{"gene":"CD4","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1984,"finding":"CD4 (T4 antigen) is an essential and specific cell-surface receptor component for the AIDS retrovirus (HTLV-III/LAV-1). Anti-CD4 monoclonal antibodies blocked syncytia formation and pseudotype infection, and productive HIV infection markedly reduced cell-surface CD4 expression.","method":"Pseudotype VSV infection assay, syncytia formation assay, monoclonal antibody blocking experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (pseudotype infection, syncytia, antibody blocking), replicated across multiple virus isolates, foundational paper with broad independent replication","pmids":["6096719"],"is_preprint":false},{"year":1988,"finding":"A soluble form of CD4 (sCD4) retains the structural and biological properties of cell-surface CD4, binds HIV envelope glycoprotein gp110, and inhibits HIV binding to CD4+ lymphocytes, resulting in striking inhibition of virus infectivity.","method":"Recombinant protein expression, binding assay, viral infectivity inhibition assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding and functional inhibition assays with recombinant protein, multiple orthogonal readouts","pmids":["3257544"],"is_preprint":false},{"year":1986,"finding":"HIV infection reduces cell-surface CD4 through at least three mechanisms: (1) reduced steady-state CD4 mRNA levels, (2) reduced immunoprecipitable CD4 protein, and (3) intracellular complexing of CD4 with viral envelope glycoproteins gp120 and gp150 precursor within infected cells.","method":"Metabolic labeling, co-immunoprecipitation, Northern blot analysis of CD4 mRNA","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-immunoprecipitation, Northern blot, and metabolic labeling across multiple T-cell lines, three orthogonal mechanisms identified","pmids":["3095925"],"is_preprint":false},{"year":1996,"finding":"CD4 functions as both an adhesion molecule and a signaling co-receptor. Its co-receptor function depends on association with the Src-family tyrosine kinase Lck via Lck's unique N-terminal domain; Lck kinase activity appears dispensable for CD4 co-receptor activity, suggesting Lck may function as an adapter recruiting other signaling proteins to the TCR/CD3 complex.","method":"Biochemical association studies, domain mutagenesis, T cell functional assays","journal":"Current topics in microbiology and immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — review synthesizing co-immunoprecipitation and mutational data from multiple studies, but abstract-level description limits tier assignment","pmids":["8575197"],"is_preprint":false},{"year":1995,"finding":"Myxoma virus infection of rabbit CD4+ T cells causes CD4 downregulation via a protein kinase C-independent pathway, leading to dissociation of p56lck from CD4 and lysosomal degradation of CD4. Total p56lck kinase activity is unaffected, but the amount of p56lck physically associated with CD4 declines in parallel with CD4 loss.","method":"Flow cytometry, co-immunoprecipitation, kinase activity assay, NH4Cl lysosomal inhibitor experiments","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-immunoprecipitation and pharmacological inhibitors with multiple readouts, single lab","pmids":["7636966"],"is_preprint":false},{"year":1998,"finding":"CD4 and CXCR4 co-mediate a rapid, CD95-independent cell death in CD4+ T cells upon HIV-1 gp120 engagement. The induced cell death is independent of known caspases, lacks oligonucleosomal DNA fragmentation, and is not propagated via p56lck or Giα, but shows chromatin condensation, membrane inversion, and reduced mitochondrial transmembrane potential. Apoptosis triggered via CXCR4 was inhibited by SDF-1.","method":"CD4/CXCR4 transfection experiments, flow cytometry, mitochondrial membrane potential assay, caspase inhibitor experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transfectant model with multiple orthogonal readouts, single lab","pmids":["9770524"],"is_preprint":false},{"year":1993,"finding":"CD4 is not strictly required for helper T-cell lineage commitment or peripheral function. CD4-null mice develop functional CD8-negative, αβ TCR+ MHC class II-restricted T cells that produce IFN-γ upon parasite antigen challenge, demonstrating that T lymphocyte lineage commitment can occur independently of CD4 function.","method":"CD4 gene knockout (null mutation), Leishmania infection model, MHC class II restriction assay, cytokine (IFN-γ) measurement","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined cellular and functional phenotype, multiple orthogonal readouts","pmids":["8367726"],"is_preprint":false},{"year":2008,"finding":"Atlantic salmon CD4-1 and CD4-2 homologues possess conserved Lck-binding motifs in their cytoplasmic domains, consistent with the mammalian CD4 mechanism of coupling to p56lck for TCR signaling. CD4-2 variants have only two extracellular Ig-like domains versus four in CD4-1.","method":"cDNA sequencing, synteny analysis, qRT-PCR expression profiling, motif analysis","journal":"Fish & shellfish immunology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — sequence/motif analysis only, no direct functional assay of Lck binding","pmids":["18983924"],"is_preprint":false},{"year":1990,"finding":"CD4-negative fibroblastoid cells can be productively infected by HIV-1, HIV-2, and SIVagm at higher virus doses, indicating a second CD4-independent pathway of cellular infection. For most lines, anti-CD4 antibodies blocked infection, confirming CD4-receptor-mediated entry as the primary mechanism.","method":"Immunoperoxidase staining, anti-CD4 antibody blocking, Northern blot for CD4 mRNA","journal":"AIDS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody blocking and CD4 expression analysis with functional infection readout, single lab","pmids":["1974766"],"is_preprint":false}],"current_model":"CD4 is a transmembrane glycoprotein that functions as the essential receptor for HIV on T lymphocytes and as a TCR co-receptor on helper T cells, operating through its constitutive association with the Src-family tyrosine kinase p56lck via its cytoplasmic tail; HIV engagement causes CD4 downregulation through mRNA reduction, intracellular complexing with viral envelope proteins, and lysosomal degradation with concurrent p56lck dissociation, while soluble CD4 retains gp120-binding activity sufficient to block viral infectivity."},"narrative":{"mechanistic_narrative":"CD4 is a transmembrane glycoprotein that acts both as a T-cell co-receptor coupling antigen recognition to intracellular signaling and as the essential cellular receptor for HIV [PMID:6096719, PMID:8575197]. As an immune receptor, CD4 functions as an adhesion molecule and signaling co-receptor whose co-receptor activity depends on constitutive association of its cytoplasmic tail with the Src-family tyrosine kinase Lck through Lck's unique N-terminal domain, recruiting Lck to the TCR/CD3 complex; Lck catalytic activity is dispensable for this co-receptor function, consistent with an adapter role [PMID:8575197]. Genetic ablation establishes that CD4 is not strictly required for helper T-cell lineage commitment, since CD4-null mice generate functional MHC class II-restricted αβ TCR+ T cells [PMID:8367726]. CD4 is the primary specific surface receptor for HIV: anti-CD4 antibodies block syncytia formation and viral entry, and a soluble CD4 ectodomain binds the HIV envelope glycoprotein gp120/gp110 and inhibits virus infectivity, although a secondary CD4-independent entry pathway operates in some non-T cells at high virus doses [PMID:6096719, PMID:3257544, PMID:1974766]. HIV downregulates surface CD4 through multiple mechanisms—reduced CD4 mRNA, reduced CD4 protein, and intracellular sequestration of CD4 with viral envelope glycoproteins gp120 and the gp150 precursor [PMID:3095925]; a parallel virus-driven program (defined in poxvirus-infected T cells) couples CD4 loss to dissociation of p56lck and lysosomal degradation of CD4 [PMID:7636966]. Engagement of CD4 together with the coreceptor CXCR4 by gp120 can also trigger a rapid, caspase- and CD95-independent cell death marked by mitochondrial depolarization and chromatin condensation [PMID:9770524].","teleology":[{"year":1984,"claim":"Established that CD4 is the specific cell-surface receptor required for HIV entry, defining the molecular basis of viral tropism for helper T cells.","evidence":"Pseudotype VSV infection, syncytia formation, and anti-CD4 monoclonal antibody blocking across HIV isolates","pmids":["6096719"],"confidence":"High","gaps":["Did not resolve the post-binding entry steps or coreceptor requirement","Mechanism of infection-induced CD4 surface loss not defined here"]},{"year":1986,"claim":"Resolved how HIV infection depletes surface CD4, showing it occurs through reduced CD4 mRNA, reduced protein, and intracellular complexing of CD4 with viral envelope glycoproteins.","evidence":"Metabolic labeling, co-immunoprecipitation, and Northern blot across T-cell lines","pmids":["3095925"],"confidence":"High","gaps":["Did not establish whether env-CD4 complexing causes degradation or retention","Relative contribution of each mechanism not quantified"]},{"year":1988,"claim":"Showed the CD4 ectodomain alone is sufficient to bind gp120 and neutralize HIV, separating receptor-binding function from the membrane-anchored signaling protein and providing an antiviral strategy.","evidence":"Recombinant soluble CD4 binding assay and viral infectivity inhibition","pmids":["3257544"],"confidence":"High","gaps":["Did not address in vivo efficacy or resistance","Structural basis of gp120 binding not defined"]},{"year":1990,"claim":"Demonstrated that while CD4 is the primary entry receptor, a secondary CD4-independent infection pathway exists in non-T cells at high virus doses.","evidence":"Immunoperoxidase staining of infected fibroblastoid cells with anti-CD4 antibody blocking and CD4 mRNA analysis","pmids":["1974766"],"confidence":"Medium","gaps":["Receptor or mechanism for CD4-independent entry not identified","Single-lab observation"]},{"year":1993,"claim":"Tested whether CD4 is essential for T-cell development, showing helper-lineage commitment and MHC class II-restricted function can proceed without CD4.","evidence":"CD4-null mice with Leishmania challenge and IFN-γ measurement","pmids":["8367726"],"confidence":"High","gaps":["Did not define what compensates for CD4 loss","Quantitative effects on T-cell efficiency not fully resolved"]},{"year":1995,"claim":"Linked virus-induced CD4 downregulation to dissociation of p56lck and lysosomal CD4 degradation, mechanistically connecting receptor turnover to signaling decoupling.","evidence":"Flow cytometry, co-immunoprecipitation, kinase assays, and NH4Cl lysosomal inhibition in myxoma virus-infected rabbit T cells","pmids":["7636966"],"confidence":"Medium","gaps":["Mechanism of Lck dissociation not defined","Generalizability to HIV-driven CD4 loss not directly tested"]},{"year":1996,"claim":"Defined the molecular basis of CD4 co-receptor signaling as Lck recruitment via Lck's N-terminal domain, with kinase activity dispensable, framing Lck as an adapter to the TCR/CD3 complex.","evidence":"Biochemical association studies, domain mutagenesis, and T-cell functional assays (review synthesis)","pmids":["8575197"],"confidence":"Medium","gaps":["Identity of downstream signaling proteins recruited not resolved","Abstract/review-level synthesis limits mechanistic granularity"]},{"year":1998,"claim":"Showed CD4 with CXCR4 can transduce a gp120-triggered death signal, revealing a signaling/pathological role beyond viral entry and TCR co-reception.","evidence":"CD4/CXCR4 transfectants with flow cytometry, mitochondrial potential and caspase-inhibitor assays","pmids":["9770524"],"confidence":"Medium","gaps":["Death effector pathway downstream of CD4/CXCR4 not identified","Single-lab transfectant model"]},{"year":null,"claim":"The structural details of how the CD4 cytoplasmic tail engages and releases Lck during signaling versus virus-induced downregulation remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the CD4-Lck interface in the corpus","Mechanism unifying TCR co-reception and HIV-driven receptor turnover not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,1,8]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5]}],"complexes":["TCR/CD3 complex"],"partners":["LCK","CXCR4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P01730","full_name":"T-cell surface glycoprotein CD4","aliases":["T-cell surface antigen T4/Leu-3"],"length_aa":458,"mass_kda":51.1,"function":"Integral membrane glycoprotein that plays an essential role in the immune response and serves multiple functions in responses against both external and internal offenses. In T-cells, functions primarily as a coreceptor for MHC class II molecule:peptide complex. The antigens presented by class II peptides are derived from extracellular proteins while class I peptides are derived from cytosolic proteins. Interacts simultaneously with the T-cell receptor (TCR) and the MHC class II presented by antigen presenting cells (APCs). In turn, recruits the Src kinase LCK to the vicinity of the TCR-CD3 complex. LCK then initiates different intracellular signaling pathways by phosphorylating various substrates ultimately leading to lymphokine production, motility, adhesion and activation of T-helper cells. In other cells such as macrophages or NK cells, plays a role in differentiation/activation, cytokine expression and cell migration in a TCR/LCK-independent pathway. Participates in the development of T-helper cells in the thymus and triggers the differentiation of monocytes into functional mature macrophages (Microbial infection) Primary receptor for human immunodeficiency virus-1 (HIV-1) (PubMed:12089508, PubMed:16331979, PubMed:2214026, PubMed:9641677). Down-regulated by HIV-1 Vpu (PubMed:17346169). Acts as a receptor for Human Herpes virus 7/HHV-7 (PubMed:7909607)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P01730/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD4","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD4","total_profiled":1310},"omim":[{"mim_id":"621523","title":"SPONDYLOCOSTAL DYSOSTOSIS 7, AUTOSOMAL RECESSIVE; SCDO7","url":"https://www.omim.org/entry/621523"},{"mim_id":"621405","title":"IMMUNODEFICIENCY 134 (EPSTEIN-BARR VIRUS-SPECIFIC); IMD134","url":"https://www.omim.org/entry/621405"},{"mim_id":"621254","title":"IMMUNODEFICIENCY 133 WITH ECTODERMAL DYSPLASIA WITH OR WITHOUT PERIPHERAL NEUROPATHY; IMD133","url":"https://www.omim.org/entry/621254"},{"mim_id":"621235","title":"AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET, 5; ADMIO5","url":"https://www.omim.org/entry/621235"},{"mim_id":"621234","title":"ICHAD SYNDROME; ICHAD","url":"https://www.omim.org/entry/621234"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":143.1},{"tissue":"lymphoid tissue","ntpm":204.2},{"tissue":"parathyroid gland","ntpm":163.6}],"url":"https://www.proteinatlas.org/search/CD4"},"hgnc":{"alias_symbol":["T4","Leu-3"],"prev_symbol":[]},"alphafold":{"accession":"P01730","domains":[{"cath_id":"2.60.40.10","chopping":"26-121","consensus_level":"high","plddt":93.5803,"start":26,"end":121},{"cath_id":"2.60.40.10","chopping":"128-201","consensus_level":"high","plddt":92.4285,"start":128,"end":201},{"cath_id":"2.60.40.10","chopping":"207-315","consensus_level":"medium","plddt":93.1041,"start":207,"end":315},{"cath_id":"2.60.40.10","chopping":"318-385","consensus_level":"medium","plddt":92.0228,"start":318,"end":385}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P01730","model_url":"https://alphafold.ebi.ac.uk/files/AF-P01730-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P01730-F1-predicted_aligned_error_v6.png","plddt_mean":85.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD4","jax_strain_url":"https://www.jax.org/strain/search?query=CD4"},"sequence":{"accession":"P01730","fasta_url":"https://rest.uniprot.org/uniprotkb/P01730.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P01730/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P01730"}},"corpus_meta":[{"pmid":"6096719","id":"PMC_6096719","title":"The 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Anti-CD4 monoclonal antibodies blocked syncytia formation and pseudotype infection, and productive HIV infection markedly reduced cell-surface CD4 expression.\",\n      \"method\": \"Pseudotype VSV infection assay, syncytia formation assay, monoclonal antibody blocking experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (pseudotype infection, syncytia, antibody blocking), replicated across multiple virus isolates, foundational paper with broad independent replication\",\n      \"pmids\": [\"6096719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"A soluble form of CD4 (sCD4) retains the structural and biological properties of cell-surface CD4, binds HIV envelope glycoprotein gp110, and inhibits HIV binding to CD4+ lymphocytes, resulting in striking inhibition of virus infectivity.\",\n      \"method\": \"Recombinant protein expression, binding assay, viral infectivity inhibition assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding and functional inhibition assays with recombinant protein, multiple orthogonal readouts\",\n      \"pmids\": [\"3257544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"HIV infection reduces cell-surface CD4 through at least three mechanisms: (1) reduced steady-state CD4 mRNA levels, (2) reduced immunoprecipitable CD4 protein, and (3) intracellular complexing of CD4 with viral envelope glycoproteins gp120 and gp150 precursor within infected cells.\",\n      \"method\": \"Metabolic labeling, co-immunoprecipitation, Northern blot analysis of CD4 mRNA\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-immunoprecipitation, Northern blot, and metabolic labeling across multiple T-cell lines, three orthogonal mechanisms identified\",\n      \"pmids\": [\"3095925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CD4 functions as both an adhesion molecule and a signaling co-receptor. Its co-receptor function depends on association with the Src-family tyrosine kinase Lck via Lck's unique N-terminal domain; Lck kinase activity appears dispensable for CD4 co-receptor activity, suggesting Lck may function as an adapter recruiting other signaling proteins to the TCR/CD3 complex.\",\n      \"method\": \"Biochemical association studies, domain mutagenesis, T cell functional assays\",\n      \"journal\": \"Current topics in microbiology and immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — review synthesizing co-immunoprecipitation and mutational data from multiple studies, but abstract-level description limits tier assignment\",\n      \"pmids\": [\"8575197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Myxoma virus infection of rabbit CD4+ T cells causes CD4 downregulation via a protein kinase C-independent pathway, leading to dissociation of p56lck from CD4 and lysosomal degradation of CD4. Total p56lck kinase activity is unaffected, but the amount of p56lck physically associated with CD4 declines in parallel with CD4 loss.\",\n      \"method\": \"Flow cytometry, co-immunoprecipitation, kinase activity assay, NH4Cl lysosomal inhibitor experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-immunoprecipitation and pharmacological inhibitors with multiple readouts, single lab\",\n      \"pmids\": [\"7636966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CD4 and CXCR4 co-mediate a rapid, CD95-independent cell death in CD4+ T cells upon HIV-1 gp120 engagement. The induced cell death is independent of known caspases, lacks oligonucleosomal DNA fragmentation, and is not propagated via p56lck or Giα, but shows chromatin condensation, membrane inversion, and reduced mitochondrial transmembrane potential. Apoptosis triggered via CXCR4 was inhibited by SDF-1.\",\n      \"method\": \"CD4/CXCR4 transfection experiments, flow cytometry, mitochondrial membrane potential assay, caspase inhibitor experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transfectant model with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"9770524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CD4 is not strictly required for helper T-cell lineage commitment or peripheral function. CD4-null mice develop functional CD8-negative, αβ TCR+ MHC class II-restricted T cells that produce IFN-γ upon parasite antigen challenge, demonstrating that T lymphocyte lineage commitment can occur independently of CD4 function.\",\n      \"method\": \"CD4 gene knockout (null mutation), Leishmania infection model, MHC class II restriction assay, cytokine (IFN-γ) measurement\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined cellular and functional phenotype, multiple orthogonal readouts\",\n      \"pmids\": [\"8367726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Atlantic salmon CD4-1 and CD4-2 homologues possess conserved Lck-binding motifs in their cytoplasmic domains, consistent with the mammalian CD4 mechanism of coupling to p56lck for TCR signaling. CD4-2 variants have only two extracellular Ig-like domains versus four in CD4-1.\",\n      \"method\": \"cDNA sequencing, synteny analysis, qRT-PCR expression profiling, motif analysis\",\n      \"journal\": \"Fish & shellfish immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — sequence/motif analysis only, no direct functional assay of Lck binding\",\n      \"pmids\": [\"18983924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"CD4-negative fibroblastoid cells can be productively infected by HIV-1, HIV-2, and SIVagm at higher virus doses, indicating a second CD4-independent pathway of cellular infection. For most lines, anti-CD4 antibodies blocked infection, confirming CD4-receptor-mediated entry as the primary mechanism.\",\n      \"method\": \"Immunoperoxidase staining, anti-CD4 antibody blocking, Northern blot for CD4 mRNA\",\n      \"journal\": \"AIDS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody blocking and CD4 expression analysis with functional infection readout, single lab\",\n      \"pmids\": [\"1974766\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD4 is a transmembrane glycoprotein that functions as the essential receptor for HIV on T lymphocytes and as a TCR co-receptor on helper T cells, operating through its constitutive association with the Src-family tyrosine kinase p56lck via its cytoplasmic tail; HIV engagement causes CD4 downregulation through mRNA reduction, intracellular complexing with viral envelope proteins, and lysosomal degradation with concurrent p56lck dissociation, while soluble CD4 retains gp120-binding activity sufficient to block viral infectivity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD4 is a transmembrane glycoprotein that acts both as a T-cell co-receptor coupling antigen recognition to intracellular signaling and as the essential cellular receptor for HIV [#0, #3]. As an immune receptor, CD4 functions as an adhesion molecule and signaling co-receptor whose co-receptor activity depends on constitutive association of its cytoplasmic tail with the Src-family tyrosine kinase Lck through Lck's unique N-terminal domain, recruiting Lck to the TCR/CD3 complex; Lck catalytic activity is dispensable for this co-receptor function, consistent with an adapter role [#3]. Genetic ablation establishes that CD4 is not strictly required for helper T-cell lineage commitment, since CD4-null mice generate functional MHC class II-restricted αβ TCR+ T cells [#6]. CD4 is the primary specific surface receptor for HIV: anti-CD4 antibodies block syncytia formation and viral entry, and a soluble CD4 ectodomain binds the HIV envelope glycoprotein gp120/gp110 and inhibits virus infectivity, although a secondary CD4-independent entry pathway operates in some non-T cells at high virus doses [#0, #1, #8]. HIV downregulates surface CD4 through multiple mechanisms—reduced CD4 mRNA, reduced CD4 protein, and intracellular sequestration of CD4 with viral envelope glycoproteins gp120 and the gp150 precursor [#2]; a parallel virus-driven program (defined in poxvirus-infected T cells) couples CD4 loss to dissociation of p56lck and lysosomal degradation of CD4 [#4]. Engagement of CD4 together with the coreceptor CXCR4 by gp120 can also trigger a rapid, caspase- and CD95-independent cell death marked by mitochondrial depolarization and chromatin condensation [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1984,\n      \"claim\": \"Established that CD4 is the specific cell-surface receptor required for HIV entry, defining the molecular basis of viral tropism for helper T cells.\",\n      \"evidence\": \"Pseudotype VSV infection, syncytia formation, and anti-CD4 monoclonal antibody blocking across HIV isolates\",\n      \"pmids\": [\"6096719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the post-binding entry steps or coreceptor requirement\", \"Mechanism of infection-induced CD4 surface loss not defined here\"]\n    },\n    {\n      \"year\": 1986,\n      \"claim\": \"Resolved how HIV infection depletes surface CD4, showing it occurs through reduced CD4 mRNA, reduced protein, and intracellular complexing of CD4 with viral envelope glycoproteins.\",\n      \"evidence\": \"Metabolic labeling, co-immunoprecipitation, and Northern blot across T-cell lines\",\n      \"pmids\": [\"3095925\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether env-CD4 complexing causes degradation or retention\", \"Relative contribution of each mechanism not quantified\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Showed the CD4 ectodomain alone is sufficient to bind gp120 and neutralize HIV, separating receptor-binding function from the membrane-anchored signaling protein and providing an antiviral strategy.\",\n      \"evidence\": \"Recombinant soluble CD4 binding assay and viral infectivity inhibition\",\n      \"pmids\": [\"3257544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address in vivo efficacy or resistance\", \"Structural basis of gp120 binding not defined\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Demonstrated that while CD4 is the primary entry receptor, a secondary CD4-independent infection pathway exists in non-T cells at high virus doses.\",\n      \"evidence\": \"Immunoperoxidase staining of infected fibroblastoid cells with anti-CD4 antibody blocking and CD4 mRNA analysis\",\n      \"pmids\": [\"1974766\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor or mechanism for CD4-independent entry not identified\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Tested whether CD4 is essential for T-cell development, showing helper-lineage commitment and MHC class II-restricted function can proceed without CD4.\",\n      \"evidence\": \"CD4-null mice with Leishmania challenge and IFN-γ measurement\",\n      \"pmids\": [\"8367726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define what compensates for CD4 loss\", \"Quantitative effects on T-cell efficiency not fully resolved\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Linked virus-induced CD4 downregulation to dissociation of p56lck and lysosomal CD4 degradation, mechanistically connecting receptor turnover to signaling decoupling.\",\n      \"evidence\": \"Flow cytometry, co-immunoprecipitation, kinase assays, and NH4Cl lysosomal inhibition in myxoma virus-infected rabbit T cells\",\n      \"pmids\": [\"7636966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Lck dissociation not defined\", \"Generalizability to HIV-driven CD4 loss not directly tested\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defined the molecular basis of CD4 co-receptor signaling as Lck recruitment via Lck's N-terminal domain, with kinase activity dispensable, framing Lck as an adapter to the TCR/CD3 complex.\",\n      \"evidence\": \"Biochemical association studies, domain mutagenesis, and T-cell functional assays (review synthesis)\",\n      \"pmids\": [\"8575197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of downstream signaling proteins recruited not resolved\", \"Abstract/review-level synthesis limits mechanistic granularity\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed CD4 with CXCR4 can transduce a gp120-triggered death signal, revealing a signaling/pathological role beyond viral entry and TCR co-reception.\",\n      \"evidence\": \"CD4/CXCR4 transfectants with flow cytometry, mitochondrial potential and caspase-inhibitor assays\",\n      \"pmids\": [\"9770524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Death effector pathway downstream of CD4/CXCR4 not identified\", \"Single-lab transfectant model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural details of how the CD4 cytoplasmic tail engages and releases Lck during signaling versus virus-induced downregulation remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the CD4-Lck interface in the corpus\", \"Mechanism unifying TCR co-reception and HIV-driven receptor turnover not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"TCR/CD3 complex\"],\n    \"partners\": [\"LCK\", \"CXCR4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}