The antigenic variability of HCV in viral HLA-Ag binding is related to the activation of the host immune response

• Published in: Scientific reports 2017-11, Vol.7 (1), p.15513-10, Article 15513
• Main Authors: Muñoz de Rueda, P., Jiménez-Ruiz, S. M., Quiles, R., Pavón-Castillero, E. J., Muñoz-Gámez, J. A., Casado, J., Gila, A., Ruiz-Extremera, A., Salmerón, J.
• Format: Article
• Language: English
• Subjects: 13/31; 45/91; 692/4020/4021/234/2513; 692/699/1503/234/2513/1551; Alleles; CD4 antigen; Epitopes; Haplotypes; Hepatitis C; Histocompatibility antigen HLA; Humanities and Social Sciences; Immune response; Immunodominance; multidisciplinary; Peptides; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-15605-0

Our previous data show that hepatitis C virus (HCV) genotype 1 patients expressing the HLA-DQB1 * 0301 allele have a combined response probability of 69%, while the remaining 31% do not respond, probably because the HCV immunodominant epitope (IE) against the DQB1 * 0301 allele is mutated. HCV IE (region sequenced in NS3 is a region encoding aa 1253–1272) from 37 patients (21 Sustained Virological Response, SVR; 16 non-SVR) HLA-DQB1 * 0301+, were analysed by pyrosequencing. In vitro cultures were also determined by CD4+ proliferation, using non-mutated IE (wild-type synthetic peptide) and synthetic mutated peptide. The pyrosequencing study revealed 34 different haplotypes. The SVR patients had fewer haplotypes (P = 0.07), mutations/haplotypes (P = 0.01) and polymorphic sites (P = 0.02) than non-SVR. Three polymorphic sites were associated with the non-SVR patients: haplotype 7 (L5P); haplotype 11 (L7P); and haplotype 15, (L15S) (P = 0.02). The in vitro study (n = 7) showed that in 4/7 patients (Group 1) the CD4+ proliferation obtained with wild-type synthetic peptide was higher than that obtained with the negative control and with the synthetic mutated peptide (P = 0.039). However, in the remaining 3/7 patients (Group 2) this pattern was not observed (P = 0.7). Our findings suggest that HLA-DQB1 * 0301+ patients with high antigenic variability in HCV IE (NS31253-1272) have a lower SVR rate, due to reduced CD4+ proliferation as a result of incorrect viral HLA-Ag binding.