; genetics; genome to genome analysis; genomics; human; infectious disease; integration analysis; interferon lambda polymorphism; microbiology.

Figure 1.. Per genotype integrated association analysis results.

Manhattan plot for associations between human SNP rs12979860 and HCV amino acid variants. The dotted line shows the Bonferroni-corrected significance threshold.

Figure 1—figure supplement 1.. Per genotype integrated association analysis results corrected for HCV viral load.

Manhattan plot for associations between human SNP rs12979860 and HCV amino acid variants, with (filled dots) and without HCV (filled triangles) viral load. The dotted line shows the Bonferroni-corrected significance threshold.

Figure 1—figure supplement 2.. Boxplot of transformed viral load stratified by rs12979860 genotypes (CC, CT, TT).

The association p-values, together with r-squared and beta values, given in the brackets are for associations between rs12979860 and transformed HCV viral load.

Figure 2.. Per genotype viral load GWAS analysis results.

Manhattan plot for associations between human Box-Cox transformed pre-treatment viral load and HCV amino acid variants. The dotted line shows the Bonferroni-corrected significance threshold.

Figure 3.. Associations between amino acid variables at position 2224 of NS5A, rs12979860 genotypes and HCV viral load in the group of patients infected with HCV genotype 1b.

(A) Boxplot of transformed viral load stratified by amino acids present at position 2224 of NS5A. (B): Boxplot of transformed viral load stratified by rs12979860 genotypes (CC, CT, TT) and by presence or absence of leucine at position 2224 of NS5A.

Figure 3—figure supplement 1.. Boxplot of transformed viral load stratified by rs12979860 genotypes (CC, CT, TT) in samples infected with viral genotype 3a, whose virus carries Serine at position 2414.

Figure 3—figure supplement 2.. Per genotype viral load residual analysis results.

Manhattan plot for associations between viral load residual and HCV amino acid variants. The dotted line shows the Bonferroni-corrected significance threshold.

Figure 3—figure supplement 3.. Per genotype integrated association analysis results in the European subgroup.

Manhattan plot for associations between human SNP rs12979860 and HCV amino acid variants. The dotted line shows the Bonferroni-corrected significance threshold.

Figure 3—figure supplement 4.. European per genotype viral load GWAS analysis results.

Manhattan plot for associations between human Box-Cox transformed pre-treatment viral load and HCV amino acid variants. The dotted line shows the Bonferroni-corrected significance threshold.

Figure 3—figure supplement 5.. European per genotype viral load residual GWAS analysis results.

Manhattan plot for associations between viral load residual and HCV amino acid variants. The dotted line shows the Bonferroni-corrected significance threshold.