KIR2DS2 recognizes conserved peptides derived from viral helicases in the context of HLA-C

Abstract

Killer 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 HLAC*
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.

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Identifiers

ORCID for Mohammed M. Naiyer: orcid.org/0000-0002-4441-311X

ORCID for Salah Mansour: orcid.org/0000-0002-5982-734X

ORCID for Salim I. Khakoo: orcid.org/0000-0002-4057-9091

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