title: MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape.
abstract: Major histocompatibility complex class I (MHC-I) molecules play a crucial role in immunity by capturing peptides for presentation to T cells and natural killer (NK) cells. The peptide termini are tethered within the MHC-I antigen-binding groove, but it is unknown whether other presentation modes occur. Here we show that 20% of the HLA-B*57:01 peptide repertoire comprises N-terminally extended sets characterized by a common motif at position 1 (P1) to P2. Structures of HLA-B*57:01 presenting N-terminally extended peptides, including the immunodominant HIV-1 Gag epitope TW10 (TSTLQEQIGW), showed that the N terminus protrudes from the peptide-binding groove. The common escape mutant TSNLQEQIGW bound HLA-B*57:01 canonically, adopting a dramatically different conformation than the TW10 peptide. This affected recognition by killer cell immunoglobulin-like receptor (KIR) 3DL1 expressed on NK cells. We thus define a previously uncharacterized feature of the human leukocyte antigen class I (HLA-I) immunopeptidome that has implications for viral immune escape. We further suggest that recognition of the HLA-B*57:01-TW10 epitope is governed by a 'molecular tension' between the adaptive and innate immune systems.
authors.affiliation: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.
authors.forename: Phillip
authors.initials: P
authors.lastname: Pymm
authors.affiliation: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
authors.forename: Patricia T
authors.initials: PT
authors.lastname: Illing
authors.affiliation: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
authors.forename: Sri H
authors.identifier: 0000-0002-2787-1282
authors.initials: SH
authors.lastname: Ramarathinam
authors.affiliation: Department of Biological Sciences, University of Chester, Chester, UK.
authors.forename: Geraldine M
authors.initials: GM
authors.lastname: O'Connor
authors.affiliation: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Hughes
authors.affiliation: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
authors.forename: Corinne
authors.initials: C
authors.lastname: Hitchen
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.|Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
authors.forename: Bosco K
authors.initials: BK
authors.lastname: Ho
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute-Frederick, Frederick, Maryland, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: McVicar
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Brooks
authors.affiliation: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
authors.forename: Anthony W
authors.identifier: 0000-0003-0532-8331
authors.initials: AW
authors.lastname: Purcell
authors.affiliation: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.|Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.affiliation: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.
authors.forename: Julian P
authors.initials: JP
authors.lastname: Vivian
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry; D057809:HEK293 Cells; D015497:HIV-1 / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000737:chemistry*; D006801:Humans; D057131:Immune Evasion; D055442:Metabolome; D050505:Mutant Proteins / Q000737:chemistry; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D054341:Receptors, KIR3DL1 / Q000378:metabolism; D020349:Surface Plasmon Resonance; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism
chemical_list: D000939:Epitopes; D015395:Histocompatibility Antigens Class I; C515083:KIR3DL1 protein, human; D050505:Mutant Proteins; D010455:Peptides; D054341:Receptors, KIR3DL1; D054301:gag Gene Products, Human Immunodeficiency Virus