{"gene":"CCR5","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1996,"finding":"CC-CKR-5 (CCR5) functions as a second receptor (coreceptor) for NSI/macrophage-tropic HIV-1 strains: expression of CCR5 in CD4+, non-permissive human and non-human cells renders them susceptible to infection by NSI strains and allows env-mediated membrane fusion.","method":"Expression of CCR5 in non-permissive CD4+ cells, infection assay and cell-cell fusion assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct functional reconstitution in non-permissive cells, independently replicated in multiple 1996 papers (PMID:8649512, 8658171, 8674120)","pmids":["8649512","8658171","8674120"],"is_preprint":false},{"year":1996,"finding":"CC CKR5 is a G protein-coupled receptor for RANTES, MIP-1alpha, and MIP-1beta, and serves as a fusion cofactor specifically for macrophage-tropic (R5) HIV-1 envelope glycoproteins; CCR5 mRNA expression is selective for cell types susceptible to macrophage-tropic isolates.","method":"Recombinant CCR5 expression in CD4+ non-human cells, cell fusion assay with macrophage-tropic vs. T-cell line-tropic Envs, RT-PCR for CCR5 mRNA in susceptible cell types","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in non-human cells with orthogonal methods, replicated across labs","pmids":["8658171"],"is_preprint":false},{"year":1996,"finding":"CKR-5 (CCR5) functions as a cofactor for M-tropic HIV-1 entry and cell-cell syncytia formation when co-expressed with CD4; a dual-tropic HIV-1 isolate (89.6) can use both CCR5 and Fusin (CXCR4) as entry cofactors.","method":"Expression of CCR5/CD4 in non-permissive QT6 cells, syncytia formation and viral entry assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in non-permissive cells, multiple HIV-1 strains tested, independent replication","pmids":["8674120"],"is_preprint":false},{"year":1996,"finding":"CCR5 selectively binds MIP-1alpha, MIP-1beta, and RANTES as agonists (EC50 = 3–30 nM for calcium flux); CCR5-mediated calcium flux responses are completely blocked by pertussis toxin, indicating coupling to Gi-class G proteins.","method":"Calcium flux assay in transfected HEK 293 cells, pertussis toxin inhibition, radioligand binding assay","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct functional reconstitution in transfected cells with pharmacological inhibition, replicated in subsequent studies","pmids":["8699119"],"is_preprint":false},{"year":1998,"finding":"CCR5 activation by RANTES stimulates membrane-associated inhibitory G proteins (specifically Gialpha2), inhibits adenylyl cyclase activity (reducing cAMP), and undergoes rapid agonist-dependent desensitization and internalization; these effects are blocked by pertussis toxin.","method":"[35S]GTPgammaS binding assay, adenylyl cyclase inhibition assay, Gialpha2 overexpression, pertussis toxin treatment, flow cytometry for surface receptor levels in stably transfected CHO and NG108-15 cells","journal":"Journal of cellular biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods in stable cell lines with pharmacological controls","pmids":["9736452"],"is_preprint":false},{"year":1998,"finding":"MCP-2 (CCL8) binds and activates CCR5 (competing with MIP-1beta binding), induces CCR5 internalization, and blocks HIV-1 entry/replication in CCR5/CD4-co-expressing cells, identifying MCP-2 as an additional natural CCR5 agonist and HIV-1 inhibitor.","method":"Competitive radioligand binding on CCR5-transfected HEK293 cells, chemotaxis assay, confocal microscopy for receptor internalization, HIV-1 infection assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (binding, chemotaxis, confocal, infection assay) in a single study","pmids":["9468473"],"is_preprint":false},{"year":1998,"finding":"CCR5 internalization is induced by the beta-chemokine RANTES but not by phorbol esters; CCR5 lacks the Ser/IleLeu sequence required for phorbol ester-induced uptake seen with CXCR4, indicating distinct endocytosis mechanisms for CCR5 vs. CXCR4.","method":"Internalization assays with RANTES and phorbol esters, mutagenesis of endocytosis signal motifs, comparison with CXCR4","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of signaling motifs combined with functional internalization assays, single lab","pmids":["9718374"],"is_preprint":false},{"year":1999,"finding":"CD4 and CCR5 are constitutively associated on the cell surface in the absence of gp120; this interaction involves the second extracellular loop of CCR5 and the first two domains of CD4, and can be inhibited by CCR5- and CD4-specific antibodies that also interfere with HIV-1 infection.","method":"Co-immunoprecipitation, antibody competition assay, comparison with CD4-CXCR4 co-IP","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with domain mapping and functional antibody inhibition, single lab","pmids":["10377443"],"is_preprint":false},{"year":2002,"finding":"CCR5 undergoes ligand-induced internalization via clathrin-coated pits (inhibited by sucrose, associated with arrestin-2 translocation) and caveolae (inhibited by nystatin/filipin); CCR5 recycling to the cell surface is independent of the Golgi apparatus and late endosomes, consistent with routing through early endosomes.","method":"Pharmacological inhibitors (sucrose, nystatin, filipin, vesicle transport inhibitors), arrestin-2 movement tracking, receptor recovery assays in CCR5-expressing CHO cells","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological pathway inhibitors in stable cell line, single lab","pmids":["11806977"],"is_preprint":false},{"year":2002,"finding":"Following CCR5 ligand stimulation, serine 337 is phosphorylated exclusively by PKC in a rapid but transient manner, while serine 349 is phosphorylated by GRK in a time-dependent manner; phosphorylated receptors accumulate in perinuclear recycling endosomes; protein phosphatases active at neutral pH dephosphorylate these sites.","method":"Phosphosite-specific monoclonal antibodies, immunofluorescence microscopy, in vitro phosphatase assay with okadaic acid in CCR5-expressing cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — phosphosite-specific antibodies with kinase/phosphatase dissection and spatial localization, multiple orthogonal methods in single study","pmids":["12403770"],"is_preprint":false},{"year":2004,"finding":"CCR5 internalization and recycling are regulated by actin polymerization and activation of small GTPases (Rho family); treatment with cytochalasin D (actin depolymerizer), Toxin B, or C3 exoenzyme inhibited both CCR5 internalization and recycling; Rho kinase inhibitor Y27632 had no effect on internalization/recycling but ligand-induced CCR5 activation leads to Rho kinase-dependent focal adhesion complex formation.","method":"Pharmacological inhibitors (cytochalasin D, Toxin B, C3 exoenzyme, Y27632), stably transfected CHO cells and monocytic THP-1 cells","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological pathway inhibitors in two cell systems, single lab","pmids":["14717692"],"is_preprint":false},{"year":2006,"finding":"CCR5 inhibitors (including aplaviroc) bind in a predominantly lipophilic pocket at the interface of extracellular loops and within the upper transmembrane (TM) domain of CCR5; mutations in CCR5 binding sites decreased both gp120 binding to CCR5 and HIV-1 susceptibility; mutations in TM4/TM5 decreased gp120 binding and HIV-1 infectivity with less effect on CC-chemokine binding, indicating that appropriate CCR5 inhibitor binding can be HIV-1-specific while preserving chemokine-CCR5 interactions.","method":"Saturation binding assays, site-directed mutagenesis of CCR5 TM domains, gp120 binding assay, HIV-1 infection assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with binding and infection assays, multiple CCR5 inhibitors characterized","pmids":["16476734"],"is_preprint":false},{"year":2008,"finding":"CCR5 and CXCR4 physically associate in a signaling complex; simultaneous expression and cooperation between CCR5 and CXCR4 are required for chemokine-induced T cell costimulation at the immunological synapse; CCR5 is recruited to the immunological synapse during human T cell activation.","method":"Co-immunoprecipitation demonstrating physical association, live imaging of receptor recruitment to the immunological synapse, functional costimulation assays in human T cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus live imaging and functional readout, single lab","pmids":["18632580"],"is_preprint":false},{"year":2009,"finding":"CCR5 mediates its profibrogenic effects in resident liver cells (hepatic stellate cells, HSCs), promoting HSC migration through a redox-sensitive, PI3K-dependent pathway; CCR5-deficient HSCs display strongly suppressed CC chemokine-induced migration.","method":"CCR5-deficient mouse chimeras (bone marrow transplant), in vitro HSC migration assays with PI3K inhibitors and redox manipulation, experimental fibrosis models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout chimeras plus mechanistic inhibitor assays, two experimental fibrosis models","pmids":["19603542"],"is_preprint":false},{"year":2010,"finding":"During CCR5 desensitization, the receptor cycles to and from the cell surface via the endosome recycling compartment and the trans-Golgi network; both the native ligand CCL5 and the chemokine analog PSC-RANTES cause CCR5 accumulation in the trans-Golgi network, but CCR5 sequestered by PSC-RANTES cannot be returned to the cell surface by the small molecule inhibitor TAK-779 and shows more durable association with CCR5 than CCL5.","method":"Fluorescence microscopy, subcellular fractionation, inhibitor competition assays in CCR5-expressing cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization imaging with functional consequence, single lab","pmids":["21041313"],"is_preprint":false},{"year":2011,"finding":"Maraviroc binds CCR5 at a transmembrane cavity and prevents CCL3 and gp120 binding by an allosteric mechanism; maraviroc can insert in three different binding positions in the TM cavity; residues in the CCR5 dimer interface are required for gp120 binding, suggesting receptor dimerization is important for HIV-1 entry.","method":"Site-directed mutagenesis combined with homology modeling, automated docking using CXCR4 crystal structure, virtual screening, CCR5 chimera analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus structural modeling with functional binding data, single lab","pmids":["21775441"],"is_preprint":false},{"year":2011,"finding":"Using CCR5/CCR2 chimeric receptors, orthosteric chemokine binding sites (extracellular) and allosteric small molecule binding sites (transmembrane) in CCR5 can be structurally separated yet still functionally communicate agonism and antagonism; allosteric enhancement of chemokine binding is disrupted when extracellular regions are replaced.","method":"CCR5/CCR2 chimeric receptor construction, ligand binding assays, signaling assays, CCR5-selective small molecule agonist/antagonist testing","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — chimeric receptor approach with binding and functional assays, single lab","pmids":["21878623"],"is_preprint":false},{"year":2018,"finding":"CCR5 forms three distinct homodimeric conformations involving transmembrane helix 5; two dimeric states correspond to unliganded receptors and one is stabilized by the inverse agonist maraviroc; CCR5 dimerization is required for targeting the receptor to the plasma membrane.","method":"Receptor cross-linking, FRET/BRET energy transfer, functional export assay (RUSH system), computational modeling, site-directed mutagenesis of TM5 interface residues","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biophysical methods (crosslinking, FRET, export assay) with mutagenesis in single study","pmids":["29739880"],"is_preprint":false},{"year":2018,"finding":"CCR5 exists in multiple structurally and antigenically distinct conformations at the cell surface; gp120s from different HIV-1 strains exhibit divergent binding to different CCR5 populations/conformations; HIV-1 preferentially uses CCR5 monomers (not oligomers) for entry; CCR5 conformational diversity shapes HIV-1 cellular tropism and sensitivity to CCR5 ligand inhibition.","method":"Mutagenesis of CCR5 dimerization interface, gp120 binding assays on cell lines and primary cells, viral entry assays, CD4i monoclonal antibody epitope mapping, T-cell vs. macrophage CCR5 comparison","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus multiple cell-type comparisons and binding/entry assays, single lab","pmids":["30521629"],"is_preprint":false},{"year":2019,"finding":"CCR5 palmitoylation is critical for its delivery to the plasma membrane via the secretory pathway; small molecules that inhibit CCR5 palmitoylation trap CCR5 in the early secretory pathway, reducing plasma membrane expression and markedly decreasing HIV entry in primary macrophages.","method":"Cell-based assay monitoring differential protein transport (RUSH), high-content screening, palmitoylation assay, HIV entry assay in primary macrophages","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical demonstration of palmitoylation requirement combined with trafficking assay and functional HIV entry readout in primary cells","pmids":["31663020"],"is_preprint":false},{"year":2021,"finding":"CCR5 activation by CCL5 (from pericytes) promotes DNA-PKcs-mediated DNA damage repair in glioblastoma cells, inducing temozolomide chemoresistance; disrupting CCL5-CCR5 paracrine signaling with maraviroc inhibits pericyte-promoted DDR.","method":"Genetic depletion of pericytes in GBM xenografts, CCR5 activation/inhibition (maraviroc), DNA-PKcs assay, survival analysis in tumor-bearing mice, patient-derived xenografts","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological perturbation in xenograft models with defined molecular pathway, single lab","pmids":["34239070"],"is_preprint":false},{"year":2021,"finding":"CCR5 activation in neurons after intracerebral hemorrhage promotes neuronal pyroptosis via the CCR5/PKA/CREB/NLRP1 signaling pathway: CCR5 activation suppresses PKA-Cα and p-CREB, which upregulates NLRP1/ASC/caspase-1/GSDMD and IL-1β/IL-18; CCR5 inhibition with maraviroc or PKA activation reversed these effects.","method":"Intranasal maraviroc administration in ICH mice, CREB inhibitor (666-15) intracerebroventricular injection, rCCL5 and 8-Bromo-cAMP intracerebroventricular injection, Western blot, immunofluorescence, behavioral assays","journal":"Stroke","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and exogenous ligand interventions with defined pathway in mouse ICH model, single lab","pmids":["34719258"],"is_preprint":false},{"year":2022,"finding":"A delayed (12–24 h) increase in CCR5 expression in mouse dorsal CA1 neurons after contextual memory formation decreases neuronal excitability, reduces overlap between memory ensembles, and closes the temporal window for memory linking; age-related increase in neuronal CCR5 and CCL5 impairs memory linking, reversible by CCR5 knockout or maraviroc.","method":"CCR5 knockout mice, maraviroc pharmacological inhibition, in vivo electrophysiology (neuronal excitability), activity-dependent neuronal labeling (memory ensemble overlap), behavioral memory linking tests in mice","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout plus pharmacological inhibition with electrophysiological and behavioral readouts, replicated across approaches","pmids":["35614219"],"is_preprint":false},{"year":2023,"finding":"Activated microglial-derived CCL3/CCL4/CCL5 bind neuronal CCR5 and activate mTORC1, inhibiting neuronal autophagy and impairing clearance of aggregate-prone proteins; CCR5 upregulation is self-sustaining because CCL5-CCR5-mediated autophagy inhibition impairs CCR5 degradation itself; pharmacological or genetic CCR5 inhibition rescues autophagy and ameliorates Huntington's disease and tau pathology in mice.","method":"CCR5 knockout mice, pharmacological CCR5 inhibition, mTORC1 activity assays, autophagy flux assays, aggregate-prone protein clearance assays, HD and tauopathy mouse models","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout plus pharmacological inhibition with mechanistic mTORC1/autophagy pathway dissection in multiple disease mouse models","pmids":["37105172"],"is_preprint":false},{"year":2023,"finding":"CCR5 C-terminal phosphorylation at a pXpp motif (three phosphoresidues) is essential for stable arrestin2 complex formation; crystal structures of arrestin2 with CCR5 C-terminal phosphopeptides revealed the structural basis of this interaction; GRK- and PKC-mediated multi-site phosphorylation controls the CCR5-arrestin2 interaction.","method":"X-ray crystallography of arrestin2-CCR5 phosphopeptide complexes, NMR, site-directed mutagenesis of CCR5 phosphorylation sites, biochemical pulldown assays, functional arrestin recruitment assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with NMR, mutagenesis, biochemical and functional validation in a single study","pmids":["37244255"],"is_preprint":false},{"year":2023,"finding":"CCR5 and CXCR4 form symmetric and asymmetric homodimers and heterodimers; CCR5/CCR5 homodimers preferentially use TM4-TM5 as the binding interface; CXCR4/CXCR4 uses TM6-TM7; distinct dimeric states differ in access to ligand and G protein binding sites, suggesting dimerization as an allosteric regulatory mechanism.","method":"Coarse-grained metadynamics free-energy simulation (computational), validated against existing structural and functional data","journal":"Nature communications","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational free-energy simulation only, no direct experimental structural validation in this paper","pmids":["37833254"],"is_preprint":false},{"year":2018,"finding":"CCR5 downregulation by RANKL is mediated through MEK and JNK signaling pathways in preosteoclast cells; CCR5 downregulation promotes osteoclastogenesis; IFN-γ can restore RANKL-reduced CCR5 expression.","method":"MEK and JNK inhibitors, Western blot, osteoclast differentiation assay, migration assay in mouse preosteoclast cells","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway inhibition with functional differentiation and migration readouts, single lab","pmids":["29717113"],"is_preprint":false},{"year":2012,"finding":"CCL5-CCR5 interaction in osteosarcoma cells activates MEK, ERK, and NF-κB pathways, resulting in upregulation of αvβ3 integrin and enhanced cell migration; CCR5 siRNA/mAb/inhibitor reduced CCL5-enhanced migration and integrin upregulation.","method":"CCR5 siRNA knockdown, CCR5 mAb blocking, kinase pathway inhibitors (MEK, ERK, NF-κB dominant-negative mutants), migration assay, integrin expression by flow cytometry","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown plus pharmacological inhibition with defined pathway and functional readout, single lab","pmids":["22506069"],"is_preprint":false},{"year":2020,"finding":"IL-6 upregulates CCR5 expression and arginase 1 in MDSCs through a STAT3-dependent mechanism; CCR5+ MDSCs differentiated in the presence of IL-6 exhibit strongly enhanced immunosuppressive activity.","method":"In vitro MDSC differentiation with IL-6, STAT3 inhibition, RT-PCR and Western blot for CCR5/arginase 1, T cell suppression assay, validation in RET transgenic melanoma mouse model","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro mechanistic pathway analysis with in vivo validation, single lab","pmids":["32788238"],"is_preprint":false}],"current_model":"CCR5 is a seven-transmembrane Gi-coupled chemokine receptor that binds CCL3, CCL4, CCL5, and CCL8, signals through pertussis-toxin-sensitive Gi proteins to inhibit cAMP and mobilize Ca2+, serves as the principal coreceptor for R5-tropic HIV-1 entry in complex with CD4, undergoes GRK/PKC-mediated phosphorylation at specific C-terminal serines (including a pXpp motif critical for arrestin2 recruitment), internalizes via clathrin-coated pits and caveolae in an actin/Rho-GTPase-dependent manner, cycles through early endosomes and the trans-Golgi network, requires palmitoylation and homodimerization (via TM5) for plasma membrane delivery, forms a constitutive complex with CD4, physically interacts with CXCR4 at the immunological synapse to co-stimulate T cells, and outside of immunity plays roles in hepatic stellate cell migration (PI3K/redox), neuronal excitability and memory linking (reducing CA1 neuronal excitability), autophagy regulation in neurons via mTORC1, and DNA damage repair signaling in cancer cells via DNA-PKcs."},"narrative":{"mechanistic_narrative":"CCR5 is a Gi-coupled seven-transmembrane chemokine receptor that binds the CC-chemokines MIP-1alpha (CCL3), MIP-1beta (CCL4), RANTES (CCL5), and MCP-2 (CCL8) as agonists and signals through pertussis-toxin-sensitive Gialpha2 to inhibit adenylyl cyclase and mobilize calcium [PMID:8699119, PMID:9736452, PMID:9468473]. It serves as the principal coreceptor for macrophage-tropic (R5) HIV-1 entry, conferring envelope-mediated fusion and infection when co-expressed with CD4 in otherwise non-permissive cells, with which it forms a constitutive surface complex via its second extracellular loop and the first two CD4 domains [PMID:8649512, PMID:8658171, PMID:8674120, PMID:10377443]. Agonist binding triggers GRK- and PKC-mediated C-terminal phosphorylation—including a pXpp phosphomotif at the receptor tail that is required for stable arrestin2 recruitment—driving desensitization and internalization through clathrin-coated pits and caveolae, with recycling routed through early endosomes and the trans-Golgi network under actin/Rho-GTPase control [PMID:9736452, PMID:11806977, PMID:12403770, PMID:14717692, PMID:37244255]. Plasma-membrane delivery of CCR5 requires palmitoylation and TM5-mediated homodimerization, and the receptor adopts multiple conformational and oligomeric states that govern HIV-1 strain tropism and discriminate chemokine binding from allosteric small-molecule inhibitor binding, the structural basis exploited by maraviroc and aplaviroc [PMID:16476734, PMID:21775441, PMID:21878623, PMID:29739880, PMID:31663020]. Beyond immune cell signaling, CCR5 drives hepatic stellate cell migration through a redox-sensitive PI3K pathway in fibrosis [PMID:19603542], and in the CNS controls neuronal excitability and the temporal window for memory linking [PMID:35614219] and suppresses neuronal autophagy via mTORC1 to impair clearance of aggregate-prone proteins [PMID:37105172].","teleology":[{"year":1996,"claim":"Established that CCR5 is the missing coreceptor enabling macrophage-tropic HIV-1 entry, answering why CD4 alone is insufficient for infection by these strains.","evidence":"Reconstitution of CCR5/CD4 in non-permissive human and non-human cells with infection and cell-cell fusion assays, across multiple HIV-1 strains","pmids":["8649512","8658171","8674120"],"confidence":"High","gaps":["Did not resolve the gp120-CCR5 binding interface at atomic resolution","Did not establish the relative roles of CCR5 monomers vs oligomers in entry"]},{"year":1996,"claim":"Defined the native ligand and signaling identity of CCR5 as a Gi-coupled CC-chemokine receptor, distinguishing its physiological role from its HIV coreceptor function.","evidence":"Calcium flux and radioligand binding in transfected cells with pertussis toxin inhibition; CCL3/CCL4/CCL5 as agonists","pmids":["8699119"],"confidence":"High","gaps":["Specific Galpha isoform coupling not yet pinned to Gialpha2","Downstream effector cascade beyond calcium/cAMP not defined"]},{"year":1998,"claim":"Showed CCR5 couples specifically to Gialpha2 to inhibit adenylyl cyclase and undergoes rapid agonist-dependent desensitization, defining its canonical GPCR output.","evidence":"GTPgammaS binding, adenylyl cyclase assay, Gialpha2 overexpression and pertussis toxin in stable CHO/NG108-15 cells; competitive binding and internalization for CCL8 as an additional agonist/HIV inhibitor","pmids":["9736452","9468473"],"confidence":"High","gaps":["Quantitative contribution of each Galpha subtype in primary leukocytes unknown","Link between desensitization kinetics and HIV inhibition not fully resolved"]},{"year":1998,"claim":"Distinguished CCR5 endocytic machinery from CXCR4 by showing it is internalized by ligand but not phorbol esters, indicating a distinct C-terminal endocytosis signal.","evidence":"RANTES vs phorbol ester internalization assays and mutagenesis of endocytosis motifs","pmids":["9718374"],"confidence":"High","gaps":["Precise residues governing constitutive vs ligand-induced uptake not mapped here"]},{"year":1999,"claim":"Demonstrated a pre-formed CD4-CCR5 complex on the cell surface, explaining the efficiency of the gp120-triggered entry mechanism.","evidence":"Reciprocal co-immunoprecipitation with domain mapping and functional antibody inhibition","pmids":["10377443"],"confidence":"Medium","gaps":["Stoichiometry of the complex not determined","Single lab; structural model of the interface absent"]},{"year":2002,"claim":"Resolved the trafficking itinerary and phosphoregulation of CCR5, establishing how the receptor is internalized, phosphorylated, and recycled.","evidence":"Pharmacological pathway inhibitors with arrestin-2 tracking; phosphosite-specific antibodies identifying PKC at Ser337 and GRK at Ser349 with phosphatase dissection","pmids":["11806977","12403770"],"confidence":"High","gaps":["Functional consequence of each phosphosite for signaling vs trafficking not fully separated","Identity of the responsible GRK isoform not established"]},{"year":2004,"claim":"Identified actin polymerization and Rho-family GTPases as cytoskeletal regulators of CCR5 internalization and recycling, linking receptor traffic to cell motility machinery.","evidence":"Cytochalasin D, Toxin B, C3 exoenzyme and Y27632 in CHO and THP-1 cells","pmids":["14717692"],"confidence":"Medium","gaps":["Direct effectors connecting Rho GTPases to endocytic vesicles unidentified","Single lab, pharmacological inference"]},{"year":2006,"claim":"Localized small-molecule inhibitor and gp120 binding determinants to the TM cavity and extracellular loops, showing inhibitors can block HIV while sparing chemokine binding.","evidence":"Saturation binding and site-directed mutagenesis of CCR5 TM domains with gp120 binding and HIV infection assays; aplaviroc","pmids":["16476734"],"confidence":"High","gaps":["Atomic-resolution structure of the inhibitor pocket not yet available"]},{"year":2008,"claim":"Revealed a CCR5-CXCR4 signaling complex required for chemokine-driven T-cell costimulation at the immunological synapse, extending CCR5 function into adaptive immune activation.","evidence":"Co-immunoprecipitation, live imaging of synapse recruitment, and costimulation assays in human T cells","pmids":["18632580"],"confidence":"Medium","gaps":["Molecular interface of the CCR5-CXCR4 complex not mapped","Single lab"]},{"year":2009,"claim":"Extended CCR5 function to tissue fibrosis by showing it drives hepatic stellate cell migration through a redox/PI3K pathway.","evidence":"CCR5-deficient bone marrow chimeras with HSC migration assays, PI3K inhibitors, and fibrosis models","pmids":["19603542"],"confidence":"High","gaps":["Downstream PI3K effectors in HSCs not specified","Relative contribution of resident vs infiltrating CCR5+ cells incompletely resolved"]},{"year":2011,"claim":"Defined the allosteric mechanism of maraviroc and the structural separation of orthosteric chemokine and allosteric inhibitor sites, clarifying how TM-cavity drugs antagonize an extracellular ligand.","evidence":"Mutagenesis with homology modeling/docking and CCR5/CCR2 chimeric receptor binding and signaling assays","pmids":["21775441","21878623"],"confidence":"Medium","gaps":["Conclusions rely on homology to CXCR4 rather than CCR5 crystal structure","Allosteric communication pathway between sites not structurally defined"]},{"year":2018,"claim":"Established TM5-mediated homodimerization as a requirement for CCR5 plasma-membrane targeting and identified conformationally distinct receptor populations that shape HIV tropism.","evidence":"Cross-linking, FRET/BRET, RUSH export assay and TM5 mutagenesis; gp120 binding and entry assays across cell types with epitope mapping","pmids":["29739880","30521629"],"confidence":"High","gaps":["Functional signaling differences between dimer states not fully resolved","In vivo relevance of conformational heterogeneity untested"]},{"year":2019,"claim":"Identified palmitoylation as a checkpoint for CCR5 secretory transport, providing a druggable node that limits surface expression and HIV entry.","evidence":"RUSH transport assay, high-content screening, palmitoylation assay, and HIV entry in primary macrophages","pmids":["31663020"],"confidence":"High","gaps":["Responsible palmitoyl-acyltransferase not identified","Palmitoylation sites not individually mapped"]},{"year":2021,"claim":"Uncovered non-immune CCR5 signaling in disease: promotion of DNA-PKcs-mediated DNA repair and chemoresistance in glioblastoma, and PKA/CREB/NLRP1-dependent neuronal pyroptosis after hemorrhage.","evidence":"Pericyte depletion in GBM xenografts with maraviroc and DNA-PKcs assays; intranasal maraviroc and pathway inhibitors in an ICH mouse model","pmids":["34239070","34719258"],"confidence":"Medium","gaps":["Mechanism linking CCR5 to DNA-PKcs activation not biochemically defined","Single lab per model; human relevance correlative"]},{"year":2022,"claim":"Defined a CNS role for CCR5 in regulating neuronal excitability and the temporal window for memory linking, with implications for age-related memory decline.","evidence":"CCR5 knockout and maraviroc with in vivo electrophysiology, neuronal ensemble labeling, and behavioral memory tests in mice","pmids":["35614219"],"confidence":"High","gaps":["Signaling cascade from CCR5 to excitability changes not delineated","Source of neuronal CCL5 increase incompletely defined"]},{"year":2023,"claim":"Established that CCR5 suppresses neuronal autophagy via mTORC1 in a self-amplifying loop, linking microglial chemokine signaling to neurodegenerative proteostasis failure, and defined the structural basis of the CCR5-arrestin2 interaction.","evidence":"CCR5 knockout and pharmacology with mTORC1/autophagy assays in HD and tauopathy models; crystallography, NMR and mutagenesis of the pXpp arrestin2 phosphomotif","pmids":["37105172","37244255"],"confidence":"High","gaps":["G-protein vs arrestin bias in neuronal autophagy signaling not dissected","Full-length CCR5-arrestin2 complex structure not solved"]},{"year":null,"claim":"How CCR5 conformational and oligomeric heterogeneity, biased signaling, and tissue-specific effector coupling are integrated into a single regulatory logic across immune, neural, fibrotic and oncogenic contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking dimer state to ligand-, G-protein-, and arrestin-biased outputs","Tissue-specific determinants of CCR5 effector choice unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,17,19]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[8,14]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[14]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[23]}],"complexes":["CD4-CCR5 entry complex","CCR5 homodimer","CCR5-CXCR4 heterodimer/signaling complex"],"partners":["CD4","CXCR4","ARRB2","CCL5","CCL3","CCL4","CCL8","GNAI2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P51681","full_name":"C-C chemokine receptor type 5","aliases":["CHEMR13","HIV-1 fusion coreceptor"],"length_aa":352,"mass_kda":40.5,"function":"Receptor for a number of inflammatory CC-chemokines including CCL3/MIP-1-alpha, CCL4/MIP-1-beta and RANTES and subsequently transduces a signal by increasing the intracellular calcium ion level. May play a role in the control of granulocytic lineage proliferation or differentiation. 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Against Cerebral Ischemia and Reperfusion Injury.","date":"2017","source":"Current neurovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/28294064","citation_count":31,"is_preprint":false},{"pmid":"16880184","id":"PMC_16880184","title":"The Black Death and AIDS: CCR5-Delta32 in genetics and history.","date":"2006","source":"QJM : monthly journal of the Association of Physicians","url":"https://pubmed.ncbi.nlm.nih.gov/16880184","citation_count":29,"is_preprint":false},{"pmid":"15128728","id":"PMC_15128728","title":"CC-chemokine receptor 5 (CCR5) in hepatitis C--at the crossroads of the antiviral immune response?","date":"2004","source":"The Journal of antimicrobial chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/15128728","citation_count":29,"is_preprint":false},{"pmid":"24855645","id":"PMC_24855645","title":"Targeting spare CC chemokine receptor 5 (CCR5) as a principle to inhibit HIV-1 entry.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24855645","citation_count":29,"is_preprint":false},{"pmid":"19339948","id":"PMC_19339948","title":"CCR5 monoclonal antibodies for HIV-1 therapy.","date":"2009","source":"Current opinion in HIV and AIDS","url":"https://pubmed.ncbi.nlm.nih.gov/19339948","citation_count":29,"is_preprint":false},{"pmid":"24381033","id":"PMC_24381033","title":"CCR5 as a natural and modulated target for inhibition of HIV.","date":"2013","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/24381033","citation_count":29,"is_preprint":false},{"pmid":"30521629","id":"PMC_30521629","title":"CCR5 structural plasticity shapes HIV-1 phenotypic properties.","date":"2018","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/30521629","citation_count":28,"is_preprint":false},{"pmid":"38561044","id":"PMC_38561044","title":"CCR5 and inflammatory storm.","date":"2024","source":"Ageing research 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chemoattraction.","date":"2011","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/21245464","citation_count":25,"is_preprint":false},{"pmid":"39303165","id":"PMC_39303165","title":"Blockade of CCR5+ T Cell Accumulation in the Tumor Microenvironment Optimizes Anti-TGF-β/PD-L1 Bispecific Antibody.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39303165","citation_count":24,"is_preprint":false},{"pmid":"25757618","id":"PMC_25757618","title":"Editing CCR5: a novel approach to HIV gene therapy.","date":"2015","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/25757618","citation_count":24,"is_preprint":false},{"pmid":"31663020","id":"PMC_31663020","title":"Targeting CCR5 trafficking to inhibit HIV-1 infection.","date":"2019","source":"Science 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Disease.","date":"2019","source":"Frontiers in aging neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31447666","citation_count":22,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46930,"output_tokens":7188,"usd":0.124305,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16447,"output_tokens":5153,"usd":0.10553,"stage2_stop_reason":"end_turn"},"total_usd":0.229835,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"CC-CKR-5 (CCR5) functions as a second receptor (coreceptor) for NSI/macrophage-tropic HIV-1 strains: expression of CCR5 in CD4+, non-permissive human and non-human cells renders them susceptible to infection by NSI strains and allows env-mediated membrane fusion.\",\n      \"method\": \"Expression of CCR5 in non-permissive CD4+ cells, infection assay and cell-cell fusion assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct functional reconstitution in non-permissive cells, independently replicated in multiple 1996 papers (PMID:8649512, 8658171, 8674120)\",\n      \"pmids\": [\"8649512\", \"8658171\", \"8674120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CC CKR5 is a G protein-coupled receptor for RANTES, MIP-1alpha, and MIP-1beta, and serves as a fusion cofactor specifically for macrophage-tropic (R5) HIV-1 envelope glycoproteins; CCR5 mRNA expression is selective for cell types susceptible to macrophage-tropic isolates.\",\n      \"method\": \"Recombinant CCR5 expression in CD4+ non-human cells, cell fusion assay with macrophage-tropic vs. T-cell line-tropic Envs, RT-PCR for CCR5 mRNA in susceptible cell types\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in non-human cells with orthogonal methods, replicated across labs\",\n      \"pmids\": [\"8658171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CKR-5 (CCR5) functions as a cofactor for M-tropic HIV-1 entry and cell-cell syncytia formation when co-expressed with CD4; a dual-tropic HIV-1 isolate (89.6) can use both CCR5 and Fusin (CXCR4) as entry cofactors.\",\n      \"method\": \"Expression of CCR5/CD4 in non-permissive QT6 cells, syncytia formation and viral entry assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in non-permissive cells, multiple HIV-1 strains tested, independent replication\",\n      \"pmids\": [\"8674120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CCR5 selectively binds MIP-1alpha, MIP-1beta, and RANTES as agonists (EC50 = 3–30 nM for calcium flux); CCR5-mediated calcium flux responses are completely blocked by pertussis toxin, indicating coupling to Gi-class G proteins.\",\n      \"method\": \"Calcium flux assay in transfected HEK 293 cells, pertussis toxin inhibition, radioligand binding assay\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct functional reconstitution in transfected cells with pharmacological inhibition, replicated in subsequent studies\",\n      \"pmids\": [\"8699119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CCR5 activation by RANTES stimulates membrane-associated inhibitory G proteins (specifically Gialpha2), inhibits adenylyl cyclase activity (reducing cAMP), and undergoes rapid agonist-dependent desensitization and internalization; these effects are blocked by pertussis toxin.\",\n      \"method\": \"[35S]GTPgammaS binding assay, adenylyl cyclase inhibition assay, Gialpha2 overexpression, pertussis toxin treatment, flow cytometry for surface receptor levels in stably transfected CHO and NG108-15 cells\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods in stable cell lines with pharmacological controls\",\n      \"pmids\": [\"9736452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"MCP-2 (CCL8) binds and activates CCR5 (competing with MIP-1beta binding), induces CCR5 internalization, and blocks HIV-1 entry/replication in CCR5/CD4-co-expressing cells, identifying MCP-2 as an additional natural CCR5 agonist and HIV-1 inhibitor.\",\n      \"method\": \"Competitive radioligand binding on CCR5-transfected HEK293 cells, chemotaxis assay, confocal microscopy for receptor internalization, HIV-1 infection assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (binding, chemotaxis, confocal, infection assay) in a single study\",\n      \"pmids\": [\"9468473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CCR5 internalization is induced by the beta-chemokine RANTES but not by phorbol esters; CCR5 lacks the Ser/IleLeu sequence required for phorbol ester-induced uptake seen with CXCR4, indicating distinct endocytosis mechanisms for CCR5 vs. CXCR4.\",\n      \"method\": \"Internalization assays with RANTES and phorbol esters, mutagenesis of endocytosis signal motifs, comparison with CXCR4\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of signaling motifs combined with functional internalization assays, single lab\",\n      \"pmids\": [\"9718374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD4 and CCR5 are constitutively associated on the cell surface in the absence of gp120; this interaction involves the second extracellular loop of CCR5 and the first two domains of CD4, and can be inhibited by CCR5- and CD4-specific antibodies that also interfere with HIV-1 infection.\",\n      \"method\": \"Co-immunoprecipitation, antibody competition assay, comparison with CD4-CXCR4 co-IP\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with domain mapping and functional antibody inhibition, single lab\",\n      \"pmids\": [\"10377443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CCR5 undergoes ligand-induced internalization via clathrin-coated pits (inhibited by sucrose, associated with arrestin-2 translocation) and caveolae (inhibited by nystatin/filipin); CCR5 recycling to the cell surface is independent of the Golgi apparatus and late endosomes, consistent with routing through early endosomes.\",\n      \"method\": \"Pharmacological inhibitors (sucrose, nystatin, filipin, vesicle transport inhibitors), arrestin-2 movement tracking, receptor recovery assays in CCR5-expressing CHO cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological pathway inhibitors in stable cell line, single lab\",\n      \"pmids\": [\"11806977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Following CCR5 ligand stimulation, serine 337 is phosphorylated exclusively by PKC in a rapid but transient manner, while serine 349 is phosphorylated by GRK in a time-dependent manner; phosphorylated receptors accumulate in perinuclear recycling endosomes; protein phosphatases active at neutral pH dephosphorylate these sites.\",\n      \"method\": \"Phosphosite-specific monoclonal antibodies, immunofluorescence microscopy, in vitro phosphatase assay with okadaic acid in CCR5-expressing cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — phosphosite-specific antibodies with kinase/phosphatase dissection and spatial localization, multiple orthogonal methods in single study\",\n      \"pmids\": [\"12403770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CCR5 internalization and recycling are regulated by actin polymerization and activation of small GTPases (Rho family); treatment with cytochalasin D (actin depolymerizer), Toxin B, or C3 exoenzyme inhibited both CCR5 internalization and recycling; Rho kinase inhibitor Y27632 had no effect on internalization/recycling but ligand-induced CCR5 activation leads to Rho kinase-dependent focal adhesion complex formation.\",\n      \"method\": \"Pharmacological inhibitors (cytochalasin D, Toxin B, C3 exoenzyme, Y27632), stably transfected CHO cells and monocytic THP-1 cells\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological pathway inhibitors in two cell systems, single lab\",\n      \"pmids\": [\"14717692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CCR5 inhibitors (including aplaviroc) bind in a predominantly lipophilic pocket at the interface of extracellular loops and within the upper transmembrane (TM) domain of CCR5; mutations in CCR5 binding sites decreased both gp120 binding to CCR5 and HIV-1 susceptibility; mutations in TM4/TM5 decreased gp120 binding and HIV-1 infectivity with less effect on CC-chemokine binding, indicating that appropriate CCR5 inhibitor binding can be HIV-1-specific while preserving chemokine-CCR5 interactions.\",\n      \"method\": \"Saturation binding assays, site-directed mutagenesis of CCR5 TM domains, gp120 binding assay, HIV-1 infection assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with binding and infection assays, multiple CCR5 inhibitors characterized\",\n      \"pmids\": [\"16476734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CCR5 and CXCR4 physically associate in a signaling complex; simultaneous expression and cooperation between CCR5 and CXCR4 are required for chemokine-induced T cell costimulation at the immunological synapse; CCR5 is recruited to the immunological synapse during human T cell activation.\",\n      \"method\": \"Co-immunoprecipitation demonstrating physical association, live imaging of receptor recruitment to the immunological synapse, functional costimulation assays in human T cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus live imaging and functional readout, single lab\",\n      \"pmids\": [\"18632580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CCR5 mediates its profibrogenic effects in resident liver cells (hepatic stellate cells, HSCs), promoting HSC migration through a redox-sensitive, PI3K-dependent pathway; CCR5-deficient HSCs display strongly suppressed CC chemokine-induced migration.\",\n      \"method\": \"CCR5-deficient mouse chimeras (bone marrow transplant), in vitro HSC migration assays with PI3K inhibitors and redox manipulation, experimental fibrosis models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout chimeras plus mechanistic inhibitor assays, two experimental fibrosis models\",\n      \"pmids\": [\"19603542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"During CCR5 desensitization, the receptor cycles to and from the cell surface via the endosome recycling compartment and the trans-Golgi network; both the native ligand CCL5 and the chemokine analog PSC-RANTES cause CCR5 accumulation in the trans-Golgi network, but CCR5 sequestered by PSC-RANTES cannot be returned to the cell surface by the small molecule inhibitor TAK-779 and shows more durable association with CCR5 than CCL5.\",\n      \"method\": \"Fluorescence microscopy, subcellular fractionation, inhibitor competition assays in CCR5-expressing cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization imaging with functional consequence, single lab\",\n      \"pmids\": [\"21041313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Maraviroc binds CCR5 at a transmembrane cavity and prevents CCL3 and gp120 binding by an allosteric mechanism; maraviroc can insert in three different binding positions in the TM cavity; residues in the CCR5 dimer interface are required for gp120 binding, suggesting receptor dimerization is important for HIV-1 entry.\",\n      \"method\": \"Site-directed mutagenesis combined with homology modeling, automated docking using CXCR4 crystal structure, virtual screening, CCR5 chimera analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus structural modeling with functional binding data, single lab\",\n      \"pmids\": [\"21775441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Using CCR5/CCR2 chimeric receptors, orthosteric chemokine binding sites (extracellular) and allosteric small molecule binding sites (transmembrane) in CCR5 can be structurally separated yet still functionally communicate agonism and antagonism; allosteric enhancement of chemokine binding is disrupted when extracellular regions are replaced.\",\n      \"method\": \"CCR5/CCR2 chimeric receptor construction, ligand binding assays, signaling assays, CCR5-selective small molecule agonist/antagonist testing\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — chimeric receptor approach with binding and functional assays, single lab\",\n      \"pmids\": [\"21878623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CCR5 forms three distinct homodimeric conformations involving transmembrane helix 5; two dimeric states correspond to unliganded receptors and one is stabilized by the inverse agonist maraviroc; CCR5 dimerization is required for targeting the receptor to the plasma membrane.\",\n      \"method\": \"Receptor cross-linking, FRET/BRET energy transfer, functional export assay (RUSH system), computational modeling, site-directed mutagenesis of TM5 interface residues\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biophysical methods (crosslinking, FRET, export assay) with mutagenesis in single study\",\n      \"pmids\": [\"29739880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CCR5 exists in multiple structurally and antigenically distinct conformations at the cell surface; gp120s from different HIV-1 strains exhibit divergent binding to different CCR5 populations/conformations; HIV-1 preferentially uses CCR5 monomers (not oligomers) for entry; CCR5 conformational diversity shapes HIV-1 cellular tropism and sensitivity to CCR5 ligand inhibition.\",\n      \"method\": \"Mutagenesis of CCR5 dimerization interface, gp120 binding assays on cell lines and primary cells, viral entry assays, CD4i monoclonal antibody epitope mapping, T-cell vs. macrophage CCR5 comparison\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus multiple cell-type comparisons and binding/entry assays, single lab\",\n      \"pmids\": [\"30521629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CCR5 palmitoylation is critical for its delivery to the plasma membrane via the secretory pathway; small molecules that inhibit CCR5 palmitoylation trap CCR5 in the early secretory pathway, reducing plasma membrane expression and markedly decreasing HIV entry in primary macrophages.\",\n      \"method\": \"Cell-based assay monitoring differential protein transport (RUSH), high-content screening, palmitoylation assay, HIV entry assay in primary macrophages\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical demonstration of palmitoylation requirement combined with trafficking assay and functional HIV entry readout in primary cells\",\n      \"pmids\": [\"31663020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCR5 activation by CCL5 (from pericytes) promotes DNA-PKcs-mediated DNA damage repair in glioblastoma cells, inducing temozolomide chemoresistance; disrupting CCL5-CCR5 paracrine signaling with maraviroc inhibits pericyte-promoted DDR.\",\n      \"method\": \"Genetic depletion of pericytes in GBM xenografts, CCR5 activation/inhibition (maraviroc), DNA-PKcs assay, survival analysis in tumor-bearing mice, patient-derived xenografts\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological perturbation in xenograft models with defined molecular pathway, single lab\",\n      \"pmids\": [\"34239070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCR5 activation in neurons after intracerebral hemorrhage promotes neuronal pyroptosis via the CCR5/PKA/CREB/NLRP1 signaling pathway: CCR5 activation suppresses PKA-Cα and p-CREB, which upregulates NLRP1/ASC/caspase-1/GSDMD and IL-1β/IL-18; CCR5 inhibition with maraviroc or PKA activation reversed these effects.\",\n      \"method\": \"Intranasal maraviroc administration in ICH mice, CREB inhibitor (666-15) intracerebroventricular injection, rCCL5 and 8-Bromo-cAMP intracerebroventricular injection, Western blot, immunofluorescence, behavioral assays\",\n      \"journal\": \"Stroke\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and exogenous ligand interventions with defined pathway in mouse ICH model, single lab\",\n      \"pmids\": [\"34719258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A delayed (12–24 h) increase in CCR5 expression in mouse dorsal CA1 neurons after contextual memory formation decreases neuronal excitability, reduces overlap between memory ensembles, and closes the temporal window for memory linking; age-related increase in neuronal CCR5 and CCL5 impairs memory linking, reversible by CCR5 knockout or maraviroc.\",\n      \"method\": \"CCR5 knockout mice, maraviroc pharmacological inhibition, in vivo electrophysiology (neuronal excitability), activity-dependent neuronal labeling (memory ensemble overlap), behavioral memory linking tests in mice\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout plus pharmacological inhibition with electrophysiological and behavioral readouts, replicated across approaches\",\n      \"pmids\": [\"35614219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Activated microglial-derived CCL3/CCL4/CCL5 bind neuronal CCR5 and activate mTORC1, inhibiting neuronal autophagy and impairing clearance of aggregate-prone proteins; CCR5 upregulation is self-sustaining because CCL5-CCR5-mediated autophagy inhibition impairs CCR5 degradation itself; pharmacological or genetic CCR5 inhibition rescues autophagy and ameliorates Huntington's disease and tau pathology in mice.\",\n      \"method\": \"CCR5 knockout mice, pharmacological CCR5 inhibition, mTORC1 activity assays, autophagy flux assays, aggregate-prone protein clearance assays, HD and tauopathy mouse models\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout plus pharmacological inhibition with mechanistic mTORC1/autophagy pathway dissection in multiple disease mouse models\",\n      \"pmids\": [\"37105172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCR5 C-terminal phosphorylation at a pXpp motif (three phosphoresidues) is essential for stable arrestin2 complex formation; crystal structures of arrestin2 with CCR5 C-terminal phosphopeptides revealed the structural basis of this interaction; GRK- and PKC-mediated multi-site phosphorylation controls the CCR5-arrestin2 interaction.\",\n      \"method\": \"X-ray crystallography of arrestin2-CCR5 phosphopeptide complexes, NMR, site-directed mutagenesis of CCR5 phosphorylation sites, biochemical pulldown assays, functional arrestin recruitment assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with NMR, mutagenesis, biochemical and functional validation in a single study\",\n      \"pmids\": [\"37244255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCR5 and CXCR4 form symmetric and asymmetric homodimers and heterodimers; CCR5/CCR5 homodimers preferentially use TM4-TM5 as the binding interface; CXCR4/CXCR4 uses TM6-TM7; distinct dimeric states differ in access to ligand and G protein binding sites, suggesting dimerization as an allosteric regulatory mechanism.\",\n      \"method\": \"Coarse-grained metadynamics free-energy simulation (computational), validated against existing structural and functional data\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational free-energy simulation only, no direct experimental structural validation in this paper\",\n      \"pmids\": [\"37833254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CCR5 downregulation by RANKL is mediated through MEK and JNK signaling pathways in preosteoclast cells; CCR5 downregulation promotes osteoclastogenesis; IFN-γ can restore RANKL-reduced CCR5 expression.\",\n      \"method\": \"MEK and JNK inhibitors, Western blot, osteoclast differentiation assay, migration assay in mouse preosteoclast cells\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway inhibition with functional differentiation and migration readouts, single lab\",\n      \"pmids\": [\"29717113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CCL5-CCR5 interaction in osteosarcoma cells activates MEK, ERK, and NF-κB pathways, resulting in upregulation of αvβ3 integrin and enhanced cell migration; CCR5 siRNA/mAb/inhibitor reduced CCL5-enhanced migration and integrin upregulation.\",\n      \"method\": \"CCR5 siRNA knockdown, CCR5 mAb blocking, kinase pathway inhibitors (MEK, ERK, NF-κB dominant-negative mutants), migration assay, integrin expression by flow cytometry\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown plus pharmacological inhibition with defined pathway and functional readout, single lab\",\n      \"pmids\": [\"22506069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-6 upregulates CCR5 expression and arginase 1 in MDSCs through a STAT3-dependent mechanism; CCR5+ MDSCs differentiated in the presence of IL-6 exhibit strongly enhanced immunosuppressive activity.\",\n      \"method\": \"In vitro MDSC differentiation with IL-6, STAT3 inhibition, RT-PCR and Western blot for CCR5/arginase 1, T cell suppression assay, validation in RET transgenic melanoma mouse model\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro mechanistic pathway analysis with in vivo validation, single lab\",\n      \"pmids\": [\"32788238\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCR5 is a seven-transmembrane Gi-coupled chemokine receptor that binds CCL3, CCL4, CCL5, and CCL8, signals through pertussis-toxin-sensitive Gi proteins to inhibit cAMP and mobilize Ca2+, serves as the principal coreceptor for R5-tropic HIV-1 entry in complex with CD4, undergoes GRK/PKC-mediated phosphorylation at specific C-terminal serines (including a pXpp motif critical for arrestin2 recruitment), internalizes via clathrin-coated pits and caveolae in an actin/Rho-GTPase-dependent manner, cycles through early endosomes and the trans-Golgi network, requires palmitoylation and homodimerization (via TM5) for plasma membrane delivery, forms a constitutive complex with CD4, physically interacts with CXCR4 at the immunological synapse to co-stimulate T cells, and outside of immunity plays roles in hepatic stellate cell migration (PI3K/redox), neuronal excitability and memory linking (reducing CA1 neuronal excitability), autophagy regulation in neurons via mTORC1, and DNA damage repair signaling in cancer cells via DNA-PKcs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCR5 is a Gi-coupled seven-transmembrane chemokine receptor that binds the CC-chemokines MIP-1alpha (CCL3), MIP-1beta (CCL4), RANTES (CCL5), and MCP-2 (CCL8) as agonists and signals through pertussis-toxin-sensitive Gialpha2 to inhibit adenylyl cyclase and mobilize calcium [#3, #4, #5]. It serves as the principal coreceptor for macrophage-tropic (R5) HIV-1 entry, conferring envelope-mediated fusion and infection when co-expressed with CD4 in otherwise non-permissive cells, with which it forms a constitutive surface complex via its second extracellular loop and the first two CD4 domains [#0, #1, #2, #7]. Agonist binding triggers GRK- and PKC-mediated C-terminal phosphorylation—including a pXpp phosphomotif at the receptor tail that is required for stable arrestin2 recruitment—driving desensitization and internalization through clathrin-coated pits and caveolae, with recycling routed through early endosomes and the trans-Golgi network under actin/Rho-GTPase control [#4, #8, #9, #10, #24]. Plasma-membrane delivery of CCR5 requires palmitoylation and TM5-mediated homodimerization, and the receptor adopts multiple conformational and oligomeric states that govern HIV-1 strain tropism and discriminate chemokine binding from allosteric small-molecule inhibitor binding, the structural basis exploited by maraviroc and aplaviroc [#11, #15, #16, #17, #19]. Beyond immune cell signaling, CCR5 drives hepatic stellate cell migration through a redox-sensitive PI3K pathway in fibrosis [#13], and in the CNS controls neuronal excitability and the temporal window for memory linking [#22] and suppresses neuronal autophagy via mTORC1 to impair clearance of aggregate-prone proteins [#23].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that CCR5 is the missing coreceptor enabling macrophage-tropic HIV-1 entry, answering why CD4 alone is insufficient for infection by these strains.\",\n      \"evidence\": \"Reconstitution of CCR5/CD4 in non-permissive human and non-human cells with infection and cell-cell fusion assays, across multiple HIV-1 strains\",\n      \"pmids\": [\"8649512\", \"8658171\", \"8674120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the gp120-CCR5 binding interface at atomic resolution\", \"Did not establish the relative roles of CCR5 monomers vs oligomers in entry\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defined the native ligand and signaling identity of CCR5 as a Gi-coupled CC-chemokine receptor, distinguishing its physiological role from its HIV coreceptor function.\",\n      \"evidence\": \"Calcium flux and radioligand binding in transfected cells with pertussis toxin inhibition; CCL3/CCL4/CCL5 as agonists\",\n      \"pmids\": [\"8699119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific Galpha isoform coupling not yet pinned to Gialpha2\", \"Downstream effector cascade beyond calcium/cAMP not defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed CCR5 couples specifically to Gialpha2 to inhibit adenylyl cyclase and undergoes rapid agonist-dependent desensitization, defining its canonical GPCR output.\",\n      \"evidence\": \"GTPgammaS binding, adenylyl cyclase assay, Gialpha2 overexpression and pertussis toxin in stable CHO/NG108-15 cells; competitive binding and internalization for CCL8 as an additional agonist/HIV inhibitor\",\n      \"pmids\": [\"9736452\", \"9468473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of each Galpha subtype in primary leukocytes unknown\", \"Link between desensitization kinetics and HIV inhibition not fully resolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Distinguished CCR5 endocytic machinery from CXCR4 by showing it is internalized by ligand but not phorbol esters, indicating a distinct C-terminal endocytosis signal.\",\n      \"evidence\": \"RANTES vs phorbol ester internalization assays and mutagenesis of endocytosis motifs\",\n      \"pmids\": [\"9718374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise residues governing constitutive vs ligand-induced uptake not mapped here\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrated a pre-formed CD4-CCR5 complex on the cell surface, explaining the efficiency of the gp120-triggered entry mechanism.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation with domain mapping and functional antibody inhibition\",\n      \"pmids\": [\"10377443\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry of the complex not determined\", \"Single lab; structural model of the interface absent\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Resolved the trafficking itinerary and phosphoregulation of CCR5, establishing how the receptor is internalized, phosphorylated, and recycled.\",\n      \"evidence\": \"Pharmacological pathway inhibitors with arrestin-2 tracking; phosphosite-specific antibodies identifying PKC at Ser337 and GRK at Ser349 with phosphatase dissection\",\n      \"pmids\": [\"11806977\", \"12403770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of each phosphosite for signaling vs trafficking not fully separated\", \"Identity of the responsible GRK isoform not established\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified actin polymerization and Rho-family GTPases as cytoskeletal regulators of CCR5 internalization and recycling, linking receptor traffic to cell motility machinery.\",\n      \"evidence\": \"Cytochalasin D, Toxin B, C3 exoenzyme and Y27632 in CHO and THP-1 cells\",\n      \"pmids\": [\"14717692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effectors connecting Rho GTPases to endocytic vesicles unidentified\", \"Single lab, pharmacological inference\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Localized small-molecule inhibitor and gp120 binding determinants to the TM cavity and extracellular loops, showing inhibitors can block HIV while sparing chemokine binding.\",\n      \"evidence\": \"Saturation binding and site-directed mutagenesis of CCR5 TM domains with gp120 binding and HIV infection assays; aplaviroc\",\n      \"pmids\": [\"16476734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of the inhibitor pocket not yet available\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed a CCR5-CXCR4 signaling complex required for chemokine-driven T-cell costimulation at the immunological synapse, extending CCR5 function into adaptive immune activation.\",\n      \"evidence\": \"Co-immunoprecipitation, live imaging of synapse recruitment, and costimulation assays in human T cells\",\n      \"pmids\": [\"18632580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular interface of the CCR5-CXCR4 complex not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended CCR5 function to tissue fibrosis by showing it drives hepatic stellate cell migration through a redox/PI3K pathway.\",\n      \"evidence\": \"CCR5-deficient bone marrow chimeras with HSC migration assays, PI3K inhibitors, and fibrosis models\",\n      \"pmids\": [\"19603542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream PI3K effectors in HSCs not specified\", \"Relative contribution of resident vs infiltrating CCR5+ cells incompletely resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the allosteric mechanism of maraviroc and the structural separation of orthosteric chemokine and allosteric inhibitor sites, clarifying how TM-cavity drugs antagonize an extracellular ligand.\",\n      \"evidence\": \"Mutagenesis with homology modeling/docking and CCR5/CCR2 chimeric receptor binding and signaling assays\",\n      \"pmids\": [\"21775441\", \"21878623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conclusions rely on homology to CXCR4 rather than CCR5 crystal structure\", \"Allosteric communication pathway between sites not structurally defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established TM5-mediated homodimerization as a requirement for CCR5 plasma-membrane targeting and identified conformationally distinct receptor populations that shape HIV tropism.\",\n      \"evidence\": \"Cross-linking, FRET/BRET, RUSH export assay and TM5 mutagenesis; gp120 binding and entry assays across cell types with epitope mapping\",\n      \"pmids\": [\"29739880\", \"30521629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional signaling differences between dimer states not fully resolved\", \"In vivo relevance of conformational heterogeneity untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified palmitoylation as a checkpoint for CCR5 secretory transport, providing a druggable node that limits surface expression and HIV entry.\",\n      \"evidence\": \"RUSH transport assay, high-content screening, palmitoylation assay, and HIV entry in primary macrophages\",\n      \"pmids\": [\"31663020\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Responsible palmitoyl-acyltransferase not identified\", \"Palmitoylation sites not individually mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered non-immune CCR5 signaling in disease: promotion of DNA-PKcs-mediated DNA repair and chemoresistance in glioblastoma, and PKA/CREB/NLRP1-dependent neuronal pyroptosis after hemorrhage.\",\n      \"evidence\": \"Pericyte depletion in GBM xenografts with maraviroc and DNA-PKcs assays; intranasal maraviroc and pathway inhibitors in an ICH mouse model\",\n      \"pmids\": [\"34239070\", \"34719258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking CCR5 to DNA-PKcs activation not biochemically defined\", \"Single lab per model; human relevance correlative\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a CNS role for CCR5 in regulating neuronal excitability and the temporal window for memory linking, with implications for age-related memory decline.\",\n      \"evidence\": \"CCR5 knockout and maraviroc with in vivo electrophysiology, neuronal ensemble labeling, and behavioral memory tests in mice\",\n      \"pmids\": [\"35614219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling cascade from CCR5 to excitability changes not delineated\", \"Source of neuronal CCL5 increase incompletely defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that CCR5 suppresses neuronal autophagy via mTORC1 in a self-amplifying loop, linking microglial chemokine signaling to neurodegenerative proteostasis failure, and defined the structural basis of the CCR5-arrestin2 interaction.\",\n      \"evidence\": \"CCR5 knockout and pharmacology with mTORC1/autophagy assays in HD and tauopathy models; crystallography, NMR and mutagenesis of the pXpp arrestin2 phosphomotif\",\n      \"pmids\": [\"37105172\", \"37244255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"G-protein vs arrestin bias in neuronal autophagy signaling not dissected\", \"Full-length CCR5-arrestin2 complex structure not solved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CCR5 conformational and oligomeric heterogeneity, biased signaling, and tissue-specific effector coupling are integrated into a single regulatory logic across immune, neural, fibrotic and oncogenic contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking dimer state to ligand-, G-protein-, and arrestin-biased outputs\", \"Tissue-specific determinants of CCR5 effector choice unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0004930\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 17, 19]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [8, 14]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"complexes\": [\n      \"CD4-CCR5 entry complex\",\n      \"CCR5 homodimer\",\n      \"CCR5-CXCR4 heterodimer/signaling complex\"\n    ],\n    \"partners\": [\n      \"CD4\",\n      \"CXCR4\",\n      \"ARRB2\",\n      \"CCL5\",\n      \"CCL3\",\n      \"CCL4\",\n      \"CCL8\",\n      \"GNAI2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}