{"gene":"KIR3DS1","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2002,"finding":"Genetic epistasis analysis demonstrated that KIR3DS1, in combination with HLA-B alleles encoding isoleucine at position 80 (HLA-B Bw4-80Ile), is associated with delayed progression to AIDS in HIV-1-infected individuals, suggesting an epistatic interaction between the two loci in NK cell-mediated protection.","method":"Genetic epistasis analysis in HIV-1 cohort studies","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — epistatic genetic interaction replicated across multiple cohorts, 928 citations, foundational study","pmids":["12134147"],"is_preprint":false},{"year":2007,"finding":"KIR3DS1 associates with the ITAM-bearing adaptor protein DAP12 (demonstrated by cotransfection and coimmunoprecipitation), and its ligation triggers NK cell cytotoxicity and IFN-gamma production. Soluble KIR3DS1-Ig fusion proteins did not bind HLA-Bw4 80I or 80T allotypes on EBV-transformed B cell lines, suggesting HLA-Bw4 ligand recognition may be peptide-dependent.","method":"Cotransfection, coimmunoprecipitation, in vitro cytotoxicity assay, cytokine production assay, flow cytometry with soluble fusion proteins","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal Co-IP for DAP12 association plus functional assays; replicated by Trundley et al. same year","pmids":["17202323"],"is_preprint":false},{"year":2007,"finding":"KIR3DS1 surface expression on NK cells is dependent on the adaptor protein DAP12; without DAP12, KIR3DS1 is not expressed on the cell surface. KIR3DS1 is recognized by the antibody Z27 and is expressed on a substantial subset of peripheral NK cells and a small proportion of CD56+ T cells.","method":"Transfection, flow cytometry, antibody staining (Z27, DX9), surface expression analysis","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — replicated across two independent papers (Trundley et al. and Carr et al. 2007) using transfection and primary cells","pmids":["17301953","17202323"],"is_preprint":false},{"year":2007,"finding":"KIR3DS1 ligation by antibody Z27 leads to NK cell IFN-gamma production and degranulation (CD107a expression), confirming activating receptor function on peripheral NK cells.","method":"Antibody-mediated ligation, flow cytometry (IFN-gamma, CD107a)","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — clean functional assay on primary NK cells with defined readout, replicated across studies","pmids":["17641029"],"is_preprint":false},{"year":2011,"finding":"The rare KIR3DS1 allotype KIR3DS1*014 (differing from KIR3DS1*013 at position 138) directly binds HLA-Bw4, providing the first direct evidence of KIR3DS1 binding to HLA-Bw4. Position 138 is a key determinant of ligand specificity, and reactivity is dependent on complex interactions between multiple residues (including positions 199 and 138).","method":"Mutagenesis, cell binding assay (flow cytometry with HLA-Bw4-expressing cells), recombinant protein analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding demonstrated with mutagenesis to identify key residues, multiple orthogonal approaches","pmids":["21804024"],"is_preprint":false},{"year":2015,"finding":"KIR3DS1 recognition of HLA-B*57:01 is peptide-dependent: specific HIV-derived peptide epitopes presented by HLA-B*57:01 facilitate productive interactions between HLA-B*57:01 and KIR3DS1, while other peptides do not support binding.","method":"Structure-driven approach, peptide binding assays, flow cytometry with KIR3DS1-expressing cells and HLA-peptide complexes","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 — structure-guided identification of peptide specificity with direct binding assays and mutagenesis-level controls","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, disrupt surface expression and HLA-Bw4 binding, establishing that these residues are critical for KIR3DS1's distinct ligand binding properties.","method":"Mutagenesis, flow cytometry, recombinant protein binding assay, primary NK cell functional assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — site-directed mutagenesis combined with surface expression and binding assays identifying specific causal residues","pmids":["26109640"],"is_preprint":false},{"year":2016,"finding":"KIR3DS1 binds specifically to HLA-F open conformers (peptide-free, beta-2-microglobulin-free forms of HLA-F), but not to peptide-loaded classical HLA class I. Primary KIR3DS1+ NK cells degranulate and produce antiviral cytokines upon encountering HLA-F, and inhibit HIV-1 replication in vitro. HLA-F surface expression is upregulated on activated CD4+ T cells and HIV-infected cells.","method":"Screening of 100 HLA class I proteins, biochemical binding assays, surface plasmon resonance, flow cytometry, in vitro HIV replication inhibition assay, primary NK cell functional assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1 — large-scale HLA screen, biochemical binding, SPR, and functional validation with primary cells; 190 citations","pmids":["27455421"],"is_preprint":false},{"year":2016,"finding":"Physical binding of KIR3DS1 (but not KIR3DL1) to HLA-F and other MHC-I open conformers was demonstrated by surface plasmon resonance, biochemical pulldown from cell lines, and heterodimerization with recombinant proteins. KIR3DS1 engagement by surface-bound HLA-F increases granule exocytosis in activated NK cells.","method":"Surface plasmon resonance, biochemical pulldown, recombinant protein heterodimerization, granule exocytosis assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal biochemical and biophysical methods independently confirming HLA-F/KIR3DS1 binding","pmids":["27649529"],"is_preprint":false},{"year":2017,"finding":"KIR3DS1 mediates activation signals upon recognition of HLA-B*51 (Bw4-I80) surface molecules on target cells, but this activation occurs only in Bw4-I80-negative individuals, suggesting HLA-B*51 serves as a KIR3DS1 ligand. KIR3DS1-mediated recognition of HLA-B*51 also plays a role in NK cell education/licensing.","method":"NK cell clone functional assays, antibody-mediated blocking, KIR3DS1+ clone killing assays, flow cytometry","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — single lab with multiple functional readouts but indirect evidence for direct HLA-B*51 binding","pmids":["28603523"],"is_preprint":false},{"year":2018,"finding":"KIR3DS1 binding to HLA-F on HCV-infected cells activates NK cells to control HCV replication in cell culture. HLA-F is upregulated on HCV-infected cells, and the KIR3DS1/HLA-F interaction contributes to NK cell-mediated antiviral response.","method":"Cell culture HCV infection model, NK cell activation assays, in vitro viral replication assay, humanized mouse liver model, primary liver tissue analysis","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 — multiple experimental systems (cell culture, humanized mice, primary tissue) with functional readouts","pmids":["30031767"],"is_preprint":false},{"year":2018,"finding":"HLA-F on HLA-null 721.221 cells activates primary KIR3DS1+ NK cells to secrete CCL4 and IFN-gamma and express CD107a. Blocking the HLA-F/KIR3DS1 interaction with KIR3DS1-Fc chimeric protein or anti-HLA-F antibodies reduced this activation, establishing HLA-F as sufficient to activate KIR3DS1+ NK cells.","method":"Primary NK cell co-culture with HLA-null cell line, antibody-mediated blocking, flow cytometry (CCL4, IFN-gamma, CD107a), exclusive gating strategies","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — blocking experiments and exclusive gating provide strong evidence for sufficiency of HLA-F/KIR3DS1 interaction","pmids":["29743316"],"is_preprint":false},{"year":2019,"finding":"HLA-F on HIV-infected CD4+ T cells activates KIR3DS1+ NK cells to produce CCL4, IFN-gamma, and CD107a. Blocking HLA-F on infected cells with KIR3DS1-Fc chimeric protein or anti-HLA-F monoclonal antibody reduced KIR3DS1+ NK cell activation, demonstrating that the HLA-F/KIR3DS1 interaction is sufficient for NK cell activation against HIV-infected cells.","method":"Primary NK cell co-culture with sorted HIV-infected CD4+ T cells, KIR3DS1-Fc blocking, anti-HLA-F antibody blocking, flow cytometry","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — blocking experiments with two orthogonal reagents in physiologically relevant HIV-infected primary cell system","pmids":["31270222"],"is_preprint":false},{"year":2020,"finding":"BK polyomavirus infection of kidney tubular cells upregulates surface HLA-F expression, which increases KIR3DS1 binding to infected cells and activates primary KIR3DS1+ NK cells, establishing a mechanism for NK cell recognition of BK polyomavirus-infected cells.","method":"In vitro BK polyomavirus infection model, flow cytometry (HLA-F surface expression, KIR3DS1 binding), primary NK cell activation assay, kidney biopsy analysis","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 — in vitro infection model combined with primary NK cell functional assays and patient biopsy validation","pmids":["33359499"],"is_preprint":false},{"year":2020,"finding":"HLA-F loaded with hemoglobin-derived peptides loses affinity for KIR3DS1: peptide-free HLA-F open conformers bind KIR3DS1, but acid elution restoring open conformers rescues binding, while addition of hemoglobin peptide fractions to HLA-F open conformers significantly reduces KIR3DS1 recognition — identifying a mechanism for HIV immune escape via HLA-F peptide loading.","method":"Soluble HLA technology, mass spectrometry peptidome analysis, recombinant KIR3DS1-Fc binding assays, K562 cell transfection","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical binding assays with MS peptide identification, single lab study","pmids":["33126487"],"is_preprint":false},{"year":2021,"finding":"HLA-F is strongly upregulated on HAdV5-infected intestinal organoid cells, enabling KIR3DS1+ NK cells to kill infected cells more efficiently via the KIR3DS1/HLA-F axis. In contrast, HLA-A and HLA-B are downregulated by adenoviral E3/gp19K, suggesting a viral evasion strategy against CD8+ T cells that simultaneously exposes infected cells to KIR3DS1+ NK cell killing.","method":"3D intestinal organoid infection model, flow cytometry (HLA-F, HLA-A, HLA-B expression), KIR3DS1+ NK cell killing assay, immunogenetic cohort analysis","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection in organoid model combined with clinical immunogenetic validation","pmids":["34533978"],"is_preprint":false},{"year":2009,"finding":"KIR3DS1+ NK cells specifically expand during acute HIV-1 infection in the presence of HLA-B Bw480I, demonstrating HLA class I subtype-dependent expansion of KIR3DS1+ NK cells during an acute viral infection.","method":"Longitudinal cohort study, flow cytometry, KIR/HLA genotyping","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — direct cell expansion measurement with HLA subtype stratification in human cohort","pmids":["19386717"],"is_preprint":false},{"year":2009,"finding":"KIR3DS1 expression on NK cells can be induced after exposure to stimulator cells (221, K562, EBV-B cell lines, B cells), poly(I:C), IL-15, or IL-2. KIR3DS1+ NK cell proliferation and cytotoxicity were not inhibited in a Bw4+ context (unlike KIR3DL1+ NK cells), suggesting KIR3DS1 does not recognize HLA-Bw4 in a physiological context.","method":"NK cell stimulation assays, flow cytometry, proliferation assays, cytotoxicity assays with Bw4+/- target cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple stimulation conditions and functional readouts in primary NK cells, single lab","pmids":["19454667"],"is_preprint":false},{"year":2007,"finding":"Despite testing a broad array of Bw4Ile80 HLA class I tetramers with HIV-1-derived peptide epitopes, no tetramer binding to KIR3DS1 expressed on 293-T cells was detected, indicating that HLA-Bw4 with typical CD8+ T cell peptide epitopes does not constitute a KIR3DS1 ligand.","method":"Flow cytometry, MHC class I tetramer binding assay, transient transfection of KIR3DS1 on 293-T cells","journal":"AIDS research and human retroviruses","confidence":"Medium","confidence_rationale":"Tier 2 — negative binding result with broad peptide/HLA panel, single lab","pmids":["17411378"],"is_preprint":false}],"current_model":"KIR3DS1 is an activating NK cell receptor that associates with the ITAM-bearing adaptor DAP12 (requiring it for surface expression), and signals through recognition of HLA-F open conformers (peptide-free/beta-2-microglobulin-free forms) as its primary ligand — triggering NK cell cytotoxicity, IFN-gamma production, and CCL4 secretion; HLA-F is upregulated on virally infected cells (HIV, HCV, HAdV, BK polyomavirus), and loading of HLA-F with peptides (including hemoglobin-derived peptides during HIV infection) can abrogate KIR3DS1 binding, providing a mechanism for viral immune escape, while rare KIR3DS1 allotypes (e.g., KIR3DS1*014) can also directly bind HLA-Bw4 in a peptide-dependent manner through critical residues at position 138 of the receptor."},"narrative":{"teleology":[{"year":2002,"claim":"Establishing that KIR3DS1 cooperates epistatically with HLA-B Bw4-80Ile to influence HIV-1 disease progression provided the first functional rationale for studying this receptor in antiviral immunity.","evidence":"Genetic epistasis analysis across multiple HIV-1 cohorts","pmids":["12134147"],"confidence":"High","gaps":["No direct molecular interaction between KIR3DS1 and HLA-Bw4 demonstrated","Mechanism of protection at the cellular level unresolved"]},{"year":2007,"claim":"Demonstrating that KIR3DS1 associates with DAP12 (required for surface expression) and triggers NK cell cytotoxicity and IFN-γ production established its signaling mechanism, while the failure of KIR3DS1-Ig fusions and HLA-Bw4 tetramers to bind indicated that HLA-Bw4 is not a straightforward ligand.","evidence":"Co-IP, cotransfection, functional assays on primary NK cells, soluble fusion protein and tetramer binding assays across broad peptide/HLA panels","pmids":["17202323","17301953","17641029","17411378"],"confidence":"High","gaps":["True physiological ligand unidentified","Whether peptide context could enable HLA-Bw4 binding remained untested with comprehensive peptide libraries"]},{"year":2009,"claim":"Showing that KIR3DS1+ NK cells expand during acute HIV-1 infection in an HLA-B Bw4-80Ile-dependent manner and that KIR3DS1 does not inhibit cytotoxicity against Bw4+ targets reinforced its activating function in vivo while further questioning direct Bw4 recognition.","evidence":"Longitudinal HIV cohort with flow cytometry; NK cell proliferation and cytotoxicity assays against Bw4+/- targets","pmids":["19386717","19454667"],"confidence":"Medium","gaps":["Molecular basis for Bw4-80Ile-dependent expansion unclear","Indirect genetic association rather than direct binding evidence"]},{"year":2011,"claim":"Identifying that the rare KIR3DS1*014 allotype directly binds HLA-Bw4, with position 138 as a key determinant, provided the first direct binding evidence and revealed that allotypic variation dictates ligand specificity.","evidence":"Site-directed mutagenesis and cell-based binding assays with recombinant proteins","pmids":["21804024"],"confidence":"High","gaps":["Binding restricted to a rare allotype; generalizability to common allotypes unclear","Structural basis of position 138 contribution unresolved"]},{"year":2015,"claim":"Establishing peptide-dependent recognition of HLA-B*57:01 by KIR3DS1 and identifying D0-domain residues (positions 58, 92) critical for ligand binding explained why standard tetramer assays had failed and defined the molecular determinants distinguishing KIR3DS1 from KIR3DL1.","evidence":"Structure-guided peptide binding assays; mutagenesis of D0 domain residues with surface expression and binding readouts","pmids":["25740999","26109640"],"confidence":"High","gaps":["No crystal structure of KIR3DS1–HLA complex available","Full peptide repertoire enabling binding unknown"]},{"year":2016,"claim":"The identification of HLA-F open conformers as the primary KIR3DS1 ligand resolved the long-standing ligand question, showing that peptide-free, β2m-free HLA-F drives NK cell degranulation, cytokine production, and HIV replication control.","evidence":"Screening of 100 HLA class I proteins, SPR, biochemical pulldown, primary NK cell functional assays, in vitro HIV inhibition","pmids":["27455421","27649529"],"confidence":"High","gaps":["Structural basis of KIR3DS1–HLA-F interaction unresolved","Relative contribution of HLA-F versus HLA-Bw4 recognition in vivo unclear"]},{"year":2018,"claim":"Blocking experiments with KIR3DS1-Fc and anti-HLA-F antibodies on both HLA-null cells and HIV-infected CD4+ T cells established that HLA-F is sufficient to activate KIR3DS1+ NK cells, and extended the axis to HCV infection.","evidence":"Primary NK cell co-culture with HLA-null 721.221 cells and HIV-infected CD4+ T cells; antibody/Fc blocking; HCV cell-culture infection model and humanized mouse model","pmids":["29743316","31270222","30031767"],"confidence":"High","gaps":["Contribution of other activating receptors to the observed antiviral effects not fully delineated","In vivo relevance in human infection awaits clinical intervention studies"]},{"year":2020,"claim":"Demonstrating that peptide loading of HLA-F (particularly with hemoglobin-derived peptides) abrogates KIR3DS1 binding, and that BK polyomavirus infection upregulates HLA-F to activate KIR3DS1+ NK cells, broadened the ligand model to include a peptide-based escape mechanism and a fourth viral context.","evidence":"MS peptidome analysis with recombinant KIR3DS1-Fc binding assays; in vitro BK polyomavirus kidney tubular cell infection with primary NK cell assays and patient biopsy validation","pmids":["33126487","33359499"],"confidence":"High","gaps":["Peptide-mediated immune escape mechanism demonstrated only in biochemical assays, not in infected-cell cocultures","Whether HLA-F peptide loading is actively promoted by viral factors is unknown"]},{"year":2021,"claim":"Showing that adenoviral E3/gp19K downregulates HLA-A/B while HLA-F is upregulated on infected organoid cells, enabling KIR3DS1+ NK cell killing, revealed a viral immune-evasion trade-off that exposes infected cells to activating NK receptor surveillance.","evidence":"3D intestinal organoid HAdV5 infection model, flow cytometry, KIR3DS1+ NK cell killing assays, immunogenetic cohort analysis","pmids":["34533978"],"confidence":"High","gaps":["Whether other viruses that downregulate classical HLA-I similarly expose HLA-F is untested","In vivo outcome data linking KIR3DS1 genotype to adenoviral disease severity are limited"]},{"year":null,"claim":"No crystal or cryo-EM structure of the KIR3DS1–HLA-F complex exists, leaving the atomic basis of open-conformer selectivity and peptide-mediated escape unresolved; the relative contribution of HLA-F versus HLA-Bw4 recognition to in vivo antiviral protection also remains undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of KIR3DS1–HLA-F interaction","In vivo hierarchy of HLA-F versus HLA-Bw4 ligand engagement unknown","Whether KIR3DS1 has additional non-HLA ligands is unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,3,7,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3,7]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,7,10,12,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,7,11]}],"complexes":["KIR3DS1–DAP12 signaling complex"],"partners":["TYROBP","HLA-F"],"other_free_text":[]},"mechanistic_narrative":"KIR3DS1 is an activating killer-cell immunoglobulin-like receptor on NK cells that signals through the ITAM-bearing adaptor DAP12 to trigger cytotoxicity, IFN-γ production, and CCL4 secretion upon engagement of its ligand. KIR3DS1 requires DAP12 for surface expression and preferentially recognizes HLA-F open conformers (peptide-free, β2-microglobulin-free forms), which are upregulated on cells infected by HIV, HCV, HAdV, and BK polyomavirus, thereby enabling NK cell-mediated antiviral immunity [PMID:27455421, PMID:30031767, PMID:34533978, PMID:33359499]. Loading of HLA-F with peptides—including hemoglobin-derived peptides during HIV infection—abrogates KIR3DS1 binding, providing a potential viral immune-escape mechanism, while rare allotypic variants such as KIR3DS1*014 can additionally bind HLA-Bw4 in a peptide-dependent manner through critical residues at receptor position 138 [PMID:33126487, PMID:21804024, PMID:25740999]. The compound genotype of KIR3DS1 with HLA-B Bw4-80Ile is associated with delayed progression to AIDS in HIV-1-infected individuals, consistent with epistatic cooperation between this receptor–ligand pair in antiviral defense [PMID:12134147]."},"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":928,"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":190,"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":156,"is_preprint":false},{"pmid":"18317000","id":"PMC_18317000","title":"Increased proportion of KIR3DS1 homozygotes in HIV-exposed uninfected individuals.","date":"2008","source":"AIDS (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18317000","citation_count":146,"is_preprint":false},{"pmid":"17202323","id":"PMC_17202323","title":"Cutting Edge: KIR3DS1, a gene implicated in resistance to progression to AIDS, encodes a DAP12-associated receptor expressed on NK cells that triggers NK cell activation.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17202323","citation_count":117,"is_preprint":false},{"pmid":"27649529","id":"PMC_27649529","title":"HLA-F and MHC-I Open Conformers Bind Natural Killer Cell Ig-Like Receptor KIR3DS1.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27649529","citation_count":98,"is_preprint":false},{"pmid":"18305035","id":"PMC_18305035","title":"Conferral of enhanced natural killer cell function by KIR3DS1 in early human immunodeficiency virus type 1 infection.","date":"2008","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/18305035","citation_count":93,"is_preprint":false},{"pmid":"20124216","id":"PMC_20124216","title":"Donor activating KIR3DS1 is associated with decreased acute GVHD in unrelated allogeneic hematopoietic stem cell transplantation.","date":"2010","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/20124216","citation_count":83,"is_preprint":false},{"pmid":"25740999","id":"PMC_25740999","title":"Peptide-Dependent Recognition of HLA-B*57:01 by KIR3DS1.","date":"2015","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/25740999","citation_count":69,"is_preprint":false},{"pmid":"15580659","id":"PMC_15580659","title":"The silent KIR3DP1 gene (CD158c) is transcribed and might encode a secreted receptor in a minority of humans, in whom the KIR3DP1, KIR2DL4 and KIR3DL1/KIR3DS1 genes are duplicated.","date":"2005","source":"European journal of 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progression to AIDS in HIV-1-infected individuals, suggesting an epistatic interaction between the two loci in NK cell-mediated protection.\",\n      \"method\": \"Genetic epistasis analysis in HIV-1 cohort studies\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistatic genetic interaction replicated across multiple cohorts, 928 citations, foundational study\",\n      \"pmids\": [\"12134147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KIR3DS1 associates with the ITAM-bearing adaptor protein DAP12 (demonstrated by cotransfection and coimmunoprecipitation), and its ligation triggers NK cell cytotoxicity and IFN-gamma production. Soluble KIR3DS1-Ig fusion proteins did not bind HLA-Bw4 80I or 80T allotypes on EBV-transformed B cell lines, suggesting HLA-Bw4 ligand recognition may be peptide-dependent.\",\n      \"method\": \"Cotransfection, coimmunoprecipitation, in vitro cytotoxicity assay, cytokine production assay, flow cytometry with soluble fusion proteins\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP for DAP12 association plus functional assays; replicated by Trundley et al. same year\",\n      \"pmids\": [\"17202323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KIR3DS1 surface expression on NK cells is dependent on the adaptor protein DAP12; without DAP12, KIR3DS1 is not expressed on the cell surface. KIR3DS1 is recognized by the antibody Z27 and is expressed on a substantial subset of peripheral NK cells and a small proportion of CD56+ T cells.\",\n      \"method\": \"Transfection, flow cytometry, antibody staining (Z27, DX9), surface expression analysis\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated across two independent papers (Trundley et al. and Carr et al. 2007) using transfection and primary cells\",\n      \"pmids\": [\"17301953\", \"17202323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KIR3DS1 ligation by antibody Z27 leads to NK cell IFN-gamma production and degranulation (CD107a expression), confirming activating receptor function on peripheral NK cells.\",\n      \"method\": \"Antibody-mediated ligation, flow cytometry (IFN-gamma, CD107a)\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean functional assay on primary NK cells with defined readout, replicated across studies\",\n      \"pmids\": [\"17641029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The rare KIR3DS1 allotype KIR3DS1*014 (differing from KIR3DS1*013 at position 138) directly binds HLA-Bw4, providing the first direct evidence of KIR3DS1 binding to HLA-Bw4. Position 138 is a key determinant of ligand specificity, and reactivity is dependent on complex interactions between multiple residues (including positions 199 and 138).\",\n      \"method\": \"Mutagenesis, cell binding assay (flow cytometry with HLA-Bw4-expressing cells), recombinant protein analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding demonstrated with mutagenesis to identify key residues, multiple orthogonal approaches\",\n      \"pmids\": [\"21804024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KIR3DS1 recognition of HLA-B*57:01 is peptide-dependent: specific HIV-derived peptide epitopes presented by HLA-B*57:01 facilitate productive interactions between HLA-B*57:01 and KIR3DS1, while other peptides do not support binding.\",\n      \"method\": \"Structure-driven approach, peptide binding assays, flow cytometry with KIR3DS1-expressing cells and HLA-peptide complexes\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — structure-guided identification of peptide specificity with direct binding assays and mutagenesis-level controls\",\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, disrupt surface expression and HLA-Bw4 binding, establishing that these residues are critical for KIR3DS1's distinct ligand binding properties.\",\n      \"method\": \"Mutagenesis, flow cytometry, recombinant protein binding assay, primary NK cell functional assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — site-directed mutagenesis combined with surface expression and binding assays identifying specific causal residues\",\n      \"pmids\": [\"26109640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIR3DS1 binds specifically to HLA-F open conformers (peptide-free, beta-2-microglobulin-free forms of HLA-F), but not to peptide-loaded classical HLA class I. Primary KIR3DS1+ NK cells degranulate and produce antiviral cytokines upon encountering HLA-F, and inhibit HIV-1 replication in vitro. HLA-F surface expression is upregulated on activated CD4+ T cells and HIV-infected cells.\",\n      \"method\": \"Screening of 100 HLA class I proteins, biochemical binding assays, surface plasmon resonance, flow cytometry, in vitro HIV replication inhibition assay, primary NK cell functional assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — large-scale HLA screen, biochemical binding, SPR, and functional validation with primary cells; 190 citations\",\n      \"pmids\": [\"27455421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Physical binding of KIR3DS1 (but not KIR3DL1) to HLA-F and other MHC-I open conformers was demonstrated by surface plasmon resonance, biochemical pulldown from cell lines, and heterodimerization with recombinant proteins. KIR3DS1 engagement by surface-bound HLA-F increases granule exocytosis in activated NK cells.\",\n      \"method\": \"Surface plasmon resonance, biochemical pulldown, recombinant protein heterodimerization, granule exocytosis assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal biochemical and biophysical methods independently confirming HLA-F/KIR3DS1 binding\",\n      \"pmids\": [\"27649529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KIR3DS1 mediates activation signals upon recognition of HLA-B*51 (Bw4-I80) surface molecules on target cells, but this activation occurs only in Bw4-I80-negative individuals, suggesting HLA-B*51 serves as a KIR3DS1 ligand. KIR3DS1-mediated recognition of HLA-B*51 also plays a role in NK cell education/licensing.\",\n      \"method\": \"NK cell clone functional assays, antibody-mediated blocking, KIR3DS1+ clone killing assays, flow cytometry\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab with multiple functional readouts but indirect evidence for direct HLA-B*51 binding\",\n      \"pmids\": [\"28603523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KIR3DS1 binding to HLA-F on HCV-infected cells activates NK cells to control HCV replication in cell culture. HLA-F is upregulated on HCV-infected cells, and the KIR3DS1/HLA-F interaction contributes to NK cell-mediated antiviral response.\",\n      \"method\": \"Cell culture HCV infection model, NK cell activation assays, in vitro viral replication assay, humanized mouse liver model, primary liver tissue analysis\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple experimental systems (cell culture, humanized mice, primary tissue) with functional readouts\",\n      \"pmids\": [\"30031767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HLA-F on HLA-null 721.221 cells activates primary KIR3DS1+ NK cells to secrete CCL4 and IFN-gamma and express CD107a. Blocking the HLA-F/KIR3DS1 interaction with KIR3DS1-Fc chimeric protein or anti-HLA-F antibodies reduced this activation, establishing HLA-F as sufficient to activate KIR3DS1+ NK cells.\",\n      \"method\": \"Primary NK cell co-culture with HLA-null cell line, antibody-mediated blocking, flow cytometry (CCL4, IFN-gamma, CD107a), exclusive gating strategies\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — blocking experiments and exclusive gating provide strong evidence for sufficiency of HLA-F/KIR3DS1 interaction\",\n      \"pmids\": [\"29743316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HLA-F on HIV-infected CD4+ T cells activates KIR3DS1+ NK cells to produce CCL4, IFN-gamma, and CD107a. Blocking HLA-F on infected cells with KIR3DS1-Fc chimeric protein or anti-HLA-F monoclonal antibody reduced KIR3DS1+ NK cell activation, demonstrating that the HLA-F/KIR3DS1 interaction is sufficient for NK cell activation against HIV-infected cells.\",\n      \"method\": \"Primary NK cell co-culture with sorted HIV-infected CD4+ T cells, KIR3DS1-Fc blocking, anti-HLA-F antibody blocking, flow cytometry\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — blocking experiments with two orthogonal reagents in physiologically relevant HIV-infected primary cell system\",\n      \"pmids\": [\"31270222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BK polyomavirus infection of kidney tubular cells upregulates surface HLA-F expression, which increases KIR3DS1 binding to infected cells and activates primary KIR3DS1+ NK cells, establishing a mechanism for NK cell recognition of BK polyomavirus-infected cells.\",\n      \"method\": \"In vitro BK polyomavirus infection model, flow cytometry (HLA-F surface expression, KIR3DS1 binding), primary NK cell activation assay, kidney biopsy analysis\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro infection model combined with primary NK cell functional assays and patient biopsy validation\",\n      \"pmids\": [\"33359499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HLA-F loaded with hemoglobin-derived peptides loses affinity for KIR3DS1: peptide-free HLA-F open conformers bind KIR3DS1, but acid elution restoring open conformers rescues binding, while addition of hemoglobin peptide fractions to HLA-F open conformers significantly reduces KIR3DS1 recognition — identifying a mechanism for HIV immune escape via HLA-F peptide loading.\",\n      \"method\": \"Soluble HLA technology, mass spectrometry peptidome analysis, recombinant KIR3DS1-Fc binding assays, K562 cell transfection\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical binding assays with MS peptide identification, single lab study\",\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 KIR3DS1+ NK cells to kill infected cells more efficiently via the KIR3DS1/HLA-F axis. In contrast, HLA-A and HLA-B are downregulated by adenoviral E3/gp19K, suggesting a viral evasion strategy against CD8+ T cells that simultaneously exposes infected cells to KIR3DS1+ NK cell killing.\",\n      \"method\": \"3D intestinal organoid infection model, flow cytometry (HLA-F, HLA-A, HLA-B expression), KIR3DS1+ NK cell killing assay, immunogenetic cohort analysis\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection in organoid model combined with clinical immunogenetic validation\",\n      \"pmids\": [\"34533978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KIR3DS1+ NK cells specifically expand during acute HIV-1 infection in the presence of HLA-B Bw480I, demonstrating HLA class I subtype-dependent expansion of KIR3DS1+ NK cells during an acute viral infection.\",\n      \"method\": \"Longitudinal cohort study, flow cytometry, KIR/HLA genotyping\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct cell expansion measurement with HLA subtype stratification in human cohort\",\n      \"pmids\": [\"19386717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KIR3DS1 expression on NK cells can be induced after exposure to stimulator cells (221, K562, EBV-B cell lines, B cells), poly(I:C), IL-15, or IL-2. KIR3DS1+ NK cell proliferation and cytotoxicity were not inhibited in a Bw4+ context (unlike KIR3DL1+ NK cells), suggesting KIR3DS1 does not recognize HLA-Bw4 in a physiological context.\",\n      \"method\": \"NK cell stimulation assays, flow cytometry, proliferation assays, cytotoxicity assays with Bw4+/- target cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple stimulation conditions and functional readouts in primary NK cells, single lab\",\n      \"pmids\": [\"19454667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Despite testing a broad array of Bw4Ile80 HLA class I tetramers with HIV-1-derived peptide epitopes, no tetramer binding to KIR3DS1 expressed on 293-T cells was detected, indicating that HLA-Bw4 with typical CD8+ T cell peptide epitopes does not constitute a KIR3DS1 ligand.\",\n      \"method\": \"Flow cytometry, MHC class I tetramer binding assay, transient transfection of KIR3DS1 on 293-T cells\",\n      \"journal\": \"AIDS research and human retroviruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — negative binding result with broad peptide/HLA panel, single lab\",\n      \"pmids\": [\"17411378\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIR3DS1 is an activating NK cell receptor that associates with the ITAM-bearing adaptor DAP12 (requiring it for surface expression), and signals through recognition of HLA-F open conformers (peptide-free/beta-2-microglobulin-free forms) as its primary ligand — triggering NK cell cytotoxicity, IFN-gamma production, and CCL4 secretion; HLA-F is upregulated on virally infected cells (HIV, HCV, HAdV, BK polyomavirus), and loading of HLA-F with peptides (including hemoglobin-derived peptides during HIV infection) can abrogate KIR3DS1 binding, providing a mechanism for viral immune escape, while rare KIR3DS1 allotypes (e.g., KIR3DS1*014) can also directly bind HLA-Bw4 in a peptide-dependent manner through critical residues at position 138 of the receptor.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KIR3DS1 is an activating killer-cell immunoglobulin-like receptor on NK cells that signals through the ITAM-bearing adaptor DAP12 to trigger cytotoxicity, IFN-γ production, and CCL4 secretion upon engagement of its ligand. KIR3DS1 requires DAP12 for surface expression and preferentially recognizes HLA-F open conformers (peptide-free, β2-microglobulin-free forms), which are upregulated on cells infected by HIV, HCV, HAdV, and BK polyomavirus, thereby enabling NK cell-mediated antiviral immunity [PMID:27455421, PMID:30031767, PMID:34533978, PMID:33359499]. Loading of HLA-F with peptides—including hemoglobin-derived peptides during HIV infection—abrogates KIR3DS1 binding, providing a potential viral immune-escape mechanism, while rare allotypic variants such as KIR3DS1*014 can additionally bind HLA-Bw4 in a peptide-dependent manner through critical residues at receptor position 138 [PMID:33126487, PMID:21804024, PMID:25740999]. The compound genotype of KIR3DS1 with HLA-B Bw4-80Ile is associated with delayed progression to AIDS in HIV-1-infected individuals, consistent with epistatic cooperation between this receptor–ligand pair in antiviral defense [PMID:12134147].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that KIR3DS1 cooperates epistatically with HLA-B Bw4-80Ile to influence HIV-1 disease progression provided the first functional rationale for studying this receptor in antiviral immunity.\",\n      \"evidence\": \"Genetic epistasis analysis across multiple HIV-1 cohorts\",\n      \"pmids\": [\"12134147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No direct molecular interaction between KIR3DS1 and HLA-Bw4 demonstrated\",\n        \"Mechanism of protection at the cellular level unresolved\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that KIR3DS1 associates with DAP12 (required for surface expression) and triggers NK cell cytotoxicity and IFN-γ production established its signaling mechanism, while the failure of KIR3DS1-Ig fusions and HLA-Bw4 tetramers to bind indicated that HLA-Bw4 is not a straightforward ligand.\",\n      \"evidence\": \"Co-IP, cotransfection, functional assays on primary NK cells, soluble fusion protein and tetramer binding assays across broad peptide/HLA panels\",\n      \"pmids\": [\"17202323\", \"17301953\", \"17641029\", \"17411378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"True physiological ligand unidentified\",\n        \"Whether peptide context could enable HLA-Bw4 binding remained untested with comprehensive peptide libraries\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showing that KIR3DS1+ NK cells expand during acute HIV-1 infection in an HLA-B Bw4-80Ile-dependent manner and that KIR3DS1 does not inhibit cytotoxicity against Bw4+ targets reinforced its activating function in vivo while further questioning direct Bw4 recognition.\",\n      \"evidence\": \"Longitudinal HIV cohort with flow cytometry; NK cell proliferation and cytotoxicity assays against Bw4+/- targets\",\n      \"pmids\": [\"19386717\", \"19454667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular basis for Bw4-80Ile-dependent expansion unclear\",\n        \"Indirect genetic association rather than direct binding evidence\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying that the rare KIR3DS1*014 allotype directly binds HLA-Bw4, with position 138 as a key determinant, provided the first direct binding evidence and revealed that allotypic variation dictates ligand specificity.\",\n      \"evidence\": \"Site-directed mutagenesis and cell-based binding assays with recombinant proteins\",\n      \"pmids\": [\"21804024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Binding restricted to a rare allotype; generalizability to common allotypes unclear\",\n        \"Structural basis of position 138 contribution unresolved\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing peptide-dependent recognition of HLA-B*57:01 by KIR3DS1 and identifying D0-domain residues (positions 58, 92) critical for ligand binding explained why standard tetramer assays had failed and defined the molecular determinants distinguishing KIR3DS1 from KIR3DL1.\",\n      \"evidence\": \"Structure-guided peptide binding assays; mutagenesis of D0 domain residues with surface expression and binding readouts\",\n      \"pmids\": [\"25740999\", \"26109640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal structure of KIR3DS1–HLA complex available\",\n        \"Full peptide repertoire enabling binding unknown\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The identification of HLA-F open conformers as the primary KIR3DS1 ligand resolved the long-standing ligand question, showing that peptide-free, β2m-free HLA-F drives NK cell degranulation, cytokine production, and HIV replication control.\",\n      \"evidence\": \"Screening of 100 HLA class I proteins, SPR, biochemical pulldown, primary NK cell functional assays, in vitro HIV inhibition\",\n      \"pmids\": [\"27455421\", \"27649529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of KIR3DS1–HLA-F interaction unresolved\",\n        \"Relative contribution of HLA-F versus HLA-Bw4 recognition in vivo unclear\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Blocking experiments with KIR3DS1-Fc and anti-HLA-F antibodies on both HLA-null cells and HIV-infected CD4+ T cells established that HLA-F is sufficient to activate KIR3DS1+ NK cells, and extended the axis to HCV infection.\",\n      \"evidence\": \"Primary NK cell co-culture with HLA-null 721.221 cells and HIV-infected CD4+ T cells; antibody/Fc blocking; HCV cell-culture infection model and humanized mouse model\",\n      \"pmids\": [\"29743316\", \"31270222\", \"30031767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Contribution of other activating receptors to the observed antiviral effects not fully delineated\",\n        \"In vivo relevance in human infection awaits clinical intervention studies\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that peptide loading of HLA-F (particularly with hemoglobin-derived peptides) abrogates KIR3DS1 binding, and that BK polyomavirus infection upregulates HLA-F to activate KIR3DS1+ NK cells, broadened the ligand model to include a peptide-based escape mechanism and a fourth viral context.\",\n      \"evidence\": \"MS peptidome analysis with recombinant KIR3DS1-Fc binding assays; in vitro BK polyomavirus kidney tubular cell infection with primary NK cell assays and patient biopsy validation\",\n      \"pmids\": [\"33126487\", \"33359499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Peptide-mediated immune escape mechanism demonstrated only in biochemical assays, not in infected-cell cocultures\",\n        \"Whether HLA-F peptide loading is actively promoted by viral factors is unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing that adenoviral E3/gp19K downregulates HLA-A/B while HLA-F is upregulated on infected organoid cells, enabling KIR3DS1+ NK cell killing, revealed a viral immune-evasion trade-off that exposes infected cells to activating NK receptor surveillance.\",\n      \"evidence\": \"3D intestinal organoid HAdV5 infection model, flow cytometry, KIR3DS1+ NK cell killing assays, immunogenetic cohort analysis\",\n      \"pmids\": [\"34533978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether other viruses that downregulate classical HLA-I similarly expose HLA-F is untested\",\n        \"In vivo outcome data linking KIR3DS1 genotype to adenoviral disease severity are limited\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No crystal or cryo-EM structure of the KIR3DS1–HLA-F complex exists, leaving the atomic basis of open-conformer selectivity and peptide-mediated escape unresolved; the relative contribution of HLA-F versus HLA-Bw4 recognition to in vivo antiviral protection also remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of KIR3DS1–HLA-F interaction\",\n        \"In vivo hierarchy of HLA-F versus HLA-Bw4 ligand engagement unknown\",\n        \"Whether KIR3DS1 has additional non-HLA ligands is unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 3, 7, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 7, 10, 12, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 7, 11]}\n    ],\n    \"complexes\": [\n      \"KIR3DS1–DAP12 signaling complex\"\n    ],\n    \"partners\": [\n      \"TYROBP\",\n      \"HLA-F\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}