{"gene":"HLA-C","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1993,"finding":"HLA-C alleles are the dominant inhibitory ligands that protect target cells from lysis by NK1- and NK2-specific NK cells. Transfection of class I-deleted mutant cell lines with HLA-C alleles encoding Asn-77/Lys-80 (e.g., HLA-Cw4, -Cw5, -Cw6) inhibited lysis by NK1-specific NK cells, while alleles encoding Ser-77/Asn-80 (e.g., HLA-Cw1, -Cw7, -Cw13) protected targets from NK2-specific NK cells. The dimorphism at positions 77–80 of HLA-C determines which NK cell subset is inhibited.","method":"Transfection of HLA-C alleles into class I-deleted mutant cell lines followed by NK cell cytotoxicity assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct functional reconstitution by transfection with allele-specific readout, foundational result replicated across multiple alleles and independently confirmed in subsequent studies","pmids":["8265660"],"is_preprint":false},{"year":1988,"finding":"HLA-Cw3 expressed in transgenic C57BL/6 mice functions as a transplantation antigen (transgenic skin rapidly rejected by normal mice) and as a restriction element for cytotoxic T lymphocytes specific for influenza and Sendai virus, demonstrating immunological functions comparable to HLA-A and -B.","method":"Transgenic mouse model; skin graft rejection assay; CTL restriction assay with viral antigens","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo functional reconstitution in transgenic animals with two independent functional readouts (transplantation rejection and viral CTL restriction)","pmids":["2840670"],"is_preprint":false},{"year":1995,"finding":"Low cell surface expression of HLA-C is caused primarily by faster degradation of HLA-C mRNA (not by intrinsic properties of the heavy chain protein), and the region determining low expression lies between the 3′ end of exon 3 and a site ~600 bases downstream of the translation stop codon in the 3′ UTR. HLA-C heavy chains associate with and dissociate from β2-microglobulin at rates comparable to HLA-A and -B, and increased β2m competition does not alter HLA-C surface expression. Chimeric B7/Cw3 proteins with the B7 peptide-binding groove can still have low surface expression, indicating peptide-binding inefficiency is not the primary cause.","method":"mRNA half-life measurement, chimeric gene transfection (HLA-B7/Cw3 and B7/Cw6), β2m competition assays, cell surface expression analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal experiments (mRNA stability, chimeric genes, protein association assays) in a single rigorous study","pmids":["7760000"],"is_preprint":false},{"year":1998,"finding":"The inhibitory p58 receptor NKAT2 binds HLA-Cw7 with rapid association and dissociation kinetics, whereas the homologous activating p50 receptors (clone 49 and clone 39) bind HLA-C only very weakly or not at all, demonstrating that the transmembrane/cytoplasmic domains—not the extracellular domains—determine functional (inhibitory vs. activating) differences in KIR binding to HLA-C.","method":"Direct binding assays comparing inhibitory and activating KIR receptors to HLA-Cw7; kinetic analysis of association/dissociation rates","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro binding assay with quantitative kinetic measurements, comparing paired inhibitory and activating receptors","pmids":["9826699"],"is_preprint":false},{"year":1997,"finding":"Recombinant soluble p58 KIR molecules (KIR-K6 and KIR-K7) directly bind recombinant soluble HLA-Cw3 and HLA-Cw6, as shown by native gel shift assay. The activating p50 KAR-K1 binds neither HLA-C molecule. KIR binding to HLA-C is influenced by the antigenic peptide bound to the MHC molecule, and requires both Ig domains of p58.","method":"Native gel shift assay with recombinant soluble KIR and HLA-C proteins; peptide competition","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro binding reconstitution but single lab, limited mechanistic follow-up","pmids":["9378975"],"is_preprint":false},{"year":2000,"finding":"HLA-C protein is expressed on the cell surface of normal extravillous trophoblast cells in association with β2-microglobulin; both paternal and maternal HLA-C alleles are transcribed and expressed. IFN-γ treatment upregulates HLA-C but not HLA-G surface expression on trophoblasts. HLA-C is expressed by all extravillous trophoblast subpopulations in vivo.","method":"cDNA sequencing of sorted trophoblast cells; biochemical analysis; flow cytometry with HLA-C-specific antibody; immunohistology; IFN-γ stimulation","journal":"Placenta","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (sequencing, biochemistry, flow cytometry, IHC) in a single study with functional IFN-γ stimulation experiment","pmids":["10833373"],"is_preprint":false},{"year":2011,"finding":"A SNP within the 3′ UTR of HLA-C regulates binding of hsa-miR-148a to the HLA-C mRNA, resulting in post-transcriptional downregulation; alleles that bind miR-148a show relatively low surface expression while alleles that escape miR-148a binding show high surface expression. This mechanism underlies differential HLA-C cell surface expression and associates with HIV control.","method":"miRNA binding assays; allele-specific 3′ UTR reporter assays; flow cytometry for surface expression; association with HIV control","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — mechanistic reporter assays directly demonstrating miR-148a binding to HLA-C 3′ UTR variants, with functional surface expression data and replicated associations","pmids":["21499264"],"is_preprint":false},{"year":2013,"finding":"A MIR148A insertion/deletion polymorphism affects miR-148a expression levels, which in turn modulates the degree of HLA-C downregulation and the level of HIV control—but only in individuals carrying an intact miR-148a binding site in the HLA-C 3′ UTR. This demonstrates a direct causal effect of HLA-C expression level on HIV control independent of other HLA loci.","method":"Genetic association of MIR148A indel with miR-148a expression, HLA-C surface levels, and HIV control; interaction analysis conditioned on HLA-C 3′ UTR genotype","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis analysis with multiple cohorts; interaction between two polymorphisms provides causal evidence for HLA-C expression level effects","pmids":["24248364"],"is_preprint":false},{"year":2016,"finding":"A promoter SNP rs2395471 located in an Oct1 transcription factor consensus binding site ~800 bp upstream of the HLA-C transcription start site regulates HLA-C expression: the A allele has higher Oct1 binding affinity and higher promoter activity than the G allele, as shown by electrophoretic mobility shift assay (Oct1 binds both alleles) and luciferase reporter assay. This variant accounts for up to 36% of explained variation in HLA-C cell surface levels.","method":"Imputed expression QTL (impeQTL) mapping; quantitative PCR; flow cytometry; electrophoretic mobility shift assay (EMSA); luciferase reporter assay","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — EMSA and luciferase reporter directly demonstrate Oct1-mediated transcriptional regulation; validated in multiple cohorts (n=369 combined for surface expression)","pmids":["27817866"],"is_preprint":false},{"year":2016,"finding":"HIV-1 Vpu mediates downregulation of HLA-C on infected cells, reducing HLA-C-restricted CTL suppression of viral replication in CD4+ cells. HLA-A and HLA-B are unaffected by Vpu. Most primary HIV-1 clones (including transmitted founder viruses) downregulate HLA-C via Vpu, in contrast to the laboratory-adapted NL4-3 strain.","method":"Primary HIV-1 clone infection assays; flow cytometry for HLA-C surface expression; CTL suppression assay; siRNA/Vpu mutant analysis","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple primary isolates tested, functional CTL assay, Vpu identified as the mediating viral protein, replicated by a follow-up study (PMID 28704647)","pmids":["27173934"],"is_preprint":false},{"year":2018,"finding":"HIV-1 downregulation of HLA-C involves specific residues in the transmembrane region of Vpu (5 residues) and the transmembrane domain of HLA-C (4 residues) that determine Vpu–HLA-C interactions. HLA-C downregulation by Vpu adapts to host HLA genotype during chronic infection; individuals with higher HLA-C expression favor greater viral downregulation.","method":"Site-directed mutagenesis of Vpu and HLA-C transmembrane domains; replication-competent viral isolates from 19 individuals; viral quasispecies analysis","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis identifies specific interacting residues, combined with in vivo viral evolution analysis across many individuals","pmids":["30180214"],"is_preprint":false},{"year":2013,"finding":"HSV-2 specifically downregulates HLA-C (but not HLA-A or HLA-B) on infected dendritic cells via the viral protein ICP47, rendering infected DCs susceptible to NK cell killing. A specific motif in the cytoplasmic tail of HLA-C is responsible for HSV-2-mediated HLA-C downregulation.","method":"Viral infection of DCs; flow cytometry; ICP47 mutagenesis/overexpression; NK cell cytotoxicity assay; identification of HLA-C cytoplasmic tail motif","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 / Strong — identifies specific viral protein (ICP47) and specific domain in HLA-C tail required for downregulation, with functional NK killing readout","pmids":["23555244"],"is_preprint":false},{"year":2017,"finding":"HIV-1-mediated downmodulation of HLA-C reduces binding to inhibitory KIRs on NK cells. Despite this, HLA-C-licensed NK cells display reduced antiviral activity compared to unlicensed NK cells, potentially due to residual KIR/HLA-C interaction. NK cells can sense the degree of HLA-C downmodulation by HIV-1, with greater downmodulation correlating with increased NK antiviral activity.","method":"Flow cytometry for HLA-C–KIR binding; NK cell antiviral activity assays; comparison of HIV-1 strains with differential HLA-C downmodulation capacity","journal":"Cell host & microbe","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays with primary NK cells and multiple viral strains; single lab with two orthogonal methods","pmids":["28704647"],"is_preprint":false},{"year":2008,"finding":"HLA-C (incorporated into HIV-1 virions) associates with envelope glycoprotein gp120 and enhances HIV-1 infectivity. Silencing HLA-C by siRNA reduces syncytia formation and pseudovirus infectivity. HLA-C co-purifies with gp120 from cells before and after fusion and is present in fusion complexes.","method":"siRNA knockdown of HLA-C; cell fusion assays; pseudovirus infectivity assays; co-purification of HLA-C with gp120","journal":"Retrovirology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown combined with binding/co-purification evidence; two orthogonal methods; single lab","pmids":["18673537"],"is_preprint":false},{"year":2017,"finding":"HIV-1 specifically increases the amount of HLA-C free chains (not bound to β2-microglobulin) on the membrane of infected cells. The association between HIV-1 Env and HLA-C at the cell membrane requires β2m to occur. The enhanced infectivity conferred by HLA-C specifically involves HLA-C free-chain molecules that have been previously correctly assembled with β2m; pseudoviruses produced in the absence of β2m are less infectious.","method":"Flow cytometry for β2m-free HLA-C chains; pseudovirus infectivity assays in β2m-present vs. β2m-absent conditions; co-immunoprecipitation of Env with HLA-C","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional pseudovirus assay with β2m dependency, co-IP evidence; single lab","pmids":["28051183"],"is_preprint":false},{"year":2017,"finding":"NLRP2 acts as a suppressor of HLA-C expression in trophoblasts: deletion of NLRP2 in JEG3 cells (trophoblast model) using TALEN technology caused a significant increase in constitutive HLA-C expression, and NLRP2 knockdown by lentiviral shRNA in JEG3 and primary EVT increased TNFα-induced NF-κB p65 phosphorylation. This indicates NLRP2 regulates HLA-C expression via suppression of NF-κB signaling.","method":"TALEN-mediated NLRP2 deletion; lentiviral shRNA knockdown; NF-κB phosphorylation assay; flow cytometry for HLA-C surface expression","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function by two methods (TALEN deletion and shRNA) with defined molecular readout (HLA-C expression and NF-κB phosphorylation); single lab","pmids":["28340094"],"is_preprint":false},{"year":2018,"finding":"An NK cell-specific HLA-C promoter (NK-Pro) drives expression of an array of alternative transcripts with varying exon content. Skipping of the first coding exon generates untranslatable HLA-C mRNAs; the proportion of untranslatable mRNA decreases as NK cells mature, correlating with increased HLA-C protein expression. A polymorphism in a key Ets-binding site of the NK-Pro generates HLA-C alleles that lack significant promoter activity, resulting in reduced HLA-C expression and increased NK functional activity.","method":"NK-specific promoter identification; RT-PCR for alternative transcripts; luciferase reporter assay for NK promoter activity; correlation of transcript ratios with NK maturation and HLA-C protein levels","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter assays plus transcript analysis during NK maturation; single lab with multiple orthogonal methods","pmids":["29329284"],"is_preprint":false},{"year":2021,"finding":"Crystal structures of KIR2DL2 and KIR2DL3 in complex with HLA-C*07:02 presenting a self-epitope reveal that KIR2DL2 adopts a different docking geometry atop HLA-C compared to KIR2DL3. Mutagenesis assays showed differences in HLA-C1 allotype recognition between KIR2DL2 and KIR2DL3. HLA-C1 allotypes differ markedly in their capacity to inhibit primary NK cell activation, and these functional differences involve KIR2DS2.","method":"X-ray crystallography; mutagenesis; primary NK cell inhibition assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with functional mutagenesis validation and primary NK cell assays in a single study","pmids":["33846289"],"is_preprint":false},{"year":2019,"finding":"The activating receptor KIR2DS4 has strong preference for peptides carrying Trp at position 8 (p8) of 9-mer peptides bound to HLA-C*05:01. A complex of HLA-C*05:01 with a p8-Trp peptide is sufficient to activate primary KIR2DS4+ NK cells independently of other activating receptors and NK cell licensing. A conserved bacterial RecA peptide motif presented by HLA-C*05:01 activates KIR2DS4+ NK cells from multiple human pathogens (Helicobacter, Chlamydia, Brucella, Campylobacter).","method":"Peptide binding assays; flow cytometry for NK cell degranulation; KIR2DS4 tetramer binding; worldwide allele frequency correlation analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined peptide-HLA-C-KIR2DS4 ternary interaction with primary NK cell functional readout; peptide specificity mapped; replicated across multiple bacterial peptides","pmids":["31138701"],"is_preprint":false},{"year":2022,"finding":"The C1/C2 dimorphism at positions 77 and 80 of HLA-C impacts peptide presentation: Ser77 (C1) vs. Asn77 (C2) influences amino acid preference near the peptide C-terminus (pΩ and pΩ-1 positions), with C1 favoring small and C2 preferring large residues. KRAS-G12D neoantigen-specific TCRs discriminate between C1 and C2 allotypes presenting the same peptide, with weaker TCR affinity for KRAS-G12D-bound C2-HLA-C despite conserved TCR contacts.","method":"Structural analysis; immunopeptidomics; SPR (surface plasmon resonance) for TCR affinity; functional T cell assays; HLA-C allotypes differing only at C1/C2-defining residues","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural, peptidomics, and functional T cell experiments together with quantitative binding measurements in one study","pmids":["35587797"],"is_preprint":false},{"year":1990,"finding":"HLA-C blank antigens (Cb-1 and Cb-2) are functionally expressed on the surface of peripheral blood lymphocytes (EBV-transformed B cells and PHA-induced T cells), can induce allogeneic CTL responses comparable to HLA-B, and are recognized in a class I-specific manner (blocked by anti-class I monomorphic mAb), indicating HLA-C can function as an alloantigen in vivo.","method":"CTL clone cytotoxicity assays using transfected Hmy2CIR cells and primary PBL; blocking with class I monomorphic mAb","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional CTL assays with blocking antibody controls; multiple target cell types tested; single lab","pmids":["2246509"],"is_preprint":false},{"year":2012,"finding":"Donor KIR2DS1-mediated prevention of AML relapse after allogeneic HSCT is HLA-C-dependent: protection was observed in donors with KIR2DS1 who were homozygous/heterozygous for HLA-C1, but not in donors homozygous for HLA-C2 (who are auto-licensed through KIR2DS1/C2 interaction). This establishes that HLA-C2 ligand engagement of KIR2DS1 in the donor abrogates the antileukemic effect, demonstrating functional HLA-C–KIR2DS1 interaction in vivo.","method":"Retrospective clinical cohort (n=1277 AML patients); donor KIR genotyping; donor/recipient HLA-C genotyping; statistical survival/relapse analysis","journal":"The New England journal of medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large clinical cohort with clear HLA-C genotype interaction defining mechanism; genetic epistasis approach; single retrospective study","pmids":["22931314"],"is_preprint":false}],"current_model":"HLA-C is a classical MHC class I molecule that presents peptides to cytotoxic T cells and serves as the dominant ligand for inhibitory and activating KIR receptors on NK cells; its characteristically low cell surface expression is controlled by multiple mechanisms including accelerated mRNA degradation mediated by a 3′ UTR element, post-transcriptional suppression via miR-148a binding to a 3′ UTR polymorphism, an Oct1-binding promoter variant that modulates transcription, and an NK cell-specific promoter that generates untranslatable alternative transcripts during NK maturation; the C1/C2 dimorphism at HLA-C positions 77/80 determines which inhibitory and activating KIR family members bind and how peptide repertoire shapes both NK and T cell recognition; HIV-1 Vpu downregulates HLA-C to evade CTL killing (with specific transmembrane residues mediating Vpu–HLA-C interaction), while HSV-2 ICP47 selectively downregulates HLA-C to redirect NK cells against infected dendritic cells; on trophoblasts, HLA-C expression is suppressed by NLRP2 via NF-κB inhibition, and KIR/HLA-C interactions at the maternal–fetal interface regulate NK cell responses during placentation."},"narrative":{"mechanistic_narrative":"HLA-C is a classical MHC class I molecule that presents peptides to cytotoxic T cells and serves as the dominant ligand for the KIR family of NK cell receptors, functioning as a transplantation antigen and CTL restriction element comparable to HLA-A and -B [PMID:2840670, PMID:2246509]. Its allotype-defining C1/C2 dimorphism at positions 77/80 partitions NK recognition: distinct residue pairs determine which inhibitory NK subset is protected [PMID:8265660], with inhibitory p58/KIR2DL receptors binding HLA-C in a peptide-influenced manner while homologous activating p50 receptors bind weakly or not at all—differences dictated by the receptor transmembrane/cytoplasmic domains [PMID:9826699, PMID:9378975]. Crystallographic and functional analyses show that closely related KIRs (KIR2DL2 vs. KIR2DL3) adopt different docking geometries on HLA-C1 and differ in allotype recognition [PMID:33846289], that the activating KIR2DS4 reads specific bound peptides including conserved bacterial motifs presented by HLA-C*05:01 [PMID:31138701], and that the C1/C2 polymorphism shapes the C-terminal peptide repertoire to influence both KIR and TCR discrimination of identical epitopes [PMID:2246509, PMID:35587797]. A defining feature of HLA-C is its characteristically low surface expression, governed by multiple layers: accelerated mRNA degradation directed by a 3′ UTR element [PMID:7760000], post-transcriptional suppression via miR-148a binding to a 3′ UTR polymorphism whose strength causally tunes HIV control [PMID:21499264, PMID:24248364], an Oct1-binding promoter SNP that modulates transcription [PMID:27817866], and an NK cell-specific promoter generating untranslatable alternative transcripts during NK maturation [PMID:29329284]. HLA-C is a target of viral immune evasion: HIV-1 Vpu selectively downregulates HLA-C through defined transmembrane residue contacts to escape CTL killing and modulate NK sensing [PMID:27173934, PMID:30180214, PMID:28704647], while HSV-2 ICP47 downregulates HLA-C via a cytoplasmic tail motif to redirect NK killing of infected dendritic cells [PMID:23555244]. At the maternal–fetal interface, HLA-C is expressed on extravillous trophoblast in association with β2-microglobulin and is upregulated by IFN-γ [PMID:10833373], with NLRP2 suppressing its expression through inhibition of NF-κB signaling [PMID:28340094].","teleology":[{"year":1988,"claim":"Established that HLA-C is a bona fide immunological MHC class I molecule rather than a vestigial locus, settling whether it could serve antigen-presentation functions like HLA-A and -B.","evidence":"HLA-Cw3 transgenic C57BL/6 mice tested in skin graft rejection and viral CTL restriction assays","pmids":["2840670"],"confidence":"High","gaps":["Did not address peptide repertoire or why HLA-C surface levels are low","Single allele tested"]},{"year":1990,"claim":"Confirmed in a human system that HLA-C functions as an alloantigen capable of priming CTL, reinforcing its role as a class I restriction element.","evidence":"CTL clone cytotoxicity using transfected and primary cells with monomorphic class I antibody blocking","pmids":["2246509"],"confidence":"Medium","gaps":["Single lab","Did not define molecular basis of recognition"]},{"year":1993,"claim":"Defined the C1/C2 dimorphism at positions 77/80 as the determinant of which NK cell subset HLA-C inhibits, founding the HLA-C–NK recognition framework.","evidence":"Allele-specific transfection into class I-deleted lines with NK cytotoxicity readout","pmids":["8265660"],"confidence":"High","gaps":["Receptor identity not molecularly resolved at the time","Did not explain inhibitory vs. activating distinction"]},{"year":1995,"claim":"Resolved why HLA-C surface expression is low, showing the cause is post-transcriptional mRNA instability rather than heavy chain or peptide-binding defects.","evidence":"mRNA half-life measurements, B7/Cw3 chimeric gene transfection, β2m competition assays","pmids":["7760000"],"confidence":"High","gaps":["Did not identify the trans-acting factor mediating 3′ UTR degradation","Polymorphic control not yet mapped"]},{"year":1997,"claim":"Demonstrated direct physical binding of inhibitory p58 KIRs to soluble HLA-C and a peptide dependence of that interaction, establishing the biochemical basis of KIR/HLA-C recognition.","evidence":"Native gel shift with recombinant soluble KIR and HLA-Cw3/Cw6, peptide competition","pmids":["9378975"],"confidence":"Medium","gaps":["Single lab","Did not explain why activating KIRs fail to bind"]},{"year":1998,"claim":"Showed that inhibitory versus activating function in KIR/HLA-C pairs is set by the transmembrane/cytoplasmic domains, not ligand affinity, since activating p50 receptors bind HLA-C poorly.","evidence":"Kinetic binding assays comparing inhibitory NKAT2 and activating p50 receptors to HLA-Cw7","pmids":["9826699"],"confidence":"High","gaps":["Did not address peptide-specific activating recognition","Structural docking not defined"]},{"year":2000,"claim":"Established that HLA-C is expressed on extravillous trophoblast as a β2m-associated, IFN-γ-responsive molecule, placing it at the maternal–fetal interface.","evidence":"cDNA sequencing, biochemistry, flow cytometry, IHC, and IFN-γ stimulation of trophoblast","pmids":["10833373"],"confidence":"High","gaps":["Functional consequence for placentation not tested here","Regulatory mechanism of trophoblast expression unknown"]},{"year":2011,"claim":"Identified miR-148a binding to a 3′ UTR polymorphism as a molecular mechanism setting allele-specific HLA-C surface levels and linked expression level to HIV control.","evidence":"Allele-specific 3′ UTR reporter and miRNA binding assays with surface expression and HIV association","pmids":["21499264"],"confidence":"High","gaps":["Did not establish causality independent of linked HLA loci","Other 3′ UTR regulators not excluded"]},{"year":2012,"claim":"Provided in vivo evidence of functional activating HLA-C2–KIR2DS1 engagement by showing HLA-C2 abrogates KIR2DS1-mediated protection against AML relapse.","evidence":"Retrospective HSCT cohort with donor KIR and donor/recipient HLA-C genotyping","pmids":["22931314"],"confidence":"Medium","gaps":["Single retrospective cohort","Direct biochemical KIR2DS1/C2 interaction not measured here"]},{"year":2013,"claim":"Demonstrated causal control of HIV outcome by HLA-C expression level via a MIR148A indel acting only when the 3′ UTR binding site is intact, isolating HLA-C dosage as the effector.","evidence":"Genetic epistasis between MIR148A indel and HLA-C 3′ UTR genotype across cohorts","pmids":["24248364"],"confidence":"High","gaps":["Mechanism by which higher HLA-C improves HIV control not fully resolved","Does not address NK vs. CTL contribution"]},{"year":2013,"claim":"Revealed selective viral targeting of HLA-C by HSV-2 ICP47 via an HLA-C cytoplasmic tail motif, redirecting NK killing toward infected dendritic cells.","evidence":"DC infection, ICP47 mutagenesis/overexpression, HLA-C tail motif mapping, NK cytotoxicity","pmids":["23555244"],"confidence":"High","gaps":["Mechanism of tail-motif-dependent downregulation not defined","In vivo relevance not established"]},{"year":2016,"claim":"Mapped an Oct1-binding promoter SNP as a major transcriptional determinant of HLA-C surface levels, adding a transcriptional layer to expression control.","evidence":"impeQTL mapping, qPCR, flow cytometry, EMSA, and luciferase reporter assays","pmids":["27817866"],"confidence":"High","gaps":["Interplay with 3′ UTR/miR-148a control not quantified","Cell-type specificity of Oct1 effect not resolved"]},{"year":2016,"claim":"Identified HIV-1 Vpu as the mediator that selectively downregulates HLA-C in primary isolates to blunt CTL suppression, distinguishing HLA-C from HLA-A/-B in viral evasion.","evidence":"Primary HIV-1 clone infection, flow cytometry, CTL suppression, siRNA/Vpu mutant analysis","pmids":["27173934"],"confidence":"High","gaps":["Molecular contact residues not yet defined at this stage","NK consequences not addressed"]},{"year":2017,"claim":"Defined the transmembrane residues mediating Vpu–HLA-C interaction and showed downregulation adapts to host HLA-C genotype during chronic infection.","evidence":"Site-directed mutagenesis of Vpu and HLA-C TM domains with viral quasispecies analysis across individuals","pmids":["30180214"],"confidence":"High","gaps":["Structural model of the TM interaction absent","Trafficking pathway of downregulated HLA-C unclear"]},{"year":2017,"claim":"Showed NK cells sense the degree of HIV-1-mediated HLA-C loss, linking inhibitory KIR/HLA-C engagement to NK antiviral activity and licensing.","evidence":"Flow cytometry for HLA-C–KIR binding and NK antiviral assays across viral strains","pmids":["28704647"],"confidence":"Medium","gaps":["Single lab","Mechanism of licensed-NK reduced activity not fully resolved"]},{"year":2017,"claim":"Implicated HLA-C free chains in HIV-1 infectivity, showing β2m-dependent Env association and a requirement for prior β2m assembly.","evidence":"Flow cytometry for β2m-free HLA-C, β2m-conditioned pseudovirus infectivity, Env co-IP","pmids":["28051183"],"confidence":"Medium","gaps":["Single lab","Mechanism by which free chains enhance infectivity unresolved"]},{"year":2017,"claim":"Identified NLRP2 as a trophoblast suppressor of HLA-C expression acting through inhibition of NF-κB signaling, defining a placental regulatory axis.","evidence":"TALEN deletion and shRNA knockdown of NLRP2 in JEG3/primary EVT with NF-κB phosphorylation and HLA-C flow cytometry","pmids":["28340094"],"confidence":"Medium","gaps":["Single lab","In vivo placental consequence not tested"]},{"year":2008,"claim":"Reported that virion-incorporated HLA-C associates with gp120 and enhances HIV-1 infectivity, proposing a non-immune role in viral entry.","evidence":"siRNA knockdown, cell fusion and pseudovirus infectivity, HLA-C/gp120 co-purification","pmids":["18673537"],"confidence":"Medium","gaps":["Single lab","Mechanism of infectivity enhancement not defined"]},{"year":2018,"claim":"Uncovered an NK-specific HLA-C promoter producing untranslatable transcripts whose proportion drops during NK maturation, coupling expression control to NK education.","evidence":"NK-Pro identification, RT-PCR of alternative transcripts, luciferase reporters, maturation correlation","pmids":["29329284"],"confidence":"Medium","gaps":["Single lab","Mechanism switching promoter usage during maturation unknown"]},{"year":2021,"claim":"Provided structural basis for differential HLA-C1 recognition by KIR2DL2 vs. KIR2DL3 and linked allotype-specific docking to functional NK inhibition involving KIR2DS2.","evidence":"X-ray crystallography of KIR2DL2/L3–HLA-C*07:02, mutagenesis, primary NK inhibition assays","pmids":["33846289"],"confidence":"High","gaps":["Did not resolve activating KIR2DS2 structural mechanism","Peptide-dependence of geometry not fully mapped"]},{"year":2019,"claim":"Showed the activating KIR2DS4 recognizes specific peptides (p8-Trp) on HLA-C*05:01, including conserved bacterial motifs, defining peptide-specific NK activation.","evidence":"Peptide binding, KIR2DS4 tetramer binding, NK degranulation, allele-frequency correlation","pmids":["31138701"],"confidence":"High","gaps":["In vivo antibacterial relevance not established","Restricted to HLA-C*05:01"]},{"year":2022,"claim":"Demonstrated that the C1/C2 dimorphism shapes C-terminal peptide preferences and modulates TCR discrimination of identical neoantigens, unifying NK and T cell relevance of the polymorphism.","evidence":"Structural analysis, immunopeptidomics, SPR for TCR affinity, T cell assays with C1/C2-matched allotypes","pmids":["35587797"],"confidence":"High","gaps":["Generalization beyond KRAS-G12D neoantigen not tested","Does not address NK consequences of repertoire shifts"]},{"year":null,"claim":"How the multiple expression-control layers (3′ UTR/miR-148a, Oct1 promoter, NK-specific promoter, NLRP2/NF-κB) are integrated across cell types and how peptide repertoire jointly tunes NK and T cell recognition remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model combining transcriptional and post-transcriptional control","Cell-type-specific weighting of each mechanism unquantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,3,17,18,21]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,5,14]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,9,11,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,9,10,11]}],"complexes":[],"partners":["KIR2DL2","KIR2DL3","KIR2DS1","KIR2DS4","B2M","VPU"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P10321","full_name":"HLA class I histocompatibility antigen, C alpha chain","aliases":["HLA-Cw","Human leukocyte antigen C"],"length_aa":366,"mass_kda":40.6,"function":"Antigen-presenting major histocompatibility complex class I (MHCI) molecule with an important role in reproduction and antiviral immunity (PubMed:11172028, PubMed:20104487, PubMed:20439706, PubMed:20972337, PubMed:24091323, PubMed:28649982, PubMed:29312307). In complex with B2M/beta 2 microglobulin displays a restricted repertoire of self and viral peptides and acts as a dominant ligand for inhibitory and activating killer immunoglobulin receptors (KIRs) expressed on NK cells (PubMed:16141329). In an allogeneic setting, such as during pregnancy, mediates interaction of extravillous trophoblasts with KIR on uterine NK cells and regulate trophoblast invasion necessary for placentation and overall fetal growth (PubMed:20972337, PubMed:24091323). During viral infection, may present viral peptides with low affinity for KIRs, impeding KIR-mediated inhibition through peptide antagonism and favoring lysis of infected cells (PubMed:20439706). Presents a restricted repertoire of viral peptides on antigen-presenting cells for recognition by alpha-beta T cell receptor (TCR) on HLA-C-restricted CD8-positive T cells, guiding antigen-specific T cell immune response to eliminate infected cells, particularly in chronic viral infection settings such as HIV-1 or CMV infection (PubMed:11172028, PubMed:20104487, PubMed:28649982). Both the peptide and the MHC molecule are recognized by TCR, the peptide is responsible for the fine specificity of antigen recognition and MHC residues account for the MHC restriction of T cells (By similarity). Typically presents intracellular peptide antigens of 9 amino acids that arise from cytosolic proteolysis via proteasome. Can bind different peptides containing allele-specific binding motifs, which are mainly defined by anchor residues at position 2 and 9. Preferentially displays peptides having a restricted repertoire of hydrophobic or aromatic amino acids (Phe, Ile, Leu, Met, Val and Tyr) at the C-terminal anchor (PubMed:25311805, PubMed:8265661) ALLELE C*01:02: The peptide-bound form interacts with KIR2DL2 and KIR2DL3 inhibitory receptors on NK cells. The low affinity peptides compete with the high affinity peptides impeding KIR-mediated inhibition and favoring lysis of infected cells (PubMed:20439706). Presents to CD8-positive T cells a CMV epitope derived from UL83/pp65 (RCPEMISVL), an immediate-early antigen necessary for initiating viral replication (PubMed:12947002) ALLELE C*04:01: Presents a conserved HIV-1 epitope derived from env (SFNCGGEFF) to memory CD8-positive T cells, eliciting very strong IFNG responses (PubMed:20104487). Presents CMV epitope derived from UL83/pp65 (QYDPVAALF) to CD8-positive T cells, triggering T cell cytotoxic response (PubMed:12947002) ALLELE C*05:01: Presents HIV-1 epitope derived from rev (SAEPVPLQL) to CD8-positive T cells, triggering T cell cytotoxic response ALLELE C*06:02: In trophoblasts, interacts with KIR2DS2 on uterine NK cells and triggers NK cell activation, including secretion of cytokines such as GMCSF that enhances trophoblast migration ALLELE C*07:02: Plays an important role in the control of chronic CMV infection. Presents immunodominant CMV epitopes derived from IE1 (LSEFCRVL and CRVLCCYVL) and UL28 (FRCPRRFCF), both antigens synthesized during immediate-early period of viral replication. Elicits a strong anti-viral CD8-positive T cell immune response that increases markedly with age ALLELE C*08:01: Presents viral epitopes derived from CMV UL83 (VVCAHELVC) and IAV M1 (GILGFVFTL), triggering CD8-positive T cell cytotoxic response ALLELE C*12:02: Presents CMV epitope derived from UL83 (VAFTSHEHF) to CD8-positive T cells ALLELE C*15:02: Presents CMV epitope derived from UL83 CC (VVCAHELVC) to CD8-positive T cells, triggering T cell cytotoxic response","subcellular_location":"Cell membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P10321/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/HLA-C","classification":"Common Essential","n_dependent_lines":471,"n_total_lines":1208,"dependency_fraction":0.38990066225165565},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HLA-C","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":"618690","title":"PSORIASIS SUSCEPTIBILITY 1 CANDIDATE GENE 3, NONCODING; PSORS1C3","url":"https://www.omim.org/entry/618690"},{"mim_id":"614070","title":"PSORIASIS 13, SUSCEPTIBILITY TO; PSORS13","url":"https://www.omim.org/entry/614070"},{"mim_id":"613787","title":"MICRO RNA 148B; MIR148B","url":"https://www.omim.org/entry/613787"},{"mim_id":"613786","title":"MICRO RNA 148A; MIR148A","url":"https://www.omim.org/entry/613786"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":1377.9}],"url":"https://www.proteinatlas.org/search/HLA-C"},"hgnc":{"alias_symbol":[],"prev_symbol":["HLA-JY3","D6S204","PSORS1"]},"alphafold":{"accession":"P10321","domains":[{"cath_id":"3.30.500.10","chopping":"26-203","consensus_level":"high","plddt":97.3451,"start":26,"end":203},{"cath_id":"2.60.40.10","chopping":"209-296","consensus_level":"high","plddt":96.5055,"start":209,"end":296}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P10321","model_url":"https://alphafold.ebi.ac.uk/files/AF-P10321-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P10321-F1-predicted_aligned_error_v6.png","plddt_mean":86.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HLA-C","jax_strain_url":"https://www.jax.org/strain/search?query=HLA-C"},"sequence":{"accession":"P10321","fasta_url":"https://rest.uniprot.org/uniprotkb/P10321.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P10321/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P10321"}},"corpus_meta":[{"pmid":"16642438","id":"PMC_16642438","title":"Sequence 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and Caucasian psoriatics shows locus heterogeneity at PSORS1.","date":"2010","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/20604894","citation_count":19,"is_preprint":false},{"pmid":"2246509","id":"PMC_2246509","title":"Functional expression of HLA-C blank antigens on human blood lymphocytes.","date":"1990","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2246509","citation_count":19,"is_preprint":false},{"pmid":"15288178","id":"PMC_15288178","title":"Role of a KIR/HLA-C allorecognition system in pregnancy.","date":"2004","source":"Journal of reproductive immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15288178","citation_count":18,"is_preprint":false},{"pmid":"27521484","id":"PMC_27521484","title":"HLA-C levels impact natural killer cell subset distribution and function.","date":"2016","source":"Human 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cells discriminate between groups C1 and C2 HLA-C.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/35587797","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51188,"output_tokens":6357,"usd":0.12446,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15186,"output_tokens":5842,"usd":0.11099,"stage2_stop_reason":"end_turn"},"total_usd":0.23545,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"HLA-C alleles are the dominant inhibitory ligands that protect target cells from lysis by NK1- and NK2-specific NK cells. Transfection of class I-deleted mutant cell lines with HLA-C alleles encoding Asn-77/Lys-80 (e.g., HLA-Cw4, -Cw5, -Cw6) inhibited lysis by NK1-specific NK cells, while alleles encoding Ser-77/Asn-80 (e.g., HLA-Cw1, -Cw7, -Cw13) protected targets from NK2-specific NK cells. The dimorphism at positions 77–80 of HLA-C determines which NK cell subset is inhibited.\",\n      \"method\": \"Transfection of HLA-C alleles into class I-deleted mutant cell lines followed by NK cell cytotoxicity assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct functional reconstitution by transfection with allele-specific readout, foundational result replicated across multiple alleles and independently confirmed in subsequent studies\",\n      \"pmids\": [\"8265660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"HLA-Cw3 expressed in transgenic C57BL/6 mice functions as a transplantation antigen (transgenic skin rapidly rejected by normal mice) and as a restriction element for cytotoxic T lymphocytes specific for influenza and Sendai virus, demonstrating immunological functions comparable to HLA-A and -B.\",\n      \"method\": \"Transgenic mouse model; skin graft rejection assay; CTL restriction assay with viral antigens\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo functional reconstitution in transgenic animals with two independent functional readouts (transplantation rejection and viral CTL restriction)\",\n      \"pmids\": [\"2840670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Low cell surface expression of HLA-C is caused primarily by faster degradation of HLA-C mRNA (not by intrinsic properties of the heavy chain protein), and the region determining low expression lies between the 3′ end of exon 3 and a site ~600 bases downstream of the translation stop codon in the 3′ UTR. HLA-C heavy chains associate with and dissociate from β2-microglobulin at rates comparable to HLA-A and -B, and increased β2m competition does not alter HLA-C surface expression. Chimeric B7/Cw3 proteins with the B7 peptide-binding groove can still have low surface expression, indicating peptide-binding inefficiency is not the primary cause.\",\n      \"method\": \"mRNA half-life measurement, chimeric gene transfection (HLA-B7/Cw3 and B7/Cw6), β2m competition assays, cell surface expression analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal experiments (mRNA stability, chimeric genes, protein association assays) in a single rigorous study\",\n      \"pmids\": [\"7760000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The inhibitory p58 receptor NKAT2 binds HLA-Cw7 with rapid association and dissociation kinetics, whereas the homologous activating p50 receptors (clone 49 and clone 39) bind HLA-C only very weakly or not at all, demonstrating that the transmembrane/cytoplasmic domains—not the extracellular domains—determine functional (inhibitory vs. activating) differences in KIR binding to HLA-C.\",\n      \"method\": \"Direct binding assays comparing inhibitory and activating KIR receptors to HLA-Cw7; kinetic analysis of association/dissociation rates\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro binding assay with quantitative kinetic measurements, comparing paired inhibitory and activating receptors\",\n      \"pmids\": [\"9826699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Recombinant soluble p58 KIR molecules (KIR-K6 and KIR-K7) directly bind recombinant soluble HLA-Cw3 and HLA-Cw6, as shown by native gel shift assay. The activating p50 KAR-K1 binds neither HLA-C molecule. KIR binding to HLA-C is influenced by the antigenic peptide bound to the MHC molecule, and requires both Ig domains of p58.\",\n      \"method\": \"Native gel shift assay with recombinant soluble KIR and HLA-C proteins; peptide competition\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro binding reconstitution but single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"9378975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"HLA-C protein is expressed on the cell surface of normal extravillous trophoblast cells in association with β2-microglobulin; both paternal and maternal HLA-C alleles are transcribed and expressed. IFN-γ treatment upregulates HLA-C but not HLA-G surface expression on trophoblasts. HLA-C is expressed by all extravillous trophoblast subpopulations in vivo.\",\n      \"method\": \"cDNA sequencing of sorted trophoblast cells; biochemical analysis; flow cytometry with HLA-C-specific antibody; immunohistology; IFN-γ stimulation\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (sequencing, biochemistry, flow cytometry, IHC) in a single study with functional IFN-γ stimulation experiment\",\n      \"pmids\": [\"10833373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A SNP within the 3′ UTR of HLA-C regulates binding of hsa-miR-148a to the HLA-C mRNA, resulting in post-transcriptional downregulation; alleles that bind miR-148a show relatively low surface expression while alleles that escape miR-148a binding show high surface expression. This mechanism underlies differential HLA-C cell surface expression and associates with HIV control.\",\n      \"method\": \"miRNA binding assays; allele-specific 3′ UTR reporter assays; flow cytometry for surface expression; association with HIV control\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mechanistic reporter assays directly demonstrating miR-148a binding to HLA-C 3′ UTR variants, with functional surface expression data and replicated associations\",\n      \"pmids\": [\"21499264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A MIR148A insertion/deletion polymorphism affects miR-148a expression levels, which in turn modulates the degree of HLA-C downregulation and the level of HIV control—but only in individuals carrying an intact miR-148a binding site in the HLA-C 3′ UTR. This demonstrates a direct causal effect of HLA-C expression level on HIV control independent of other HLA loci.\",\n      \"method\": \"Genetic association of MIR148A indel with miR-148a expression, HLA-C surface levels, and HIV control; interaction analysis conditioned on HLA-C 3′ UTR genotype\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis analysis with multiple cohorts; interaction between two polymorphisms provides causal evidence for HLA-C expression level effects\",\n      \"pmids\": [\"24248364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A promoter SNP rs2395471 located in an Oct1 transcription factor consensus binding site ~800 bp upstream of the HLA-C transcription start site regulates HLA-C expression: the A allele has higher Oct1 binding affinity and higher promoter activity than the G allele, as shown by electrophoretic mobility shift assay (Oct1 binds both alleles) and luciferase reporter assay. This variant accounts for up to 36% of explained variation in HLA-C cell surface levels.\",\n      \"method\": \"Imputed expression QTL (impeQTL) mapping; quantitative PCR; flow cytometry; electrophoretic mobility shift assay (EMSA); luciferase reporter assay\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — EMSA and luciferase reporter directly demonstrate Oct1-mediated transcriptional regulation; validated in multiple cohorts (n=369 combined for surface expression)\",\n      \"pmids\": [\"27817866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HIV-1 Vpu mediates downregulation of HLA-C on infected cells, reducing HLA-C-restricted CTL suppression of viral replication in CD4+ cells. HLA-A and HLA-B are unaffected by Vpu. Most primary HIV-1 clones (including transmitted founder viruses) downregulate HLA-C via Vpu, in contrast to the laboratory-adapted NL4-3 strain.\",\n      \"method\": \"Primary HIV-1 clone infection assays; flow cytometry for HLA-C surface expression; CTL suppression assay; siRNA/Vpu mutant analysis\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple primary isolates tested, functional CTL assay, Vpu identified as the mediating viral protein, replicated by a follow-up study (PMID 28704647)\",\n      \"pmids\": [\"27173934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HIV-1 downregulation of HLA-C involves specific residues in the transmembrane region of Vpu (5 residues) and the transmembrane domain of HLA-C (4 residues) that determine Vpu–HLA-C interactions. HLA-C downregulation by Vpu adapts to host HLA genotype during chronic infection; individuals with higher HLA-C expression favor greater viral downregulation.\",\n      \"method\": \"Site-directed mutagenesis of Vpu and HLA-C transmembrane domains; replication-competent viral isolates from 19 individuals; viral quasispecies analysis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis identifies specific interacting residues, combined with in vivo viral evolution analysis across many individuals\",\n      \"pmids\": [\"30180214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HSV-2 specifically downregulates HLA-C (but not HLA-A or HLA-B) on infected dendritic cells via the viral protein ICP47, rendering infected DCs susceptible to NK cell killing. A specific motif in the cytoplasmic tail of HLA-C is responsible for HSV-2-mediated HLA-C downregulation.\",\n      \"method\": \"Viral infection of DCs; flow cytometry; ICP47 mutagenesis/overexpression; NK cell cytotoxicity assay; identification of HLA-C cytoplasmic tail motif\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — identifies specific viral protein (ICP47) and specific domain in HLA-C tail required for downregulation, with functional NK killing readout\",\n      \"pmids\": [\"23555244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HIV-1-mediated downmodulation of HLA-C reduces binding to inhibitory KIRs on NK cells. Despite this, HLA-C-licensed NK cells display reduced antiviral activity compared to unlicensed NK cells, potentially due to residual KIR/HLA-C interaction. NK cells can sense the degree of HLA-C downmodulation by HIV-1, with greater downmodulation correlating with increased NK antiviral activity.\",\n      \"method\": \"Flow cytometry for HLA-C–KIR binding; NK cell antiviral activity assays; comparison of HIV-1 strains with differential HLA-C downmodulation capacity\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays with primary NK cells and multiple viral strains; single lab with two orthogonal methods\",\n      \"pmids\": [\"28704647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HLA-C (incorporated into HIV-1 virions) associates with envelope glycoprotein gp120 and enhances HIV-1 infectivity. Silencing HLA-C by siRNA reduces syncytia formation and pseudovirus infectivity. HLA-C co-purifies with gp120 from cells before and after fusion and is present in fusion complexes.\",\n      \"method\": \"siRNA knockdown of HLA-C; cell fusion assays; pseudovirus infectivity assays; co-purification of HLA-C with gp120\",\n      \"journal\": \"Retrovirology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown combined with binding/co-purification evidence; two orthogonal methods; single lab\",\n      \"pmids\": [\"18673537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HIV-1 specifically increases the amount of HLA-C free chains (not bound to β2-microglobulin) on the membrane of infected cells. The association between HIV-1 Env and HLA-C at the cell membrane requires β2m to occur. The enhanced infectivity conferred by HLA-C specifically involves HLA-C free-chain molecules that have been previously correctly assembled with β2m; pseudoviruses produced in the absence of β2m are less infectious.\",\n      \"method\": \"Flow cytometry for β2m-free HLA-C chains; pseudovirus infectivity assays in β2m-present vs. β2m-absent conditions; co-immunoprecipitation of Env with HLA-C\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional pseudovirus assay with β2m dependency, co-IP evidence; single lab\",\n      \"pmids\": [\"28051183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NLRP2 acts as a suppressor of HLA-C expression in trophoblasts: deletion of NLRP2 in JEG3 cells (trophoblast model) using TALEN technology caused a significant increase in constitutive HLA-C expression, and NLRP2 knockdown by lentiviral shRNA in JEG3 and primary EVT increased TNFα-induced NF-κB p65 phosphorylation. This indicates NLRP2 regulates HLA-C expression via suppression of NF-κB signaling.\",\n      \"method\": \"TALEN-mediated NLRP2 deletion; lentiviral shRNA knockdown; NF-κB phosphorylation assay; flow cytometry for HLA-C surface expression\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function by two methods (TALEN deletion and shRNA) with defined molecular readout (HLA-C expression and NF-κB phosphorylation); single lab\",\n      \"pmids\": [\"28340094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"An NK cell-specific HLA-C promoter (NK-Pro) drives expression of an array of alternative transcripts with varying exon content. Skipping of the first coding exon generates untranslatable HLA-C mRNAs; the proportion of untranslatable mRNA decreases as NK cells mature, correlating with increased HLA-C protein expression. A polymorphism in a key Ets-binding site of the NK-Pro generates HLA-C alleles that lack significant promoter activity, resulting in reduced HLA-C expression and increased NK functional activity.\",\n      \"method\": \"NK-specific promoter identification; RT-PCR for alternative transcripts; luciferase reporter assay for NK promoter activity; correlation of transcript ratios with NK maturation and HLA-C protein levels\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter assays plus transcript analysis during NK maturation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29329284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structures of KIR2DL2 and KIR2DL3 in complex with HLA-C*07:02 presenting a self-epitope reveal that KIR2DL2 adopts a different docking geometry atop HLA-C compared to KIR2DL3. Mutagenesis assays showed differences in HLA-C1 allotype recognition between KIR2DL2 and KIR2DL3. HLA-C1 allotypes differ markedly in their capacity to inhibit primary NK cell activation, and these functional differences involve KIR2DS2.\",\n      \"method\": \"X-ray crystallography; mutagenesis; primary NK cell inhibition assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with functional mutagenesis validation and primary NK cell assays in a single study\",\n      \"pmids\": [\"33846289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The activating receptor KIR2DS4 has strong preference for peptides carrying Trp at position 8 (p8) of 9-mer peptides bound to HLA-C*05:01. A complex of HLA-C*05:01 with a p8-Trp peptide is sufficient to activate primary KIR2DS4+ NK cells independently of other activating receptors and NK cell licensing. A conserved bacterial RecA peptide motif presented by HLA-C*05:01 activates KIR2DS4+ NK cells from multiple human pathogens (Helicobacter, Chlamydia, Brucella, Campylobacter).\",\n      \"method\": \"Peptide binding assays; flow cytometry for NK cell degranulation; KIR2DS4 tetramer binding; worldwide allele frequency correlation analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined peptide-HLA-C-KIR2DS4 ternary interaction with primary NK cell functional readout; peptide specificity mapped; replicated across multiple bacterial peptides\",\n      \"pmids\": [\"31138701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The C1/C2 dimorphism at positions 77 and 80 of HLA-C impacts peptide presentation: Ser77 (C1) vs. Asn77 (C2) influences amino acid preference near the peptide C-terminus (pΩ and pΩ-1 positions), with C1 favoring small and C2 preferring large residues. KRAS-G12D neoantigen-specific TCRs discriminate between C1 and C2 allotypes presenting the same peptide, with weaker TCR affinity for KRAS-G12D-bound C2-HLA-C despite conserved TCR contacts.\",\n      \"method\": \"Structural analysis; immunopeptidomics; SPR (surface plasmon resonance) for TCR affinity; functional T cell assays; HLA-C allotypes differing only at C1/C2-defining residues\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural, peptidomics, and functional T cell experiments together with quantitative binding measurements in one study\",\n      \"pmids\": [\"35587797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"HLA-C blank antigens (Cb-1 and Cb-2) are functionally expressed on the surface of peripheral blood lymphocytes (EBV-transformed B cells and PHA-induced T cells), can induce allogeneic CTL responses comparable to HLA-B, and are recognized in a class I-specific manner (blocked by anti-class I monomorphic mAb), indicating HLA-C can function as an alloantigen in vivo.\",\n      \"method\": \"CTL clone cytotoxicity assays using transfected Hmy2CIR cells and primary PBL; blocking with class I monomorphic mAb\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional CTL assays with blocking antibody controls; multiple target cell types tested; single lab\",\n      \"pmids\": [\"2246509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Donor KIR2DS1-mediated prevention of AML relapse after allogeneic HSCT is HLA-C-dependent: protection was observed in donors with KIR2DS1 who were homozygous/heterozygous for HLA-C1, but not in donors homozygous for HLA-C2 (who are auto-licensed through KIR2DS1/C2 interaction). This establishes that HLA-C2 ligand engagement of KIR2DS1 in the donor abrogates the antileukemic effect, demonstrating functional HLA-C–KIR2DS1 interaction in vivo.\",\n      \"method\": \"Retrospective clinical cohort (n=1277 AML patients); donor KIR genotyping; donor/recipient HLA-C genotyping; statistical survival/relapse analysis\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large clinical cohort with clear HLA-C genotype interaction defining mechanism; genetic epistasis approach; single retrospective study\",\n      \"pmids\": [\"22931314\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HLA-C is a classical MHC class I molecule that presents peptides to cytotoxic T cells and serves as the dominant ligand for inhibitory and activating KIR receptors on NK cells; its characteristically low cell surface expression is controlled by multiple mechanisms including accelerated mRNA degradation mediated by a 3′ UTR element, post-transcriptional suppression via miR-148a binding to a 3′ UTR polymorphism, an Oct1-binding promoter variant that modulates transcription, and an NK cell-specific promoter that generates untranslatable alternative transcripts during NK maturation; the C1/C2 dimorphism at HLA-C positions 77/80 determines which inhibitory and activating KIR family members bind and how peptide repertoire shapes both NK and T cell recognition; HIV-1 Vpu downregulates HLA-C to evade CTL killing (with specific transmembrane residues mediating Vpu–HLA-C interaction), while HSV-2 ICP47 selectively downregulates HLA-C to redirect NK cells against infected dendritic cells; on trophoblasts, HLA-C expression is suppressed by NLRP2 via NF-κB inhibition, and KIR/HLA-C interactions at the maternal–fetal interface regulate NK cell responses during placentation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HLA-C is a classical MHC class I molecule that presents peptides to cytotoxic T cells and serves as the dominant ligand for the KIR family of NK cell receptors, functioning as a transplantation antigen and CTL restriction element comparable to HLA-A and -B [#1, #20]. Its allotype-defining C1/C2 dimorphism at positions 77/80 partitions NK recognition: distinct residue pairs determine which inhibitory NK subset is protected [#0], with inhibitory p58/KIR2DL receptors binding HLA-C in a peptide-influenced manner while homologous activating p50 receptors bind weakly or not at all—differences dictated by the receptor transmembrane/cytoplasmic domains [#3, #4]. Crystallographic and functional analyses show that closely related KIRs (KIR2DL2 vs. KIR2DL3) adopt different docking geometries on HLA-C1 and differ in allotype recognition [#17], that the activating KIR2DS4 reads specific bound peptides including conserved bacterial motifs presented by HLA-C*05:01 [#18], and that the C1/C2 polymorphism shapes the C-terminal peptide repertoire to influence both KIR and TCR discrimination of identical epitopes [#20, #19]. A defining feature of HLA-C is its characteristically low surface expression, governed by multiple layers: accelerated mRNA degradation directed by a 3′ UTR element [#2], post-transcriptional suppression via miR-148a binding to a 3′ UTR polymorphism whose strength causally tunes HIV control [#6, #7], an Oct1-binding promoter SNP that modulates transcription [#8], and an NK cell-specific promoter generating untranslatable alternative transcripts during NK maturation [#16]. HLA-C is a target of viral immune evasion: HIV-1 Vpu selectively downregulates HLA-C through defined transmembrane residue contacts to escape CTL killing and modulate NK sensing [#9, #10, #12], while HSV-2 ICP47 downregulates HLA-C via a cytoplasmic tail motif to redirect NK killing of infected dendritic cells [#11]. At the maternal–fetal interface, HLA-C is expressed on extravillous trophoblast in association with β2-microglobulin and is upregulated by IFN-γ [#5], with NLRP2 suppressing its expression through inhibition of NF-κB signaling [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Established that HLA-C is a bona fide immunological MHC class I molecule rather than a vestigial locus, settling whether it could serve antigen-presentation functions like HLA-A and -B.\",\n      \"evidence\": \"HLA-Cw3 transgenic C57BL/6 mice tested in skin graft rejection and viral CTL restriction assays\",\n      \"pmids\": [\"2840670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address peptide repertoire or why HLA-C surface levels are low\", \"Single allele tested\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Confirmed in a human system that HLA-C functions as an alloantigen capable of priming CTL, reinforcing its role as a class I restriction element.\",\n      \"evidence\": \"CTL clone cytotoxicity using transfected and primary cells with monomorphic class I antibody blocking\",\n      \"pmids\": [\"2246509\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not define molecular basis of recognition\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Defined the C1/C2 dimorphism at positions 77/80 as the determinant of which NK cell subset HLA-C inhibits, founding the HLA-C–NK recognition framework.\",\n      \"evidence\": \"Allele-specific transfection into class I-deleted lines with NK cytotoxicity readout\",\n      \"pmids\": [\"8265660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor identity not molecularly resolved at the time\", \"Did not explain inhibitory vs. activating distinction\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Resolved why HLA-C surface expression is low, showing the cause is post-transcriptional mRNA instability rather than heavy chain or peptide-binding defects.\",\n      \"evidence\": \"mRNA half-life measurements, B7/Cw3 chimeric gene transfection, β2m competition assays\",\n      \"pmids\": [\"7760000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the trans-acting factor mediating 3′ UTR degradation\", \"Polymorphic control not yet mapped\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrated direct physical binding of inhibitory p58 KIRs to soluble HLA-C and a peptide dependence of that interaction, establishing the biochemical basis of KIR/HLA-C recognition.\",\n      \"evidence\": \"Native gel shift with recombinant soluble KIR and HLA-Cw3/Cw6, peptide competition\",\n      \"pmids\": [\"9378975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not explain why activating KIRs fail to bind\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed that inhibitory versus activating function in KIR/HLA-C pairs is set by the transmembrane/cytoplasmic domains, not ligand affinity, since activating p50 receptors bind HLA-C poorly.\",\n      \"evidence\": \"Kinetic binding assays comparing inhibitory NKAT2 and activating p50 receptors to HLA-Cw7\",\n      \"pmids\": [\"9826699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address peptide-specific activating recognition\", \"Structural docking not defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that HLA-C is expressed on extravillous trophoblast as a β2m-associated, IFN-γ-responsive molecule, placing it at the maternal–fetal interface.\",\n      \"evidence\": \"cDNA sequencing, biochemistry, flow cytometry, IHC, and IFN-γ stimulation of trophoblast\",\n      \"pmids\": [\"10833373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence for placentation not tested here\", \"Regulatory mechanism of trophoblast expression unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified miR-148a binding to a 3′ UTR polymorphism as a molecular mechanism setting allele-specific HLA-C surface levels and linked expression level to HIV control.\",\n      \"evidence\": \"Allele-specific 3′ UTR reporter and miRNA binding assays with surface expression and HIV association\",\n      \"pmids\": [\"21499264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish causality independent of linked HLA loci\", \"Other 3′ UTR regulators not excluded\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided in vivo evidence of functional activating HLA-C2–KIR2DS1 engagement by showing HLA-C2 abrogates KIR2DS1-mediated protection against AML relapse.\",\n      \"evidence\": \"Retrospective HSCT cohort with donor KIR and donor/recipient HLA-C genotyping\",\n      \"pmids\": [\"22931314\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single retrospective cohort\", \"Direct biochemical KIR2DS1/C2 interaction not measured here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated causal control of HIV outcome by HLA-C expression level via a MIR148A indel acting only when the 3′ UTR binding site is intact, isolating HLA-C dosage as the effector.\",\n      \"evidence\": \"Genetic epistasis between MIR148A indel and HLA-C 3′ UTR genotype across cohorts\",\n      \"pmids\": [\"24248364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which higher HLA-C improves HIV control not fully resolved\", \"Does not address NK vs. CTL contribution\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed selective viral targeting of HLA-C by HSV-2 ICP47 via an HLA-C cytoplasmic tail motif, redirecting NK killing toward infected dendritic cells.\",\n      \"evidence\": \"DC infection, ICP47 mutagenesis/overexpression, HLA-C tail motif mapping, NK cytotoxicity\",\n      \"pmids\": [\"23555244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of tail-motif-dependent downregulation not defined\", \"In vivo relevance not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped an Oct1-binding promoter SNP as a major transcriptional determinant of HLA-C surface levels, adding a transcriptional layer to expression control.\",\n      \"evidence\": \"impeQTL mapping, qPCR, flow cytometry, EMSA, and luciferase reporter assays\",\n      \"pmids\": [\"27817866\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay with 3′ UTR/miR-148a control not quantified\", \"Cell-type specificity of Oct1 effect not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified HIV-1 Vpu as the mediator that selectively downregulates HLA-C in primary isolates to blunt CTL suppression, distinguishing HLA-C from HLA-A/-B in viral evasion.\",\n      \"evidence\": \"Primary HIV-1 clone infection, flow cytometry, CTL suppression, siRNA/Vpu mutant analysis\",\n      \"pmids\": [\"27173934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular contact residues not yet defined at this stage\", \"NK consequences not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the transmembrane residues mediating Vpu–HLA-C interaction and showed downregulation adapts to host HLA-C genotype during chronic infection.\",\n      \"evidence\": \"Site-directed mutagenesis of Vpu and HLA-C TM domains with viral quasispecies analysis across individuals\",\n      \"pmids\": [\"30180214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model of the TM interaction absent\", \"Trafficking pathway of downregulated HLA-C unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed NK cells sense the degree of HIV-1-mediated HLA-C loss, linking inhibitory KIR/HLA-C engagement to NK antiviral activity and licensing.\",\n      \"evidence\": \"Flow cytometry for HLA-C–KIR binding and NK antiviral assays across viral strains\",\n      \"pmids\": [\"28704647\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of licensed-NK reduced activity not fully resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Implicated HLA-C free chains in HIV-1 infectivity, showing β2m-dependent Env association and a requirement for prior β2m assembly.\",\n      \"evidence\": \"Flow cytometry for β2m-free HLA-C, β2m-conditioned pseudovirus infectivity, Env co-IP\",\n      \"pmids\": [\"28051183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism by which free chains enhance infectivity unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified NLRP2 as a trophoblast suppressor of HLA-C expression acting through inhibition of NF-κB signaling, defining a placental regulatory axis.\",\n      \"evidence\": \"TALEN deletion and shRNA knockdown of NLRP2 in JEG3/primary EVT with NF-κB phosphorylation and HLA-C flow cytometry\",\n      \"pmids\": [\"28340094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"In vivo placental consequence not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Reported that virion-incorporated HLA-C associates with gp120 and enhances HIV-1 infectivity, proposing a non-immune role in viral entry.\",\n      \"evidence\": \"siRNA knockdown, cell fusion and pseudovirus infectivity, HLA-C/gp120 co-purification\",\n      \"pmids\": [\"18673537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of infectivity enhancement not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Uncovered an NK-specific HLA-C promoter producing untranslatable transcripts whose proportion drops during NK maturation, coupling expression control to NK education.\",\n      \"evidence\": \"NK-Pro identification, RT-PCR of alternative transcripts, luciferase reporters, maturation correlation\",\n      \"pmids\": [\"29329284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism switching promoter usage during maturation unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided structural basis for differential HLA-C1 recognition by KIR2DL2 vs. KIR2DL3 and linked allotype-specific docking to functional NK inhibition involving KIR2DS2.\",\n      \"evidence\": \"X-ray crystallography of KIR2DL2/L3–HLA-C*07:02, mutagenesis, primary NK inhibition assays\",\n      \"pmids\": [\"33846289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve activating KIR2DS2 structural mechanism\", \"Peptide-dependence of geometry not fully mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed the activating KIR2DS4 recognizes specific peptides (p8-Trp) on HLA-C*05:01, including conserved bacterial motifs, defining peptide-specific NK activation.\",\n      \"evidence\": \"Peptide binding, KIR2DS4 tetramer binding, NK degranulation, allele-frequency correlation\",\n      \"pmids\": [\"31138701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo antibacterial relevance not established\", \"Restricted to HLA-C*05:01\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that the C1/C2 dimorphism shapes C-terminal peptide preferences and modulates TCR discrimination of identical neoantigens, unifying NK and T cell relevance of the polymorphism.\",\n      \"evidence\": \"Structural analysis, immunopeptidomics, SPR for TCR affinity, T cell assays with C1/C2-matched allotypes\",\n      \"pmids\": [\"35587797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalization beyond KRAS-G12D neoantigen not tested\", \"Does not address NK consequences of repertoire shifts\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple expression-control layers (3′ UTR/miR-148a, Oct1 promoter, NK-specific promoter, NLRP2/NF-κB) are integrated across cell types and how peptide repertoire jointly tunes NK and T cell recognition remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model combining transcriptional and post-transcriptional control\", \"Cell-type-specific weighting of each mechanism unquantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 3, 17, 18, 21]},\n      {\"term_id\": \"GO:0042379\", \"supporting_discovery_ids\": []}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 5, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 9, 11, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 9, 10, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KIR2DL2\", \"KIR2DL3\", \"KIR2DS1\", \"KIR2DS4\", \"B2M\", \"Vpu\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}