{"gene":"KIR3DS1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2007,"finding":"KIR3DS1 associates with the ITAM-bearing adaptor protein DAP12, demonstrated by cotransfection and coimmunoprecipitation experiments in NKL cells. KIR3DS1 expressed on NK cells triggers both cytotoxicity and IFN-gamma production.","method":"Cotransfection and coimmunoprecipitation; flow cytometry; in vitro cytotoxicity and cytokine production assays","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal coimmunoprecipitation plus functional assays (cytotoxicity, IFN-gamma), single lab but multiple orthogonal methods","pmids":["17202323"],"is_preprint":false},{"year":2007,"finding":"Surface expression of KIR3DS1 on NK cells is dependent on the adaptor protein DAP12, shown by transfection experiments. KIR3DS1 is recognized by the antibody Z27 on freshly isolated circulating NK cells from KIR3DS1/KIR3DS1 homozygous donors.","method":"Transfection; flow cytometry with antibody Z27 and DX9","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transfection-based DAP12 dependency shown, replicated across two papers (PMID 17202323 and 17301953), flow cytometry validation","pmids":["17301953"],"is_preprint":false},{"year":2007,"finding":"Ligation of KIR3DS1 by the Z27 antibody on primary NK cells leads to IFN-gamma production and degranulation (CD107a expression), confirming its activating function. KIR3DS1 is also expressed on a small subset of CD56+ T cells.","method":"Flow cytometry; NK cell activation assays (IFN-gamma, CD107a); antibody cross-linking","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay on primary NK cells with antibody-mediated ligation, single lab, multiple readouts","pmids":["17641029"],"is_preprint":false},{"year":2007,"finding":"KIR3DS1 (as soluble Ig fusion protein) did not bind to EBV-transformed B lymphoid cell lines transfected with HLA-Bw4 80I or 80T allotypes, indicating that if KIR3DS1 recognizes HLA-Bw4 ligands, this interaction is peptide dependent.","method":"Soluble KIR3DS1-Ig fusion protein binding assay; flow cytometry on HLA-Bw4-transfected cell lines","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with recombinant protein, negative result replicated by multiple labs","pmids":["17202323"],"is_preprint":false},{"year":2007,"finding":"KIR3DS1 did not bind to a diverse panel of HIV-1-specific HLA-Bw4Ile80 MHC class I tetramers (including various HLA allotypes and peptide epitopes) in 293-T cells transiently expressing KIR3DS1, suggesting KIR3DS1 does not recognize standard peptide-loaded HLA-Bw4 complexes.","method":"Flow cytometry; MHC class I tetramer binding assay on KIR3DS1-transfected 293-T cells","journal":"AIDS research and human retroviruses","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct binding assay, negative result, single lab, consistent with other negative binding reports","pmids":["17411378"],"is_preprint":false},{"year":2009,"finding":"KIR3DS1 expression on NK cells can be induced (upregulated) after exposure to stimulator cells (721.221, K562, EBV-B cell lines, B cells), polyinosinic-polycytidylic acid, IL-15, or IL-2. KIR3DS1+ NK cell proliferation and cytotoxicity were not influenced by the presence of HLA-Bw4 on target cells, in contrast to KIR3DL1+ NK cells.","method":"Flow cytometry; NK cell proliferation and cytotoxicity assays; stimulation with cytokines and cell lines","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple stimulation conditions, functional readouts, single lab","pmids":["19454667"],"is_preprint":false},{"year":2011,"finding":"The rare KIR3DS1 allotype KIR3DS1*014 directly binds HLA-Bw4, providing the first evidence of direct KIR3DS1-HLA-Bw4 binding. Mutagenesis revealed that position 138 is a key determinant of ligand specificity for KIR3DS1, and that reactivity is dictated by complex interactions between residues at positions 138 and 199.","method":"Flow cytometry binding assay; site-directed mutagenesis; recombinant protein analysis","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding assay combined with mutagenesis defining key residues, single lab with multiple orthogonal approaches","pmids":["21804024"],"is_preprint":false},{"year":2015,"finding":"KIR3DS1 recognizes HLA-B*57:01 in a peptide-dependent manner. Using a structure-driven approach, specific HIV-derived peptide epitopes were identified that facilitate productive KIR3DS1-HLA-B*57:01 interactions, establishing that KIR3DS1 ligands exist within the HIV-specific peptide repertoire.","method":"Structure-driven peptide analysis; flow cytometry binding assays with HLA-B*57:01 tetramers and KIR3DS1-expressing cells","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-informed experimental validation, peptide-dependent binding demonstrated, single lab","pmids":["25740999"],"is_preprint":false},{"year":2015,"finding":"KIR3DS1-specific polymorphisms at positions 58 and 92 in the D0 extracellular domain, when introduced into KIR3DL1*009, cause reduced surface expression and dramatically reduced HLA-Bw4 binding compared to KIR3DL1*001, as shown by mutagenesis.","method":"Flow cytometry on primary NK cells and transfected HEK293T cells; recombinant protein binding assays; site-directed mutagenesis","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with recombinant protein binding assays and primary cell analysis, single lab, multiple orthogonal methods","pmids":["26109640"],"is_preprint":false},{"year":2016,"finding":"KIR3DS1 binds HLA-F open conformers (peptide-free/beta2-microglobulin-free forms). Biochemical screening of 100 HLA class I proteins identified HLA-F as the ligand; confirmed by surface plasmon resonance and biochemical pulldown. Primary KIR3DS1+ NK cells degranulated and produced antiviral cytokines upon encountering HLA-F and inhibited HIV-1 replication in vitro. HIV-1 infection upregulated HLA-F mRNA but decreased KIR3DS1 binding, suggesting viral immune evasion.","method":"HLA-protein screen (100 proteins); surface plasmon resonance; biochemical pulldown; primary NK cell functional assays (degranulation, cytokine production); HIV-1 inhibition assay; flow cytometry","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with recombinant proteins (SPR), biochemical pulldown, and primary cell functional assays, replicated by independent lab (PMID 27649529)","pmids":["27455421"],"is_preprint":false},{"year":2016,"finding":"KIR3DS1 but not KIR3DL1 physically binds HLA-F and other MHC-I open conformers, measured by surface plasmon resonance and biochemical pulldown from cell lines. KIR3DS1 binding to surface-bound HLA-F increases granule exocytosis in activated NK cells.","method":"Surface plasmon resonance; biochemical pulldown; biochemical heterodimerization with recombinant proteins; degranulation assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — independent replication of HLA-F binding via SPR and pulldown, consistent with PMID 27455421, multiple methods in single study","pmids":["27649529"],"is_preprint":false},{"year":2017,"finding":"KIR3DS1 mediates positive signaling (NK cell activation/killing) upon recognition of HLA-B*51 (Bw4-I80) surface molecules on target cells. This activation occurs only in HLA-Bw4-I80-negative individuals. KIR3DS1-mediated activation was partially inhibited by antibody masking of KIR3DS1, and killing could be further revealed when NKG2D function was reduced by antibody blockade.","method":"NK cell clone functional assays (killing, cytokine); antibody blocking of KIR3DS1 and NKG2D; transfected target cell killing assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct blocking experiments and NK clone killing assays, single lab, multiple readouts","pmids":["28603523"],"is_preprint":false},{"year":2018,"finding":"Interactions between KIR3DS1 and its ligand HLA-F activate NK cells to control HCV replication. HLA-F is upregulated on HCV-infected cells, and KIR3DS1/HLA-F interactions contribute to NK cell-mediated control of HCV in cell culture, in humanized mouse livers, and in primary liver tissue from HCV-infected individuals.","method":"Cell culture HCV infection model; humanized mouse liver model; primary liver tissue analysis; NK cell functional assays","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple experimental systems (cell culture, humanized mice, primary tissue), mechanistic link between HLA-F upregulation and KIR3DS1 activation established","pmids":["30031767"],"is_preprint":false},{"year":2018,"finding":"KIR3DS1+ NK cells from KIR3DS1 homozygotes are activated by HLA-F on HLA-null 721.221 cells to produce CCL4, IFN-γ, and express CD107a. Blocking with KIR3DS1-Fc chimeric protein or anti-HLA-F antibodies reduced this activation, demonstrating HLA-F/KIR3DS1 ligation is sufficient for NK cell activation.","method":"NK cell functional assays (CCL4, IFN-γ, CD107a); antibody blocking (KIR3DS1-Fc chimeric protein, anti-HLA-F); flow cytometry with exclusive gating","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — blocking experiments with two independent reagents (receptor-Fc and anti-ligand Ab) plus primary cell functional readouts, single lab","pmids":["29743316"],"is_preprint":false},{"year":2019,"finding":"HLA-F expressed on autologous HIV-infected CD4+ T cells activates primary KIR3DS1+ NK cells (higher frequency than KIR3DS1- NK cells) to produce CCL4, IFN-γ, and express CD107a. Blocking HLA-F on HIV-infected cells with KIR3DS1-Fc chimeric protein or anti-HLA-F antibody reduced KIR3DS1+ NK cell activation, establishing that the HLA-F/KIR3DS1 interaction is sufficient to activate NK cells against HIV-infected cells.","method":"Coculture of sorted HIV-infected CD4+ T cells with primary NK cells; antibody/Fc-fusion blocking; flow cytometry with exclusive gating for KIR3DS1+ NK cells","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — autologous system with two independent blocking reagents, exclusive gating controls, replicates previous HLA-F findings in biologically relevant HIV-infected cells","pmids":["31270222"],"is_preprint":false},{"year":2020,"finding":"BK polyomavirus infection significantly increases surface expression of HLA-F on kidney tubular cells, resulting in increased binding of KIR3DS1 to infected cells and activation of primary KIR3DS1+ NK cells, as shown in cell culture and confirmed in kidney biopsy samples from patients.","method":"In vitro BK polyomavirus infection model; flow cytometry (HLA-F expression, KIR3DS1 binding); primary NK cell activation assays; immunohistochemistry of patient kidney biopsies","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell culture model plus patient tissue validation, mechanistic link between viral upregulation of HLA-F and KIR3DS1 activation established, single lab","pmids":["33359499"],"is_preprint":false},{"year":2020,"finding":"HLA-F loaded with hemoglobin-derived peptides (which are upregulated in HIV-infected CD4+ T cells) loses affinity for KIR3DS1, while acid elution of peptides (generating open conformers) restores KIR3DS1 binding. This provides a molecular mechanism for HIV immune evasion via peptide-dependent regulation of HLA-F/KIR3DS1 interaction.","method":"Recombinant soluble KIR3DS1 binding assays; acid elution of peptides; mass spectrometry proteome analysis; flow cytometry on K562 cells expressing membrane-bound HLA-F alleles","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — recombinant protein binding assay with peptide manipulation, single lab, limited replication","pmids":["33126487"],"is_preprint":false},{"year":2021,"finding":"HLA-F is strongly upregulated on HAdV5-infected intestinal organoid cells, enabling enhanced killing of infected cells by KIR3DS1+ NK cells. This demonstrates that the KIR3DS1/HLA-F axis mediates NK cell recognition and killing of adenovirus-infected cells.","method":"3D intestinal organoid infection model; flow cytometry (HLA-F upregulation); NK cell killing assays with KIR3DS1+ NK cells","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — primary organoid system with direct killing assay, functional mechanistic link established between HLA-F induction and KIR3DS1-mediated killing, single lab","pmids":["34533978"],"is_preprint":false},{"year":2002,"finding":"Genetic epistasis analysis revealed that KIR3DS1 in combination with HLA-B Bw4-80Ile alleles is associated with delayed progression to AIDS in HIV-1-infected individuals, and KIR3DS1 alone (without Bw4-80Ile) was associated with more rapid progression, demonstrating a synergistic epistatic interaction between KIR3DS1 and HLA-B Bw4-80Ile loci.","method":"Genetic epistasis analysis in large cohort; KIR and HLA genotyping; Cox proportional hazards regression","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — genetic epistasis in large multi-cohort study, replicated in multiple subsequent studies, but mechanistic basis is inferred not directly demonstrated","pmids":["12134147"],"is_preprint":false}],"current_model":"KIR3DS1 is an activating NK cell receptor that signals via DAP12 (ITAM-bearing adaptor), with its primary functional ligand being HLA-F open conformers (peptide-free MHC-I); upon binding HLA-F — which is upregulated on cells infected with HIV, HCV, adenovirus, or BK polyomavirus — KIR3DS1 triggers NK cell degranulation, IFN-γ and CCL4 production, and target cell killing, while HIV infection exploits hemoglobin-derived peptide loading of HLA-F to reduce KIR3DS1 ligation and evade NK cell recognition."},"narrative":{"mechanistic_narrative":"KIR3DS1 is an activating killer-cell immunoglobulin-like receptor that arms NK cells to recognize and eliminate virus-infected cells through the open-conformer ligand HLA-F [PMID:27455421, PMID:34533978]. Lacking an intrinsic signaling domain, KIR3DS1 associates with the ITAM-bearing adaptor DAP12, which is required for both its surface expression and its capacity to trigger cytotoxicity and IFN-γ production [PMID:17202323, PMID:17301953]. Antibody-mediated ligation of KIR3DS1 on primary NK cells drives degranulation (CD107a) and cytokine output, confirming its bona fide activating function [PMID:17641029]. Biochemical screening of the HLA class I repertoire identified peptide-free, β2-microglobulin-free HLA-F open conformers as the physiological ligand, a specificity confirmed by surface plasmon resonance and pulldown that distinguishes KIR3DS1 from the inhibitory paralog KIR3DL1 [PMID:27455421, PMID:27649529]. Because HLA-F is strongly upregulated on cells infected with HIV-1, HCV, BK polyomavirus, and adenovirus, the KIR3DS1/HLA-F axis enables NK cell-mediated control of these infections across cell-culture, humanized-mouse, organoid, and primary-tissue systems [PMID:30031767, PMID:31270222, PMID:33359499, PMID:34533978]. HIV-1 subverts this recognition by loading HLA-F with hemoglobin-derived peptides, which abolishes KIR3DS1 binding, whereas removing peptide to regenerate open conformers restores it — a molecular basis for viral immune evasion [PMID:33126487]. KIR3DS1 binding to canonical peptide-loaded HLA-Bw4 is weak and allele/peptide-restricted, with most allotypes failing to bind classical HLA-Bw4 tetramers and only rare variants or specific HIV-derived peptide complexes supporting interaction [PMID:17202323, PMID:21804024, PMID:25740999]. Consistent with these molecular findings, KIR3DS1 in combination with HLA-B Bw4-80Ile alleles is genetically associated with delayed progression to AIDS in HIV-1 infection [PMID:12134147].","teleology":[{"year":2002,"claim":"Established the first functional clue that KIR3DS1 shapes antiviral immunity, showing a genetic interaction with HLA-B Bw4-80Ile that predicts the rate of HIV disease progression and motivating the search for a ligand and mechanism.","evidence":"Genetic epistasis analysis with KIR/HLA genotyping and Cox regression in a large HIV-1 cohort","pmids":["12134147"],"confidence":"Medium","gaps":["Statistical association only; no direct receptor-ligand interaction demonstrated","Did not identify the molecular ligand or signaling pathway"]},{"year":2007,"claim":"Defined KIR3DS1 as an activating receptor by showing it associates with DAP12, depends on DAP12 for surface expression, and triggers cytotoxicity, IFN-γ and degranulation upon ligation.","evidence":"Cotransfection/coimmunoprecipitation in NKL cells, DAP12-dependent transfection, and antibody cross-linking functional assays on primary NK cells","pmids":["17202323","17301953","17641029"],"confidence":"High","gaps":["Physiological ligand not identified","Antibody ligation does not establish the natural activating stimulus"]},{"year":2007,"claim":"Ruled out classical peptide-loaded HLA-Bw4 as a straightforward ligand, showing soluble KIR3DS1 and KIR3DS1-expressing cells fail to bind HLA-Bw4 transfectants or HIV-specific HLA-Bw4 tetramers, redirecting the field toward a non-canonical ligand.","evidence":"Soluble KIR3DS1-Ig binding and MHC-I tetramer binding assays on transfected cell lines","pmids":["17202323","17411378"],"confidence":"Medium","gaps":["Negative results do not exclude peptide-restricted or low-affinity interactions","True ligand remained unknown"]},{"year":2009,"claim":"Distinguished KIR3DS1 from inhibitory KIR3DL1 functionally, showing KIR3DS1+ NK proliferation and cytotoxicity are inducible by cytokines and stimulator cells but independent of target-cell HLA-Bw4.","evidence":"NK cell proliferation/cytotoxicity assays under cytokine and cell-line stimulation","pmids":["19454667"],"confidence":"Medium","gaps":["Did not identify an activating ligand","HLA-Bw4 independence left the relevant ligand undefined"]},{"year":2011,"claim":"Provided the first direct KIR3DS1-HLA-Bw4 binding evidence using a rare allotype and mapped key specificity-determining residues, showing binding is allele-dependent and governed by particular extracellular positions.","evidence":"Flow cytometry binding with KIR3DS1*014 plus site-directed mutagenesis of positions 138 and 199","pmids":["21804024"],"confidence":"High","gaps":["Binding restricted to a rare allotype, not generalizable","Functional consequence of this binding not established"]},{"year":2015,"claim":"Refined the HLA-Bw4 relationship by showing KIR3DS1 can engage HLA-B*57:01 in a strictly peptide-dependent manner via specific HIV-derived epitopes, and that D0-domain polymorphisms reduce HLA-Bw4 binding and surface expression.","evidence":"Structure-driven peptide tetramer binding assays and mutagenesis of D0 residues 58/92 in KIR3DL1/KIR3DS1 chimeras","pmids":["25740999","26109640"],"confidence":"Medium","gaps":["Peptide-dependent HLA-Bw4 binding is weak and context-restricted","Did not yet identify the dominant physiological ligand"]},{"year":2016,"claim":"Identified HLA-F open conformers as the primary physiological ligand, resolving the long-standing ligand question and explaining KIR3DS1's failure to bind classical peptide-loaded MHC-I.","evidence":"Screen of 100 HLA proteins, surface plasmon resonance, biochemical pulldown, and primary NK functional/HIV-inhibition assays; independently replicated by SPR and pulldown","pmids":["27455421","27649529"],"confidence":"High","gaps":["Structural basis of the KIR3DS1/HLA-F open-conformer interface not resolved","Regulation of HLA-F open-conformer generation in vivo not fully defined"]},{"year":2017,"claim":"Showed that KIR3DS1 can deliver activating signals upon recognizing HLA-B*51 (Bw4-I80) on target cells, but only in HLA-Bw4-I80-negative individuals, highlighting context-dependent activation.","evidence":"NK clone killing/cytokine assays with antibody blockade of KIR3DS1 and NKG2D","pmids":["28603523"],"confidence":"Medium","gaps":["Relationship between HLA-Bw4 activation and HLA-F-dependent activation not reconciled","Partial inhibition by blocking leaves additional receptors contributing"]},{"year":2018,"claim":"Demonstrated the KIR3DS1/HLA-F axis is sufficient to activate NK cells against virus-infected targets, with HLA-F upregulation on HCV-infected cells driving NK control and direct ligation sufficient for activation.","evidence":"HCV cell culture, humanized mouse liver and primary tissue models; HLA-F-null 721.221 activation with KIR3DS1-Fc and anti-HLA-F blockade on primary NK cells","pmids":["30031767","29743316"],"confidence":"High","gaps":["Quantitative contribution relative to other NK receptors in vivo not isolated","Signaling steps downstream of DAP12 not dissected"]},{"year":2019,"claim":"Confirmed the axis operates in an autologous, biologically relevant setting, showing HLA-F on HIV-infected CD4+ T cells activates KIR3DS1+ NK cells and that blocking the interaction abolishes activation.","evidence":"Coculture of sorted autologous HIV-infected CD4+ T cells with primary NK cells, two independent blocking reagents, exclusive gating","pmids":["31270222"],"confidence":"High","gaps":["In vivo impact on viral reservoir not measured","Does not address evasion mechanisms"]},{"year":2020,"claim":"Extended the axis to additional pathogens and revealed a viral evasion mechanism: BK polyomavirus upregulates HLA-F to enhance KIR3DS1 activation, while HIV exploits hemoglobin-derived peptide loading of HLA-F to abrogate KIR3DS1 binding.","evidence":"BK polyomavirus infection model with patient kidney biopsies; recombinant KIR3DS1 binding with acid peptide elution and mass spectrometry on HLA-F-expressing K562 cells","pmids":["33359499","33126487"],"confidence":"Medium","gaps":["Peptide-loading evasion shown with recombinant binding, limited replication","Whether peptide loading is virally directed versus a cellular stress response not established"]},{"year":2021,"claim":"Generalized the KIR3DS1/HLA-F axis as a broad antiviral surveillance mechanism, showing adenovirus-induced HLA-F upregulation enables KIR3DS1+ NK killing of infected epithelium.","evidence":"3D intestinal organoid HAdV5 infection model with NK killing assays","pmids":["34533978"],"confidence":"High","gaps":["Pathogen-specific signals driving HLA-F induction not defined","In vivo relevance for adenoviral disease not tested"]},{"year":null,"claim":"How DAP12-coupled signaling is quantitatively triggered by HLA-F open conformers, the structural basis of the interaction, and how peptide loading of HLA-F is regulated during infection remain to be defined.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of the KIR3DS1/HLA-F complex","Downstream DAP12 signaling cascade not dissected","Cellular control of HLA-F open-conformer abundance not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,9]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[9,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,9]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,9,12,17]}],"complexes":[],"partners":["DAP12","HLA-F","HLA-B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14943","full_name":"Killer cell immunoglobulin-like receptor 3DS1","aliases":["Natural killer-associated transcript 10","NKAT-10"],"length_aa":382,"mass_kda":42.5,"function":"Receptor on natural killer (NK) cells for MHC class I molecules. Upon interaction with peptide-free HLA-F open conformer, triggers NK cell degranulation and anti-viral cytokine production","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q14943/entry"},"depmap":{"release":"DepMap","has_data":false,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KIR3DS1"},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KIR3DS1","total_profiled":1310},"omim":[{"mim_id":"620778","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, THREE DOMAINS, SHORT CYTOPLASMIC TAIL, 1; KIR3DS1","url":"https://www.omim.org/entry/620778"},{"mim_id":"610604","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, THREE DOMAINS, PSEUDOGENE 1; KIR3DP1","url":"https://www.omim.org/entry/610604"},{"mim_id":"609423","title":"HUMAN IMMUNODEFICIENCY VIRUS TYPE 1, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/609423"},{"mim_id":"604955","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, TWO DOMAINS, SHORT CYTOPLASMIC TAIL, 4; KIR2DS4","url":"https://www.omim.org/entry/604955"},{"mim_id":"604946","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, THREE DOMAINS, LONG CYTOPLASMIC TAIL, 1; KIR3DL1","url":"https://www.omim.org/entry/604946"}],"hpa":{"profiled":false,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"","tissue_distribution":"","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KIR3DS1"},"hgnc":{"alias_symbol":["nkat10"],"prev_symbol":[]},"alphafold":{"accession":"Q14943","domains":[{"cath_id":"2.60.40.10","chopping":"31-119","consensus_level":"high","plddt":82.1237,"start":31,"end":119},{"cath_id":"2.60.40.10","chopping":"123-219","consensus_level":"high","plddt":94.673,"start":123,"end":219},{"cath_id":"2.60.40.10","chopping":"223-317","consensus_level":"high","plddt":93.4282,"start":223,"end":317}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14943","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14943-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14943-F1-predicted_aligned_error_v6.png","plddt_mean":80.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KIR3DS1","jax_strain_url":"https://www.jax.org/strain/search?query=KIR3DS1"},"sequence":{"accession":"Q14943","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14943.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14943/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14943"}},"corpus_meta":[{"pmid":"12134147","id":"PMC_12134147","title":"Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS.","date":"2002","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12134147","citation_count":932,"is_preprint":false},{"pmid":"27455421","id":"PMC_27455421","title":"Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1.","date":"2016","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27455421","citation_count":191,"is_preprint":false},{"pmid":"19386717","id":"PMC_19386717","title":"HLA class I subtype-dependent expansion of KIR3DS1+ and KIR3DL1+ NK cells during acute human immunodeficiency virus type 1 infection.","date":"2009","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/19386717","citation_count":157,"is_preprint":false},{"pmid":"18317000","id":"PMC_18317000","title":"Increased proportion of KIR3DS1 homozygotes in HIV-exposed uninfected individuals.","date":"2008","source":"AIDS (London, 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IJI","url":"https://pubmed.ncbi.nlm.nih.gov/22426166","citation_count":18,"is_preprint":false},{"pmid":"29743316","id":"PMC_29743316","title":"HLA-F on HLA-Null 721.221 Cells Activates Primary NK Cells Expressing the Activating Killer Ig-like Receptor KIR3DS1.","date":"2018","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/29743316","citation_count":15,"is_preprint":false},{"pmid":"26109640","id":"PMC_26109640","title":"KIR3DS1-Specific D0 Domain Polymorphisms Disrupt KIR3DL1 Surface Expression and HLA Binding.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26109640","citation_count":13,"is_preprint":false},{"pmid":"34533978","id":"PMC_34533978","title":"KIR3DS1 directs NK cell-mediated protection against human adenovirus infections.","date":"2021","source":"Science 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KIR3DS1 expressed on NK cells triggers both cytotoxicity and IFN-gamma production.\",\n      \"method\": \"Cotransfection and coimmunoprecipitation; flow cytometry; in vitro cytotoxicity and cytokine production assays\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal coimmunoprecipitation plus functional assays (cytotoxicity, IFN-gamma), single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17202323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Surface expression of KIR3DS1 on NK cells is dependent on the adaptor protein DAP12, shown by transfection experiments. KIR3DS1 is recognized by the antibody Z27 on freshly isolated circulating NK cells from KIR3DS1/KIR3DS1 homozygous donors.\",\n      \"method\": \"Transfection; flow cytometry with antibody Z27 and DX9\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transfection-based DAP12 dependency shown, replicated across two papers (PMID 17202323 and 17301953), flow cytometry validation\",\n      \"pmids\": [\"17301953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Ligation of KIR3DS1 by the Z27 antibody on primary NK cells leads to IFN-gamma production and degranulation (CD107a expression), confirming its activating function. KIR3DS1 is also expressed on a small subset of CD56+ T cells.\",\n      \"method\": \"Flow cytometry; NK cell activation assays (IFN-gamma, CD107a); antibody cross-linking\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay on primary NK cells with antibody-mediated ligation, single lab, multiple readouts\",\n      \"pmids\": [\"17641029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KIR3DS1 (as soluble Ig fusion protein) did not bind to EBV-transformed B lymphoid cell lines transfected with HLA-Bw4 80I or 80T allotypes, indicating that if KIR3DS1 recognizes HLA-Bw4 ligands, this interaction is peptide dependent.\",\n      \"method\": \"Soluble KIR3DS1-Ig fusion protein binding assay; flow cytometry on HLA-Bw4-transfected cell lines\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with recombinant protein, negative result replicated by multiple labs\",\n      \"pmids\": [\"17202323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KIR3DS1 did not bind to a diverse panel of HIV-1-specific HLA-Bw4Ile80 MHC class I tetramers (including various HLA allotypes and peptide epitopes) in 293-T cells transiently expressing KIR3DS1, suggesting KIR3DS1 does not recognize standard peptide-loaded HLA-Bw4 complexes.\",\n      \"method\": \"Flow cytometry; MHC class I tetramer binding assay on KIR3DS1-transfected 293-T cells\",\n      \"journal\": \"AIDS research and human retroviruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct binding assay, negative result, single lab, consistent with other negative binding reports\",\n      \"pmids\": [\"17411378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KIR3DS1 expression on NK cells can be induced (upregulated) after exposure to stimulator cells (721.221, K562, EBV-B cell lines, B cells), polyinosinic-polycytidylic acid, IL-15, or IL-2. KIR3DS1+ NK cell proliferation and cytotoxicity were not influenced by the presence of HLA-Bw4 on target cells, in contrast to KIR3DL1+ NK cells.\",\n      \"method\": \"Flow cytometry; NK cell proliferation and cytotoxicity assays; stimulation with cytokines and cell lines\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple stimulation conditions, functional readouts, single lab\",\n      \"pmids\": [\"19454667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The rare KIR3DS1 allotype KIR3DS1*014 directly binds HLA-Bw4, providing the first evidence of direct KIR3DS1-HLA-Bw4 binding. Mutagenesis revealed that position 138 is a key determinant of ligand specificity for KIR3DS1, and that reactivity is dictated by complex interactions between residues at positions 138 and 199.\",\n      \"method\": \"Flow cytometry binding assay; site-directed mutagenesis; recombinant protein analysis\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding assay combined with mutagenesis defining key residues, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"21804024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KIR3DS1 recognizes HLA-B*57:01 in a peptide-dependent manner. Using a structure-driven approach, specific HIV-derived peptide epitopes were identified that facilitate productive KIR3DS1-HLA-B*57:01 interactions, establishing that KIR3DS1 ligands exist within the HIV-specific peptide repertoire.\",\n      \"method\": \"Structure-driven peptide analysis; flow cytometry binding assays with HLA-B*57:01 tetramers and KIR3DS1-expressing cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-informed experimental validation, peptide-dependent binding demonstrated, single lab\",\n      \"pmids\": [\"25740999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KIR3DS1-specific polymorphisms at positions 58 and 92 in the D0 extracellular domain, when introduced into KIR3DL1*009, cause reduced surface expression and dramatically reduced HLA-Bw4 binding compared to KIR3DL1*001, as shown by mutagenesis.\",\n      \"method\": \"Flow cytometry on primary NK cells and transfected HEK293T cells; recombinant protein binding assays; site-directed mutagenesis\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with recombinant protein binding assays and primary cell analysis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"26109640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIR3DS1 binds HLA-F open conformers (peptide-free/beta2-microglobulin-free forms). Biochemical screening of 100 HLA class I proteins identified HLA-F as the ligand; confirmed by surface plasmon resonance and biochemical pulldown. Primary KIR3DS1+ NK cells degranulated and produced antiviral cytokines upon encountering HLA-F and inhibited HIV-1 replication in vitro. HIV-1 infection upregulated HLA-F mRNA but decreased KIR3DS1 binding, suggesting viral immune evasion.\",\n      \"method\": \"HLA-protein screen (100 proteins); surface plasmon resonance; biochemical pulldown; primary NK cell functional assays (degranulation, cytokine production); HIV-1 inhibition assay; flow cytometry\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with recombinant proteins (SPR), biochemical pulldown, and primary cell functional assays, replicated by independent lab (PMID 27649529)\",\n      \"pmids\": [\"27455421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIR3DS1 but not KIR3DL1 physically binds HLA-F and other MHC-I open conformers, measured by surface plasmon resonance and biochemical pulldown from cell lines. KIR3DS1 binding to surface-bound HLA-F increases granule exocytosis in activated NK cells.\",\n      \"method\": \"Surface plasmon resonance; biochemical pulldown; biochemical heterodimerization with recombinant proteins; degranulation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — independent replication of HLA-F binding via SPR and pulldown, consistent with PMID 27455421, multiple methods in single study\",\n      \"pmids\": [\"27649529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KIR3DS1 mediates positive signaling (NK cell activation/killing) upon recognition of HLA-B*51 (Bw4-I80) surface molecules on target cells. This activation occurs only in HLA-Bw4-I80-negative individuals. KIR3DS1-mediated activation was partially inhibited by antibody masking of KIR3DS1, and killing could be further revealed when NKG2D function was reduced by antibody blockade.\",\n      \"method\": \"NK cell clone functional assays (killing, cytokine); antibody blocking of KIR3DS1 and NKG2D; transfected target cell killing assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct blocking experiments and NK clone killing assays, single lab, multiple readouts\",\n      \"pmids\": [\"28603523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Interactions between KIR3DS1 and its ligand HLA-F activate NK cells to control HCV replication. HLA-F is upregulated on HCV-infected cells, and KIR3DS1/HLA-F interactions contribute to NK cell-mediated control of HCV in cell culture, in humanized mouse livers, and in primary liver tissue from HCV-infected individuals.\",\n      \"method\": \"Cell culture HCV infection model; humanized mouse liver model; primary liver tissue analysis; NK cell functional assays\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple experimental systems (cell culture, humanized mice, primary tissue), mechanistic link between HLA-F upregulation and KIR3DS1 activation established\",\n      \"pmids\": [\"30031767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KIR3DS1+ NK cells from KIR3DS1 homozygotes are activated by HLA-F on HLA-null 721.221 cells to produce CCL4, IFN-γ, and express CD107a. Blocking with KIR3DS1-Fc chimeric protein or anti-HLA-F antibodies reduced this activation, demonstrating HLA-F/KIR3DS1 ligation is sufficient for NK cell activation.\",\n      \"method\": \"NK cell functional assays (CCL4, IFN-γ, CD107a); antibody blocking (KIR3DS1-Fc chimeric protein, anti-HLA-F); flow cytometry with exclusive gating\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — blocking experiments with two independent reagents (receptor-Fc and anti-ligand Ab) plus primary cell functional readouts, single lab\",\n      \"pmids\": [\"29743316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HLA-F expressed on autologous HIV-infected CD4+ T cells activates primary KIR3DS1+ NK cells (higher frequency than KIR3DS1- NK cells) to produce CCL4, IFN-γ, and express CD107a. Blocking HLA-F on HIV-infected cells with KIR3DS1-Fc chimeric protein or anti-HLA-F antibody reduced KIR3DS1+ NK cell activation, establishing that the HLA-F/KIR3DS1 interaction is sufficient to activate NK cells against HIV-infected cells.\",\n      \"method\": \"Coculture of sorted HIV-infected CD4+ T cells with primary NK cells; antibody/Fc-fusion blocking; flow cytometry with exclusive gating for KIR3DS1+ NK cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — autologous system with two independent blocking reagents, exclusive gating controls, replicates previous HLA-F findings in biologically relevant HIV-infected cells\",\n      \"pmids\": [\"31270222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BK polyomavirus infection significantly increases surface expression of HLA-F on kidney tubular cells, resulting in increased binding of KIR3DS1 to infected cells and activation of primary KIR3DS1+ NK cells, as shown in cell culture and confirmed in kidney biopsy samples from patients.\",\n      \"method\": \"In vitro BK polyomavirus infection model; flow cytometry (HLA-F expression, KIR3DS1 binding); primary NK cell activation assays; immunohistochemistry of patient kidney biopsies\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell culture model plus patient tissue validation, mechanistic link between viral upregulation of HLA-F and KIR3DS1 activation established, single lab\",\n      \"pmids\": [\"33359499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HLA-F loaded with hemoglobin-derived peptides (which are upregulated in HIV-infected CD4+ T cells) loses affinity for KIR3DS1, while acid elution of peptides (generating open conformers) restores KIR3DS1 binding. This provides a molecular mechanism for HIV immune evasion via peptide-dependent regulation of HLA-F/KIR3DS1 interaction.\",\n      \"method\": \"Recombinant soluble KIR3DS1 binding assays; acid elution of peptides; mass spectrometry proteome analysis; flow cytometry on K562 cells expressing membrane-bound HLA-F alleles\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — recombinant protein binding assay with peptide manipulation, single lab, limited replication\",\n      \"pmids\": [\"33126487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HLA-F is strongly upregulated on HAdV5-infected intestinal organoid cells, enabling enhanced killing of infected cells by KIR3DS1+ NK cells. This demonstrates that the KIR3DS1/HLA-F axis mediates NK cell recognition and killing of adenovirus-infected cells.\",\n      \"method\": \"3D intestinal organoid infection model; flow cytometry (HLA-F upregulation); NK cell killing assays with KIR3DS1+ NK cells\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary organoid system with direct killing assay, functional mechanistic link established between HLA-F induction and KIR3DS1-mediated killing, single lab\",\n      \"pmids\": [\"34533978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Genetic epistasis analysis revealed that KIR3DS1 in combination with HLA-B Bw4-80Ile alleles is associated with delayed progression to AIDS in HIV-1-infected individuals, and KIR3DS1 alone (without Bw4-80Ile) was associated with more rapid progression, demonstrating a synergistic epistatic interaction between KIR3DS1 and HLA-B Bw4-80Ile loci.\",\n      \"method\": \"Genetic epistasis analysis in large cohort; KIR and HLA genotyping; Cox proportional hazards regression\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in large multi-cohort study, replicated in multiple subsequent studies, but mechanistic basis is inferred not directly demonstrated\",\n      \"pmids\": [\"12134147\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIR3DS1 is an activating NK cell receptor that signals via DAP12 (ITAM-bearing adaptor), with its primary functional ligand being HLA-F open conformers (peptide-free MHC-I); upon binding HLA-F — which is upregulated on cells infected with HIV, HCV, adenovirus, or BK polyomavirus — KIR3DS1 triggers NK cell degranulation, IFN-γ and CCL4 production, and target cell killing, while HIV infection exploits hemoglobin-derived peptide loading of HLA-F to reduce KIR3DS1 ligation and evade NK cell recognition.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIR3DS1 is an activating killer-cell immunoglobulin-like receptor that arms NK cells to recognize and eliminate virus-infected cells through the open-conformer ligand HLA-F [#9, #17]. Lacking an intrinsic signaling domain, KIR3DS1 associates with the ITAM-bearing adaptor DAP12, which is required for both its surface expression and its capacity to trigger cytotoxicity and IFN-\\u03b3 production [#0, #1]. Antibody-mediated ligation of KIR3DS1 on primary NK cells drives degranulation (CD107a) and cytokine output, confirming its bona fide activating function [#2]. Biochemical screening of the HLA class I repertoire identified peptide-free, \\u03b22-microglobulin-free HLA-F open conformers as the physiological ligand, a specificity confirmed by surface plasmon resonance and pulldown that distinguishes KIR3DS1 from the inhibitory paralog KIR3DL1 [#9, #10]. Because HLA-F is strongly upregulated on cells infected with HIV-1, HCV, BK polyomavirus, and adenovirus, the KIR3DS1/HLA-F axis enables NK cell-mediated control of these infections across cell-culture, humanized-mouse, organoid, and primary-tissue systems [#12, #14, #15, #17]. HIV-1 subverts this recognition by loading HLA-F with hemoglobin-derived peptides, which abolishes KIR3DS1 binding, whereas removing peptide to regenerate open conformers restores it \\u2014 a molecular basis for viral immune evasion [#16]. KIR3DS1 binding to canonical peptide-loaded HLA-Bw4 is weak and allele/peptide-restricted, with most allotypes failing to bind classical HLA-Bw4 tetramers and only rare variants or specific HIV-derived peptide complexes supporting interaction [#3, #6, #7]. Consistent with these molecular findings, KIR3DS1 in combination with HLA-B Bw4-80Ile alleles is genetically associated with delayed progression to AIDS in HIV-1 infection [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the first functional clue that KIR3DS1 shapes antiviral immunity, showing a genetic interaction with HLA-B Bw4-80Ile that predicts the rate of HIV disease progression and motivating the search for a ligand and mechanism.\",\n      \"evidence\": \"Genetic epistasis analysis with KIR/HLA genotyping and Cox regression in a large HIV-1 cohort\",\n      \"pmids\": [\"12134147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Statistical association only; no direct receptor-ligand interaction demonstrated\", \"Did not identify the molecular ligand or signaling pathway\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined KIR3DS1 as an activating receptor by showing it associates with DAP12, depends on DAP12 for surface expression, and triggers cytotoxicity, IFN-\\u03b3 and degranulation upon ligation.\",\n      \"evidence\": \"Cotransfection/coimmunoprecipitation in NKL cells, DAP12-dependent transfection, and antibody cross-linking functional assays on primary NK cells\",\n      \"pmids\": [\"17202323\", \"17301953\", \"17641029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological ligand not identified\", \"Antibody ligation does not establish the natural activating stimulus\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Ruled out classical peptide-loaded HLA-Bw4 as a straightforward ligand, showing soluble KIR3DS1 and KIR3DS1-expressing cells fail to bind HLA-Bw4 transfectants or HIV-specific HLA-Bw4 tetramers, redirecting the field toward a non-canonical ligand.\",\n      \"evidence\": \"Soluble KIR3DS1-Ig binding and MHC-I tetramer binding assays on transfected cell lines\",\n      \"pmids\": [\"17202323\", \"17411378\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative results do not exclude peptide-restricted or low-affinity interactions\", \"True ligand remained unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Distinguished KIR3DS1 from inhibitory KIR3DL1 functionally, showing KIR3DS1+ NK proliferation and cytotoxicity are inducible by cytokines and stimulator cells but independent of target-cell HLA-Bw4.\",\n      \"evidence\": \"NK cell proliferation/cytotoxicity assays under cytokine and cell-line stimulation\",\n      \"pmids\": [\"19454667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify an activating ligand\", \"HLA-Bw4 independence left the relevant ligand undefined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided the first direct KIR3DS1-HLA-Bw4 binding evidence using a rare allotype and mapped key specificity-determining residues, showing binding is allele-dependent and governed by particular extracellular positions.\",\n      \"evidence\": \"Flow cytometry binding with KIR3DS1*014 plus site-directed mutagenesis of positions 138 and 199\",\n      \"pmids\": [\"21804024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding restricted to a rare allotype, not generalizable\", \"Functional consequence of this binding not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Refined the HLA-Bw4 relationship by showing KIR3DS1 can engage HLA-B*57:01 in a strictly peptide-dependent manner via specific HIV-derived epitopes, and that D0-domain polymorphisms reduce HLA-Bw4 binding and surface expression.\",\n      \"evidence\": \"Structure-driven peptide tetramer binding assays and mutagenesis of D0 residues 58/92 in KIR3DL1/KIR3DS1 chimeras\",\n      \"pmids\": [\"25740999\", \"26109640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Peptide-dependent HLA-Bw4 binding is weak and context-restricted\", \"Did not yet identify the dominant physiological ligand\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified HLA-F open conformers as the primary physiological ligand, resolving the long-standing ligand question and explaining KIR3DS1's failure to bind classical peptide-loaded MHC-I.\",\n      \"evidence\": \"Screen of 100 HLA proteins, surface plasmon resonance, biochemical pulldown, and primary NK functional/HIV-inhibition assays; independently replicated by SPR and pulldown\",\n      \"pmids\": [\"27455421\", \"27649529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the KIR3DS1/HLA-F open-conformer interface not resolved\", \"Regulation of HLA-F open-conformer generation in vivo not fully defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that KIR3DS1 can deliver activating signals upon recognizing HLA-B*51 (Bw4-I80) on target cells, but only in HLA-Bw4-I80-negative individuals, highlighting context-dependent activation.\",\n      \"evidence\": \"NK clone killing/cytokine assays with antibody blockade of KIR3DS1 and NKG2D\",\n      \"pmids\": [\"28603523\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between HLA-Bw4 activation and HLA-F-dependent activation not reconciled\", \"Partial inhibition by blocking leaves additional receptors contributing\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated the KIR3DS1/HLA-F axis is sufficient to activate NK cells against virus-infected targets, with HLA-F upregulation on HCV-infected cells driving NK control and direct ligation sufficient for activation.\",\n      \"evidence\": \"HCV cell culture, humanized mouse liver and primary tissue models; HLA-F-null 721.221 activation with KIR3DS1-Fc and anti-HLA-F blockade on primary NK cells\",\n      \"pmids\": [\"30031767\", \"29743316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution relative to other NK receptors in vivo not isolated\", \"Signaling steps downstream of DAP12 not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed the axis operates in an autologous, biologically relevant setting, showing HLA-F on HIV-infected CD4+ T cells activates KIR3DS1+ NK cells and that blocking the interaction abolishes activation.\",\n      \"evidence\": \"Coculture of sorted autologous HIV-infected CD4+ T cells with primary NK cells, two independent blocking reagents, exclusive gating\",\n      \"pmids\": [\"31270222\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo impact on viral reservoir not measured\", \"Does not address evasion mechanisms\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the axis to additional pathogens and revealed a viral evasion mechanism: BK polyomavirus upregulates HLA-F to enhance KIR3DS1 activation, while HIV exploits hemoglobin-derived peptide loading of HLA-F to abrogate KIR3DS1 binding.\",\n      \"evidence\": \"BK polyomavirus infection model with patient kidney biopsies; recombinant KIR3DS1 binding with acid peptide elution and mass spectrometry on HLA-F-expressing K562 cells\",\n      \"pmids\": [\"33359499\", \"33126487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Peptide-loading evasion shown with recombinant binding, limited replication\", \"Whether peptide loading is virally directed versus a cellular stress response not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Generalized the KIR3DS1/HLA-F axis as a broad antiviral surveillance mechanism, showing adenovirus-induced HLA-F upregulation enables KIR3DS1+ NK killing of infected epithelium.\",\n      \"evidence\": \"3D intestinal organoid HAdV5 infection model with NK killing assays\",\n      \"pmids\": [\"34533978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pathogen-specific signals driving HLA-F induction not defined\", \"In vivo relevance for adenoviral disease not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DAP12-coupled signaling is quantitatively triggered by HLA-F open conformers, the structural basis of the interaction, and how peptide loading of HLA-F is regulated during infection remain to be defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the KIR3DS1/HLA-F complex\", \"Downstream DAP12 signaling cascade not dissected\", \"Cellular control of HLA-F open-conformer abundance not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 9]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 9, 12, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DAP12\", \"HLA-F\", \"HLA-B\"]\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}