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

Naiyer, M. M. et al. (2017) KIR2DS2 recognizes conserved peptides derived from viral helicases in the context of HLA-C. Science Immunology, 2(15), eaal5296. (doi: 10.1126/sciimmunol.aal5296) (PMID:28916719)

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Killer cell immunoglobulin-like receptors (KIRs) are rapidly evolving species-specific natural killer (NK) 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 major histocompatibility complex class I. We started by documenting that peptide LNPSVAATL from the hepatitis C virus (HCV) helicase binds HLA-C*0102, leading to NK cell activation through engagement of KIR2DS2. Although this region is highly conserved across HCV isolates, the sequence is not present in other flaviviral helicases. Embarking on a search for a conserved target of KIR2DS2, we show that HLA-C*0102 presents a different highly conserved peptide from the helicase motif 1b region of related flaviviruses, including dengue, Zika, yellow fever, and Japanese encephalitis viruses, to KIR2DS2. In contrast to LNPSVAATL from HCV, these flaviviral peptides all contain an “MCHAT” motif, which is present in 61 of 63 flaviviruses. Despite the difference in the peptide sequences, we show that KIR2DS2 recognizes endogenously presented helicase peptides and that 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 nonrearranging innate immune receptors with an efficient mechanism to recognize multiple, highly variable, pathogenic RNA viruses.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Cowton, Dr Vanessa and Patel, Professor Arvind and Magri, Mr Andrea
Authors: Naiyer, M. M., Cassidy, S. A., Magri, A., Cowton, V., Chen, K., Mansour, S., Kranidioti, H., Mbirbindi, B., Rettman, P., Harris, S., Fanning, L. J., Mulder, A., Claas, F. H.J., Davidson, A. D., Patel, A. H., Purbhoo, M. A., and Khakoo, S. I.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Science Immunology
Publisher:American Association for the Advancement of Science
ISSN (Online):2470-9468
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Science Immunology 2(15): eaal5296
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656491Basis of the host range and tissue tropism for hepatitis C virusArvind PatelMedical Research Council (MRC)MC_UU_12014/2MVLS III - CENTRE FOR VIRUS RESEARCH