| Popis: |
Background In acute persisting hepatitis C virus (HCV) infection, brief control of viral replication can occur with onset of a cellular immune response but is eventually lost due to selection of viral variants with escape mutations in CD8 T cell epitopes or development of T cell exhaustion. In chronic infection, the CD8s targeting remaining intact epitopes are exhausted, viral levels are stable, and selection of new escape mutations is rare. Postpartum (PP), some chronically infected women experience a drop in viremia which we hypothesize is due to recovery of the CD8 response and will be associated with selection of de novo escape mutations as seen in acute persisting infection. Methods HCV genomic evolution was assessed in 2 women with different patterns of PP viral control through consecutive pregnancies. Subject M016 experienced > 2.5 log10 drops in viral loads after each pregnancy while M062 had stable viral levels (Table 1). Longitudinal viral genomes were assessed by Illumina sequencing of near full length PCR products of viral cDNA. Reads were initially aligned to a genotype reference and then iterative consensus sequences until deep coverage was achieved across the entire PCR amplicon. To identify potential CD8 escape mutations, amino acid substitutions were counted if their frequency increased from < 10% of reads peripartum to > 90% at follow up. We focused on the nonstructural region to avoid substitutions related to antibody selection pressure. Viral Load Levels Results M016 developed 3 nonsynonomous (NS) mutations after her 1st pregnancy and 1 more after her 2nd. Of these, 3 were directed away from the consensus amino acid sequence, and one differed from consensus at baseline and changed tangentially. M062 developed 1 NS mutation within a known class I epitope following her second pregnancy which was directed toward consensus for her genotype (Fig 1). All mutations occurred within predicted class I epitopes. Nonsynonomous Substitutions in Nonstructural Region Conclusion While these pilot data require verification in additional subjects, the observed emergence of non-synonymous mutations directed away from genotype consensus in viral class I epitopes of a woman with postpartum viral control but not in a women with stable viral levels support our hypothesis enhanced CD8 T cell selection pressure contribute to enhanced control of HCV replication after childbirth. Disclosures All Authors: No reported disclosures |
