The genomic sequences of viruses that are highly mutable and cause chronic infection tend to diverge over time. We report that these changes represent both immune-driven selection and, in the absence of immune pressure, reversion toward an ancestral consensus. Sequence changes in hepatitis C virus (HCV) structural and nonstructural genes were studied in a cohort of women accidentally infected with HCV in a rare common-source outbreak. We compared sequences present in serum obtained 18–22 yr after infection to sequences present in the shared inoculum and found that HCV evolved along a distinct path in each woman. Amino acid substitutions in known epitopes were directed away from consensus in persons having the HLA allele associated with that epitope (immune selection), and toward consensus in those lacking the allele (reversion). These data suggest that vaccines for genetically diverse viruses may be more effective if they represent consensus sequence, rather than a human isolate.

This is the author accepted manuscript (AAM). The final published version (version of record) is available online via AAAS at http://immunology.sciencemag.org/content/2/15/eaal5296. Please refer to any applicable terms of use of the publisher. University of Bristol -Explore Bristol Research General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. KIR2DS2, an activating natural killer cell receptor recognizes highly conserved peptides derived from the RNA helicases of pathogenic flaviviruses. AbstractKiller cell immunoglobulin-like receptors (KIR) are rapidly evolving species-specific natural killer cell receptors associated with protection against multiple different human viral infections. We report that the activating receptor KIR2DS2 directly recognizes viral peptides derived from conserved regions of flaviviral superfamily 2 RNA helicases in the context of MHC class I. The peptide LNPSVAATL, from the HCV helicase, binds HLA-C*0102 leading to NK cell activation through engagement of KIR2DS2. Similarly, HLA-C*0102 presents highly conserved peptides from the helicase motif 1b region of related flaviviruses, including dengue, Zika, yellow fever and Japanese encephalitis viruses, to KIR2DS2. These flaviviral peptides all contain an "MCHAT" motif, which is present in 61 out of 63 flaviviruses.LNPSVAATL is also highly conserved across HCV genotypes and mutation of this epitope is poorly tolerated by HCV. KIR2DS2 recognizes endogenously presented helicase peptides and KIR2DS2 is sufficient to inhibit HCV and dengue virus replication in the context of HLA-C*0102. Targeting short, but highly conserved, viral peptides provide non-rearranging innate immune receptors with an efficient mechanism to recognize multiple, highly variable pathogenic RNA viruses.4

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All identified RF1-type strains appear to be introduced from a single source, suggesting that intergenotypic recombination in HCV is sporadic and not associated with cocirculation of different genotypes in a population. The RF1 strain in this study was responsive to interferon in vivo.