CD4

Summary

CD4 (CD4 molecule, HGNC:1678) is a protein-coding gene on chromosome 12p13.31, encoding T-cell surface glycoprotein CD4 (P01730). Integral membrane glycoprotein that plays an essential role in the immune response and serves multiple functions in responses against both external and internal offenses.

This gene encodes the CD4 membrane glycoprotein of T lymphocytes. The CD4 antigen acts as a coreceptor with the T-cell receptor on the T lymphocyte to recognize antigens displayed by an antigen presenting cell in the context of class II MHC molecules. The CD4 antigen is also a primary receptor for entry of the human immunodeficiency virus through interactions with the HIV Env gp120 subunit. This gene is expressed not only in T lymphocytes, but also in B cells, macrophages, granulocytes, as well as in various regions of the brain. The protein functions to initiate or augment the early phase of T-cell activation, and may function as an important mediator of indirect neuronal damage in infectious and immune-mediated diseases of the central nervous system. Multiple alternatively spliced transcript variants encoding different isoforms have been identified in this gene.

Source: NCBI Gene 920 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 79 (Moderate, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 64 total — 2 pathogenic
• Phenotypes (HPO): 9
• Druggable target: yes
• MANE Select transcript: NM_000616

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1678
Approved symbol	CD4
Name	CD4 molecule
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	T4, Leu-3
Ensembl gene	ENSG00000010610
Ensembl biotype	protein_coding
OMIM	186940
Entrez	920

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 7 protein_coding, 6 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000011653, ENST00000437800, ENST00000535466, ENST00000535707, ENST00000536563, ENST00000536590, ENST00000536610, ENST00000538827, ENST00000539492, ENST00000541982, ENST00000543755, ENST00000544344, ENST00000872058, ENST00000872059, ENST00000872060, ENST00000872061

RefSeq mRNA: 9 — MANE Select: NM_000616 NM_000616, NM_001195014, NM_001195015, NM_001195016, NM_001195017, NM_001382705, NM_001382706, NM_001382707, NM_001382714

CCDS: CCDS8562

Canonical transcript exons

ENST00000011653 — 10 exons

Exon	Start	End
ENSE00000716048	6816056	6816403
ENSE00001182623	6819299	6820799
ENSE00002299768	6789528	6789662
ENSE00003477403	6818847	6818914
ENSE00003497892	6814142	6814300
ENSE00003508863	6800307	6800471
ENSE00003569784	6814759	6814992
ENSE00003580321	6800072	6800187
ENSE00003595399	6817130	6817330
ENSE00003629149	6818421	6818542

Expression profiles

Bgee: expression breadth ubiquitous, 245 present calls, max score 98.84.

FANTOM5 (CAGE): breadth broad, TPM avg 22.6034 / max 555.5089, expressed in 712 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
123750	20.4024	695
123751	1.7359	334
123749	0.4542	245
206556	0.0109	5

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.84	gold quality
monocyte	CL:0000576	98.48	gold quality
leukocyte	CL:0000738	98.41	gold quality
mononuclear cell	CL:0000842	98.36	gold quality
lymph node	UBERON:0000029	96.68	gold quality
spleen	UBERON:0002106	96.33	gold quality
vermiform appendix	UBERON:0001154	95.05	gold quality
gall bladder	UBERON:0002110	94.21	gold quality
thymus	UBERON:0002370	93.99	gold quality
upper lobe of left lung	UBERON:0008952	93.67	gold quality
right lung	UBERON:0002167	93.65	gold quality
upper lobe of lung	UBERON:0008948	92.89	gold quality
right lobe of liver	UBERON:0001114	92.74	gold quality
caecum	UBERON:0001153	92.71	gold quality
blood	UBERON:0000178	91.90	gold quality
rectum	UBERON:0001052	90.84	gold quality
liver	UBERON:0002107	90.75	gold quality
type B pancreatic cell	CL:0000169	90.39	gold quality
olfactory bulb	UBERON:0002264	90.20	gold quality
lung	UBERON:0002048	89.24	gold quality
right coronary artery	UBERON:0001625	88.98	gold quality
smooth muscle tissue	UBERON:0001135	88.92	gold quality
right uterine tube	UBERON:0001302	88.90	gold quality
omental fat pad	UBERON:0010414	87.40	gold quality
peritoneum	UBERON:0002358	87.36	gold quality
bone marrow cell	CL:0002092	87.32	gold quality
decidua	UBERON:0002450	87.31	gold quality
colonic epithelium	UBERON:0000397	86.67	gold quality
subcutaneous adipose tissue	UBERON:0002190	86.55	gold quality
adipose tissue of abdominal region	UBERON:0007808	86.52	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-GEOD-70580	yes	537.62
E-MTAB-10553	yes	45.20
E-GEOD-84465	yes	38.80
E-ANND-3	yes	26.90
E-HCAD-9	yes	18.99
E-CURD-112	yes	17.20
E-MTAB-6678	yes	10.76
E-MTAB-9801	yes	7.63
E-MTAB-10042	yes	4.20
E-MTAB-7381	no	1399.71

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, CREB1, CTNNB1, EIF2AK2, ELF1, ETS1, ETS2, GATA3, HAND1, HES1, IKZF1, KAT5, KAT7, LEF1, LMO2, LYL1, MAF, MAZ, MYB, MYC, NFATC2, NFKB1, NFKB, PRDM1, RUNX1, RUNX3, STAT4, STAT5B, STAT6, TAL1, TBXT, TCF12, TCF3, TCF7, TFAP4, YY1, ZBTB7B, ZEB1

miRNA regulators (miRDB)

55 targeting CD4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-2113	99.58	71.22	1521
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-5584-5P	99.49	68.22	2814

Literature-anchored findings (GeneRIF, showing 40)

• the role of CD4, CXCR4, and CCR5 in HIV envelope-mediated apoptosis was examined in peripheral blood mononuclear cells (PMID:11878912)
• Degradation of the HIV receptor CD4 by the proteasome, mediated by the HIV-1 protein Vpu, is crucial for the release of fully infectious virions. (PMID:11893391)
• Role of CD4 hinge region in GP120 utilization by immunoglobulin domain 1 (PMID:11906183)
• cytokine regulation of CD4 expression on monocytes, monocyte-derived macrophages (MDMs), and microglia was investigated (PMID:11920312)
• Results show that the presence of an alpha-helix N-cap in the CD4 cytoplasmic domain increases CD4 affinity to Nef. (PMID:11922627)
• NF-kappaB activation upon interaction of HIV-1 envelope glycoproteins with cell surface CD4 involves IkappaB kinases. (PMID:11959143)
• All of the human testicular macrophages expressed the markers CD45 and MAC387 and most also expressed CD4. (PMID:11994538)
• Ligation of human CD4 interferes with antigen-induced activation of primary T cells derived from CD4 transgenic mice (PMID:12008044)
• CD4 represents a critical turning point that governs the apoptotic and survival programs in T cells, without modifying the physical association with the TCR-CD3 complex. (PMID:12055221)
• CD4 is active as a signaling molecule on the human monocytic cell line Thp-1 (PMID:12213222)
• The CD4 coreceptor mediates tolerance-inducing signals when triggered by an appropriate ligand in vivo. (PMID:12218108)
• coreceptor binding domain, the V3 region of the surface envelope (SU) glycoprotein, was replaced by the V3 loop of a CD4- and CXCR4-tropic HIV-1 strain; the resulting virus, termed SIVagm3-X4mc, exclusively used CD4 and CXCR4 for cell entry (PMID:12368305)
• CD4 dimerization is necessary for helper T cell function. (PMID:12444132)
• study of structural and functional homology between human apolipoprotein A-I and envelope proteins of human immunodeficiency virus type 1 in CD4 receptor binding (PMID:12462973)
• Palmitoylation of Cys394 and Cys397 in the CVRC motif of CD4 and CD4’s association with Lck are essential for keeping CD4 highly concentrated in lipid rafts. (PMID:12517957)
• evidence that neutrophils from both HIV-1-infected and uninfected donors express endogenous CD4 with conformation similar to that of CD4 expressed on T lymphocytes, and that binds HIV gp120, significantly influencing the biodistribution of HIV (PMID:12531788)
• physical association of CD4 and CCR5 results in receptor cross talk with allosteric CD4-dependent regulation of the binding and signaling properties of CCR5 (PMID:12531905)
• HIV-1 entry involves a chemokine-receptor-dependent but CD4-independent entry in neural cells. (PMID:12586555)
• Modulation of NFI-B2 by HIV-1 may represent yet another mechanism by which HIV infection reduces cell surface expression of CD4 (PMID:12639247)
• Involvement of the CD4 extracellular domain for the inhibitory effect of oxidative stress on activation-induced CD4 down-regulation in T cells. (PMID:12695117)
• RT-PCR, and related methodologies are not useful substitutes for assessment of CD4 and CD8 cell numbers in HIV-infected persons (PMID:12702212)
• overexpression of CD4 can inhibit T-cell killing by limiting CCR5-using HIV-1 envelope glycoprotein processing and membrane fusion (PMID:12767984)
• CD4 is downregulated by HIV-1 nef (PMID:12816953)
• The degree of human CD4 dependence of the agonist effects of gp120IIIB at the rat CXCR4 receptor is cell-type specific. (PMID:12864967)
• CD4 di-leucine motif is dispensable for nef binding. In contast, this motif is essential for CD4 down modulation. (PMID:13679604)
• examined the folding and solution structures of ternary CD4-Lck-Zn2+ and CD8alpha-Lck-Zn2+ complexes;coreceptor tails and the Lck N-terminus are unstructured in isolation but assemble in the presence of zinc to form compactly folded heterodimeric domains (PMID:14500983)
• downregulated by HIV-1 Nef protein in coorelation with AIDS clinical progression (PMID:14557639)
• Raft localization of CD4 is not required for hiv-1 entry, however, post-binding fusion/entry steps may require lipid raft assembly. (PMID:14570906)
• The number of CD4+CD28- cells in patients after renal transplantation, especially in graft recipients with chronic graft rejection, suggests a role of these cells in chronic graft destruction. (PMID:14697933)
• When undergoing endocytosis, a small fraction of CD4 on the surface membranes of lymphoblastoid cells is targeted to clathrin-coated pits where it becomes associated with CD71 molecules that are also targeted for endocytosis into the same pit. (PMID:14705953)
• downregulated by Hiv-1 Nef protein in association with lipid rafts (PMID:14747534)
• down-regulated by SIVcpz and HIV-1 group N or O nef alleles (PMID:15194762)
• CCR5 HIV coreceptor is significantly more mobile than CD4 and it requires membrane cholesterol for mobility (PMID:15308751)
• We have shown that 3D domain swapping is a likely candidate for the conformational change which influences permissiveness of cells to HIV infection; the hinge loop, or linker, is loop E - F. (PMID:15326605)
• HIV uptake by CD4 T cells requires cellular contacts mediated by the binding of gp120 to CD4 and intact actin cytoskeleton (PMID:15371410)
• entropy calculation of HIV-1 Env gp120, its receptor CD4, and their complex (PMID:15489307)
• CD4 recycling from the plasma membrane and the nascent CD4 in transit to the plasma membrane are susceptible to intracellular retention in HIV-1 Nef-expressing cells (PMID:15611114)
• Deficiency in function of the CD4(+)CD25(+) T-cell population may influence the pathogenesis of type 1 diabetes. (PMID:15616015)
• The T cells exclusively originating from preexisting CD4CD25 regulatory T cells and proves anergic and highly suppressive on isolation. (PMID:15665762)
• The presence of CD4+CD25+ (regulatory T cells in head and neck cancer patients might be, in part, responsible for downregulation of antitumour immune responses. (PMID:15714205)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
		ENSDARG00000034598
danio_rerio	dicp2.1	ENSDARG00000035101
danio_rerio	zmp:0000000608	ENSDARG00000041221
danio_rerio	cd4-1	ENSDARG00000070668
danio_rerio	si:ch73-322b17.4	ENSDARG00000087509
danio_rerio	dicp3.3	ENSDARG00000087706
danio_rerio	dicp2.2	ENSDARG00000099539
danio_rerio	dicp3.1	ENSDARG00000099674
danio_rerio	si:ch73-34h11.1	ENSDARG00000104422
danio_rerio	dicp1.3-4	ENSDARG00000115199
danio_rerio		ENSDARG00000115525
mus_musculus	Cd4	ENSMUSG00000023274
rattus_norvegicus	Cd4	ENSRNOG00000071219

Protein

Protein identifiers

T-cell surface glycoprotein CD4 — P01730 (reviewed: P01730)

Alternative names: T-cell surface antigen T4/Leu-3

All UniProt accessions (4): P01730, A0A4Y5UGE4, F5GYA9, F5H480

UniProt curated annotations — full annotation on UniProt →

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). Down-regulated by HIV-1 Vpu. Acts as a receptor for Human Herpes virus 7/HHV-7.

Subunit / interactions. Forms disulfide-linked homodimers at the cell surface. Interacts with LCK. Interacts with PTK2/FAK1. Binds to P4HB/PDI. Interacts with IL16; this interaction induces a CD4-dependent signaling in lymphocytes. Interacts (via Ig-like V-type domain) with MHCII alpha chain (via alpha-2 domain) and beta chain (via beta-2 domain); this interaction increases the affinity of TCR for peptide-MHCII. CD4 oligomerization via Ig-like C2-type 2 and 3 domains appears to be required for stable binding to MHCII and adhesion between T cells and APCs. Interacts with Aedes aegypti long form salivary protein D7L2. Interacts with Aedes aegypti neutrophil-stimulating factor 1. Interacts with Aedes aegypti venom allergen-1. (Microbial infection) Interacts with HIV-1 Envelope polyprotein gp160 and protein Vpu. (Microbial infection) Interacts with Human Herpes virus 7 surface proteins.

Subcellular location. Cell membrane.

Tissue specificity. Highly expressed in T-helper cells. The presence of CD4 is a hallmark of T-helper cells which are specialized in the activation and growth of cytotoxic T-cells, regulation of B cells, or activation of phagocytes. CD4 is also present in other immune cells such as macrophages, dendritic cells or NK cells.

Post-translational modifications. Palmitoylation and association with LCK contribute to the enrichment of CD4 in lipid rafts. Phosphorylated by PKC; phosphorylation at Ser-433 plays an important role for CD4 internalization.

Disease relevance. Immunodeficiency 79 (IMD79) [MIM:619238] An autosomal recessive disorder characterized by childhood onset of recurrent and recalcitrant skin warts due to uncontrolled viral infection with human papillomavirus (HPV). Some patients may also have recurrent respiratory infections. Laboratory studies show a complete absence of CD4+ T cells. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The Ig-like V-type domain mediates the interaction with MHCII.

Polymorphism. The OKT monoclonal antibodies are widely used for the analysis of human peripheral blood T-lymphocytes. OKT4 reacts with T-helper/inducer lymphocytes. The OKT4 epitope of the CD4 cell-surface protein is polymorphic in white, black, and Japanese populations. The variable phenotypic expression is due a CD4 polymorphism. OKT4 positive individuals carry Arg-265 and OKT4 negative individuals carry Trp-265 [MIM:613949].

RefSeq proteins (9): NP_000607, NP_001181943, NP_001181944, NP_001181945, NP_001181946, NP_001369634, NP_001369635, NP_001369636, NP_001369643 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000973	CD4	Family
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR008424	Ig_C2-set	Domain
IPR013106	Ig_V-set	Domain
IPR013151	Immunoglobulin_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015274	CD4-extracel	Domain
IPR021963	Tcell_CD4_Cterm	Domain
IPR036179	Ig-like_dom_sf	Homologous_superfamily

Pfam: PF00047, PF05790, PF09191, PF12104

UniProt features (64 total): strand 21, mutagenesis site 14, helix 5, domain 4, modified residue 3, disulfide bond 3, sequence variant 3, lipid moiety-binding region 2, glycosylation site 2, topological domain 2, signal peptide 1, chain 1, transmembrane region 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

84 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
8W90	X-RAY DIFFRACTION	1.81
4H8W	X-RAY DIFFRACTION	1.85
2NY1	X-RAY DIFFRACTION	1.99
1CDY	X-RAY DIFFRACTION	2
2NXY	X-RAY DIFFRACTION	2
2NY2	X-RAY DIFFRACTION	2
2NY3	X-RAY DIFFRACTION	2
2NY4	X-RAY DIFFRACTION	2
2NXZ	X-RAY DIFFRACTION	2.04
3S5L	X-RAY DIFFRACTION	2.1
3O2D	X-RAY DIFFRACTION	2.19
1G9M	X-RAY DIFFRACTION	2.2
1RZJ	X-RAY DIFFRACTION	2.2
2NY0	X-RAY DIFFRACTION	2.2
3CD4	X-RAY DIFFRACTION	2.2
1CDH	X-RAY DIFFRACTION	2.3
3S4S	X-RAY DIFFRACTION	2.4
6L1Y	X-RAY DIFFRACTION	2.47
1CDJ	X-RAY DIFFRACTION	2.5
1GC1	X-RAY DIFFRACTION	2.5
2NY5	X-RAY DIFFRACTION	2.5
3JWD	X-RAY DIFFRACTION	2.61
1CDU	X-RAY DIFFRACTION	2.7
2NY6	X-RAY DIFFRACTION	2.8
3B71	X-RAY DIFFRACTION	2.82
1CDI	X-RAY DIFFRACTION	2.9
1G9N	X-RAY DIFFRACTION	2.9
1RZK	X-RAY DIFFRACTION	2.9
9OAJ	ELECTRON MICROSCOPY	2.91
2JKR	X-RAY DIFFRACTION	2.98

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01730-F1	85.35	0.65

Antibody-complex structures (SAbDab): 49 — 1G9M, 1G9N, 1GC1, 1RZJ, 1RZK, 2B4C, 2NXY, 2NXZ, 2NY0, 2NY1, 2NY2, 2NY3, 2NY4, 2NY5, 2NY6, 2QAD, 3J70, 3JCB, 3JCC, 3JWD, 3JWO, 3LQA, 3O2D, 4H8W, 4JM2 (+24 more)

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (5): 433, 440, 456, 419, 422

Disulfide bonds (3): 41–109, 155–184, 328–370

Glycosylation sites (2): 296, 325

Mutagenesis-validated functional residues (14):

Position	Phenotype
65	increases the affinity for mhcii; when associated with w-70; r-85 and r-88.
68	abrogates the interaction with mhcii and t cell activation.
70	increases the affinity for mhcii; when associated with y-65; r-85 and r-88.
85	increases the affinity for mhcii; when associated with y-65; w-70 and r-88.
88	increases the affinity for mhcii; when associated with y-65; w-70 and r-85.
265	has no effect on the interaction with mhcii. impairs recognition by okt4 antibody.
432	no effect.
433	about 75% loss of internalization.
433	no effect.
438–439	loss of nef-induced cd4 down-modulation.
440	no effect.
445	loss of homodimerization; when associated with a-447.
447	loss of homodimerization; when associated with a-445.
457–458	abolished interaction with spg21 and induced t-cell activation.

Function

Pathways and Gene Ontology

Reactome pathways

32 pathways

ID	Pathway
R-HSA-1462054	Alpha-defensins
R-HSA-167590	Nef Mediated CD4 Down-regulation
R-HSA-173107	Binding and entry of HIV virion
R-HSA-180534	Vpu mediated degradation of CD4
R-HSA-202424	Downstream TCR signaling
R-HSA-202427	Phosphorylation of CD3 and TCR zeta chains
R-HSA-202430	Translocation of ZAP-70 to Immunological synapse
R-HSA-202433	Generation of second messenger molecules
R-HSA-389948	Co-inhibition by PD-1
R-HSA-449836	Other interleukin signaling
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1280218	Adaptive Immune System
R-HSA-1461973	Defensins
R-HSA-162587	HIV Life Cycle
R-HSA-162594	Early Phase of HIV Life Cycle
R-HSA-162906	HIV Infection
R-HSA-162909	Host Interactions of HIV factors
R-HSA-1643685	Disease
R-HSA-164938	Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters
R-HSA-164952	The role of Nef in HIV-1 replication and disease pathogenesis
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-199991	Membrane Trafficking
R-HSA-202403	TCR signaling
R-HSA-388841	Regulation of T cell activation by CD28 family
R-HSA-449147	Signaling by Interleukins
R-HSA-5653656	Vesicle-mediated transport
R-HSA-5663205	Infectious disease

MSigDB gene sets: 488 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_RESPONSE_TO_ETHANOL, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, MCLACHLAN_DENTAL_CARIES_UP, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_RESPONSE_TO_ESTRADIOL, GOBP_CELL_CHEMOTAXIS, GOBP_RESPONSE_TO_AMINE

GO Biological Process (43): adaptive immune response (GO:0002250), immune response (GO:0006955), cell adhesion (GO:0007155), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), enzyme-linked receptor protein signaling pathway (GO:0007167), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), positive regulation of calcium ion transport into cytosol (GO:0010524), calcium-mediated signaling (GO:0019722), T cell differentiation (GO:0030217), macrophage differentiation (GO:0030225), response to estradiol (GO:0032355), maintenance of protein location in cell (GO:0032507), positive regulation of interleukin-2 production (GO:0032743), response to vitamin D (GO:0033280), helper T cell enhancement of adaptive immune response (GO:0035397), interleukin-15-mediated signaling pathway (GO:0035723), positive regulation of T cell proliferation (GO:0042102), T cell selection (GO:0045058), response to ethanol (GO:0045471), positive regulation of monocyte differentiation (GO:0045657), symbiont entry into host cell (GO:0046718), defense response to Gram-negative bacterium (GO:0050829), positive regulation of calcium-mediated signaling (GO:0050850), T cell receptor signaling pathway (GO:0050852), regulation of T cell activation (GO:0050863), cellular response to granulocyte macrophage colony-stimulating factor stimulus (GO:0097011), response to methamphetamine hydrochloride (GO:1904313), cellular response to ionomycin (GO:1904637), positive regulation of protein phosphorylation (GO:0001934), immune system process (GO:0002376), positive regulation of immune system process (GO:0002684), positive regulation of kinase activity (GO:0033674), T cell activation (GO:0042110), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of MAPK cascade (GO:0043410), positive regulation of protein kinase activity (GO:0045860), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of viral entry into host cell (GO:0046598), positive regulation of T cell activation (GO:0050870)

GO Molecular Function (19): virus receptor activity (GO:0001618), transmembrane signaling receptor activity (GO:0004888), extracellular matrix structural constituent (GO:0005201), zinc ion binding (GO:0008270), lipid binding (GO:0008289), coreceptor activity (GO:0015026), immunoglobulin binding (GO:0019865), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), MHC class II protein complex binding (GO:0023026), signaling receptor activity (GO:0038023), interleukin-16 binding (GO:0042011), interleukin-16 receptor activity (GO:0042012), MHC class II protein binding (GO:0042289), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein tyrosine kinase binding (GO:1990782), signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (10): early endosome (GO:0005769), endoplasmic reticulum lumen (GO:0005788), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), clathrin-coated endocytic vesicle membrane (GO:0030669), T cell receptor complex (GO:0042101), membrane raft (GO:0045121), cell surface (GO:0009986), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
TCR signaling	4
Immune System	2
HIV Infection	2
Defensins	1
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	1
Early Phase of HIV Life Cycle	1
Host Interactions of HIV factors	1
Regulation of T cell activation by CD28 family	1
Signaling by Interleukins	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
Antimicrobial peptides	1
HIV Life Cycle	1
Viral Infection Pathways	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	3
immune system process	2
cellular process	2
response to lipid	2
response to oxygen-containing compound	2
signaling receptor activity	2
binding	2
cellular anatomical structure	2
immune response	1
response to stimulus	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signal transduction	1
cell surface receptor signaling pathway	1
enzyme-linked receptor protein signaling pathway	1
positive regulation of cytosolic calcium ion concentration	1
regulation of calcium ion transport into cytosol	1
calcium ion transport into cytosol	1
positive regulation of calcium ion transmembrane transport	1
intracellular signaling cassette	1
lymphocyte differentiation	1
T cell activation	1
myeloid leukocyte differentiation	1
mononuclear cell differentiation	1
maintenance of protein location	1
maintenance of location in cell	1
positive regulation of cytokine production	1
interleukin-2 production	1
regulation of interleukin-2 production	1
response to vitamin	1
positive regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
cytokine-mediated signaling pathway	1
cellular response to interleukin-15	1
T cell proliferation	1
regulation of T cell proliferation	1
positive regulation of lymphocyte proliferation	1
positive regulation of T cell activation	1
T cell differentiation	1

Protein interactions and networks

STRING

8138 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD4	CXCR4	P30991	999
CD4	CCR5	P51681	999
CD4	ITIH4	Q14624	999
CD4	LCK	P06239	998
CD4	ERVW-1	Q9UQF0	996
CD4	CD2	P06729	994
CD4	ENPEP	Q07075	994
CD4	CD8A	P01732	993
CD4	IFNG	P01579	991
CD4	FOXP3	Q9BZS1	979
CD4	FYN	P06241	978
CD4	CD40LG	P29965	976
CD4	IL16	Q14005	976
CD4	IL2	P01585	975
CD4	IL10	P22301	975

IntAct

52 interactions, top by confidence:

A	B	Type	Score
CD4	LCK	psi-mi:“MI:0915”(physical association)	0.700
LCK	CD4	psi-mi:“MI:0915”(physical association)	0.700
CCR5	CD4	psi-mi:“MI:0915”(physical association)	0.670
CCR5	CD4	psi-mi:“MI:0914”(association)	0.670
CD4	env	psi-mi:“MI:0407”(direct interaction)	0.620
env	CD4	psi-mi:“MI:0407”(direct interaction)	0.620
nef	CD4	psi-mi:“MI:0407”(direct interaction)	0.560
env	CD4	psi-mi:“MI:0407”(direct interaction)	0.560
CD4	env	psi-mi:“MI:0407”(direct interaction)	0.560
CD4	CD4	psi-mi:“MI:0407”(direct interaction)	0.560
LAMP2	CD4	psi-mi:“MI:0915”(physical association)	0.560
SH3GLB1	CD4	psi-mi:“MI:0915”(physical association)	0.560
CD4	CCDC85C	psi-mi:“MI:0914”(association)	0.530
CD4	vpu	psi-mi:“MI:0915”(physical association)	0.520
vpu	CD4	psi-mi:“MI:0915”(physical association)	0.520

BioGRID (141): SIVA1 (Two-hybrid), CD4 (Reconstituted Complex), LCK (Two-hybrid), KIAA0319L (Affinity Capture-MS), POGZ (Affinity Capture-MS), TMEM11 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-MS), CCDC85C (Affinity Capture-MS), ARV1 (Affinity Capture-MS), VAMP3 (Affinity Capture-MS), ATP6V0A1 (Affinity Capture-MS), EIF2B3 (Affinity Capture-MS), SAAL1 (Affinity Capture-MS), CD320 (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS)

ESM2 similar proteins: A6NJW9, O02757, P01730, P01731, P01732, P05541, P07725, P09793, P0DSE1, P10300, P10747, P10966, P15530, P16003, P16004, P16410, P30433, P30434, P31041, P31042, P31043, P31783, P33705, P33706, P40259, P41688, P42069, P42072, P50283, P79184, P79336, Q08338, Q08340, Q28071, Q2YFS1, Q2YFS2, Q2YFS3, Q3LRV9, Q495A1, Q5JXA9

Diamond homologs: P01652, P01730, P05540, P06332, P16003, P16004, P33705, P46630, P79184, P79185, Q08336, Q08338, Q08339, Q08340, Q29037, Q9XS78, P01650, P29534

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
UFD1	“down-regulates quantity by destabilization”	CD4	binding
“Class II MHC:Antigen”	“up-regulates activity”	CD4	binding
SCF-betaTRCP	“down-regulates quantity by destabilization”	CD4	polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

64 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	19
Likely benign	8
Benign	17

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1048526	NM_000616.5(CD4):c.1157-1G>A	Pathogenic
1048527	NM_000616.5(CD4):c.1A>G (p.Met1Val)	Pathogenic

SpliceAI

2109 predictions. Top by Δscore:

Variant	Effect	Δscore
12:6789660:GAG:G	donor_gain	1.0000
12:6789663:G:GG	donor_gain	1.0000
12:6789664:T:G	donor_loss	1.0000
12:6800305:A:AG	acceptor_gain	1.0000
12:6800306:G:GG	acceptor_gain	1.0000
12:6800306:GC:G	acceptor_gain	1.0000
12:6800432:A:G	donor_gain	1.0000
12:6814273:G:GT	donor_gain	1.0000
12:6814276:G:GT	donor_gain	1.0000
12:6816366:A:T	donor_gain	1.0000
12:6816379:G:GT	donor_gain	1.0000
12:6816401:GAGG:G	donor_loss	1.0000
12:6816403:GG:G	donor_loss	1.0000
12:6816404:G:A	donor_loss	1.0000
12:6817128:A:AG	acceptor_gain	1.0000
12:6817129:G:GA	acceptor_gain	1.0000
12:6817129:GCC:G	acceptor_gain	1.0000
12:6817129:GCCA:G	acceptor_gain	1.0000
12:6817328:AGG:A	donor_gain	1.0000
12:6817329:GG:G	donor_gain	1.0000
12:6817329:GGG:G	donor_gain	1.0000
12:6817330:GG:G	donor_gain	1.0000
12:6817330:GGT:G	donor_loss	1.0000
12:6817331:G:GG	donor_gain	1.0000
12:6817331:GT:G	donor_loss	1.0000
12:6817332:T:A	donor_loss	1.0000
12:6818418:CAGTT:C	acceptor_loss	1.0000
12:6818419:A:AG	acceptor_gain	1.0000
12:6818419:AGTT:A	acceptor_loss	1.0000
12:6818420:G:GT	acceptor_gain	1.0000

AlphaMissense

2981 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:6800416:G:C	W53C	0.995
12:6800416:G:T	W53C	0.995
12:6800414:T:A	W53R	0.993
12:6800414:T:C	W53R	0.993
12:6800408:T:C	F51L	0.992
12:6800410:C:A	F51L	0.992
12:6800410:C:G	F51L	0.992
12:6814252:T:A	C109S	0.992
12:6814253:G:C	C109S	0.992
12:6814253:G:A	C109Y	0.990
12:6814286:T:C	L120S	0.990
12:6817278:G:C	W368C	0.990
12:6817278:G:T	W368C	0.990
12:6814188:G:C	W87C	0.989
12:6814188:G:T	W87C	0.989
12:6814234:G:C	D103H	0.988
12:6814929:T:A	W182R	0.988
12:6814929:T:C	W182R	0.988
12:6800415:G:C	W53S	0.987
12:6814252:T:C	C109R	0.986
12:6814931:G:C	W182C	0.986
12:6814931:G:T	W182C	0.986
12:6814208:T:C	L94P	0.985
12:6814254:T:G	C109W	0.985
12:6800373:T:C	L39P	0.984
12:6814235:A:C	D103A	0.984
12:6814807:T:C	L141P	0.980
12:6817282:T:A	C370S	0.980
12:6817283:G:C	C370S	0.980
12:6814235:A:T	D103V	0.979

dbSNP variants (sampled 300 via entrez): RS1000078109 (12:6790490 G>C), RS1000166755 (12:6787857 A>G), RS1000457374 (12:6793088 G>A,T), RS1000481071 (12:6815177 T>C), RS1000638657 (12:6794572 A>G), RS1000745386 (12:6792817 C>T), RS1000770301 (12:6789255 G>A), RS1000828438 (12:6797259 C>T), RS1001146084 (12:6803030 G>A), RS1001208532 (12:6809556 A>G,T), RS1001284593 (12:6803374 T>C), RS1001316165 (12:6803397 C>A,G,T), RS1001416272 (12:6815725 G>A,C), RS1001795475 (12:6787777 G>A), RS1001850396 (12:6820075 G>A)

Disease associations

OMIM: gene MIM:186940 | disease phenotypes: MIM:619238, MIM:613949

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 79	Moderate	Autosomal recessive

Mondo (2): immunodeficiency 79 (MONDO:0030981), Okt4 epitope deficiency (MONDO:0013497)

Orphanet (0):

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000403	Recurrent otitis media
HP:0002788	Recurrent upper respiratory tract infections
HP:0002843	Abnormal T cell morphology
HP:0003621	Juvenile onset
HP:0032215	Disseminated cutaneous warts
HP:0032218	Decreased CD4+ T cell proportion
HP:0033004	Palmar warts
HP:0033005	Plantar warts

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001450_2	Response to Vitamin E supplementation	4.000000e-06
GCST006444_4	Bone mineral density (hip)	5.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007702	hip bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2754 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — CD molecules

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
adamantan-1-yl-carbamic acid (S)-2-{(2S,3R)-2-[2-((S)-2-{(S)-6-amino-2-[2-(naphthalen-2-yloxy)-acetylamino]-hexanoylamino}-3-methyl-butyrylamino)-acetylamino]-3-hydroxy-butyrylamino}-propyl ester	KD	80000 nM

ChEMBL bioactivities

22 potent at pChembl≥5 of 37 total, top 22 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.92	IC50	1.2	nM	CHEMBL5589596
6.89	IC50	130	nM	ISOCOMPLESTATIN
6.89	IC50	130	nM	CHLOROPEPTIN
6.89	IC50	130	nM	CHEMBL3143464
6.89	IC50	130	nM	CHEMBL4747494
6.68	IC50	210	nM	CHEMBL1852155
6.66	IC50	220	nM	CHEMBL4791666
6.48	IC50	330	nM	CYCLOTRIAZADISULFONAMIDE HYDROCHLORIDE
6.38	IC50	420	nM	CHEMBL4746252
6.27	IC50	540	nM	CHEMBL4750983
6.18	IC50	660	nM	CHEMBL4786809
6.13	IC50	740	nM	CHEMBL4748787
6.08	IC50	830	nM	CHEMBL4758659
6.07	IC50	860	nM	CHEMBL4755141
6.02	IC50	950	nM	CHEMBL4783761
5.82	IC50	1500	nM	CHEMBL4782080
5.78	IC50	1670	nM	CHEMBL4785236
5.73	IC50	1880	nM	CHEMBL4743003
5.55	IC50	2810	nM	CHEMBL4783030
5.40	EC50	4000	nM	CHEMBL3138187
5.22	Kd	6000	nM	CHEMBL230798
5.03	IC50	9300	nM	CHEMBL4750160

PubChem BioAssay actives

22 with measured affinity, of 115 total; 22 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[[4-[[4-(3-ethyl-7-fluoro-2-methylbenzimidazol-5-yl)-5-fluoropyrimidin-2-yl]amino]phenyl]methyl]-N’-hydroxyoctanediamide	2112985: Inhibition of CD4 (unknown origin)	ic50	0.0012	uM
(2R)-2-[[(17R,20R,23R,26R,29S)-20,26-bis(3,5-dichloro-4-hydroxyphenyl)-17-[[2-(3,5-dichloro-4-hydroxyphenyl)-2-oxoacetyl]amino]-37-hydroxy-28-methyl-18,21,24,27-tetraoxo-2-oxa-13,19,22,25,28-pentazahexacyclo[29.2.2.13,7.18,12.05,23.011,15]heptatriaconta-1(33),3,5,7(37),8(36),9,11,14,31,34-decaene-29-carbonyl]amino]-2-(4-hydroxyphenyl)acetic acid	42787: Inhibitory concentration against CD4-gp120 binding in the absence of fetal bovine serum (FBS); Range is 0.13-0.5 uM	ic50	0.1300	uM
(2R)-2-[[(18R,21R,24R,27R,30S)-21,27-bis(3,5-dichloro-4-hydroxyphenyl)-18-[[2-(3,5-dichloro-4-hydroxyphenyl)-2-oxoacetyl]amino]-37-hydroxy-29-methyl-19,22,25,28-tetraoxo-2-oxa-14,20,23,26,29-pentazahexacyclo[30.2.2.13,7.05,24.08,13.012,16]heptatriaconta-1(34),3,5,7(37),8,10,12,15,32,35-decaene-30-carbonyl]amino]-2-(4-hydroxyphenyl)acetic acid	42787: Inhibitory concentration against CD4-gp120 binding in the absence of fetal bovine serum (FBS); Range is 0.13-0.5 uM	ic50	0.1300	uM
13-(cyclohexylmethoxy)-6-methylidene-4,8-bis-(4-methylphenyl)sulfonyl-4,8,15-triazabicyclo[9.3.1]pentadeca-1(14),11(15),12-triene;hydrochloride	1682741: Binding affinity to signal peptide of human CD4-YFP expressed in CHO-K1 cells assessed down-modulation of CD4 surface expression incubated for 24 hrs by flow cytometry	ic50	0.1300	uM
(2R)-2-[[(17R,20R,23R,26R,29S)-20,26-bis(3,5-dichloro-4-hydroxyphenyl)-17-[[2-(3,5-dichloro-4-hydroxyphenyl)-2-hydroxy-4-oxopentanoyl]amino]-37-hydroxy-28-methyl-18,21,24,27-tetraoxo-2-oxa-13,19,22,25,28-pentazahexacyclo[29.2.2.13,7.18,12.05,23.011,15]heptatriaconta-1(33),3,5,7(37),8(36),9,11,14,31,34-decaene-29-carbonyl]amino]-2-(4-hydroxyphenyl)acetic acid	42787: Inhibitory concentration against CD4-gp120 binding in the absence of fetal bovine serum (FBS); Range is 0.13-0.5 uM	ic50	0.1300	uM
9-benzyl-3-methylidene-1,5-bis-(4-methylphenyl)sulfonyl-1,5,9-triazacyclododecane	1668002: Inhibition of FITC-tagged human CD4 expressed in human SUP-T1 cells after 72 hrs by FACS analysis	ic50	0.2100	uM
4-[[8-[4-(dimethylamino)phenyl]sulfonyl-13-ethyl-6-methylidene-4,8,15-triazabicyclo[9.3.1]pentadeca-1(14),11(15),12-trien-4-yl]sulfonyl]-N,N-dimethylaniline;hydrochloride	1682741: Binding affinity to signal peptide of human CD4-YFP expressed in CHO-K1 cells assessed down-modulation of CD4 surface expression incubated for 24 hrs by flow cytometry	ic50	0.2200	uM
9-benzyl-3-methylidene-1,5-bis-(4-methylphenyl)sulfonyl-1,5,9-triazacyclododecane;hydrochloride	1682741: Binding affinity to signal peptide of human CD4-YFP expressed in CHO-K1 cells assessed down-modulation of CD4 surface expression incubated for 24 hrs by flow cytometry	ic50	0.3300	uM
6-methylidene-4,8-bis-(4-methylphenyl)sulfonyl-13-phenylmethoxy-4,8,15-triazabicyclo[9.3.1]pentadeca-1(14),11(15),12-triene;hydrochloride	1682741: Binding affinity to signal peptide of human CD4-YFP expressed in CHO-K1 cells assessed down-modulation of CD4 surface expression incubated for 24 hrs by flow cytometry	ic50	0.4200	uM
13-butyl-6-methylidene-4,8-bis-(4-methylphenyl)sulfonyl-4,8,15-triazabicyclo[9.3.1]pentadeca-1(14),11(15),12-triene;hydrochloride	1682741: Binding affinity to signal peptide of human CD4-YFP expressed in CHO-K1 cells assessed down-modulation of CD4 surface expression incubated for 24 hrs by flow cytometry	ic50	0.5400	uM
6-methylidene-4,8-bis-(4-methylphenyl)sulfonyl-13-(2-methylpropyl)-4,8,15-triazabicyclo[9.3.1]pentadeca-1(14),11(15),12-triene;hydrochloride	1682741: Binding affinity to signal peptide of human CD4-YFP expressed in CHO-K1 cells assessed down-modulation of CD4 surface expression incubated for 24 hrs by flow cytometry	ic50	0.6600	uM
6-methylidene-4,8-bis-(4-methylphenyl)sulfonyl-13-phenyl-4,8,15-triazabicyclo[9.3.1]pentadeca-1(14),11(15),12-triene;hydrochloride	1682741: Binding affinity to signal peptide of human CD4-YFP expressed in CHO-K1 cells assessed down-modulation of CD4 surface expression incubated for 24 hrs by flow cytometry	ic50	0.7400	uM
6-methylidene-4,8-bis-(4-methylphenyl)sulfonyl-13-propyl-4,8,15-triazabicyclo[9.3.1]pentadeca-1(14),11(15),12-triene;hydrochloride	1682741: Binding affinity to signal peptide of human CD4-YFP expressed in CHO-K1 cells assessed down-modulation of CD4 surface expression incubated for 24 hrs by flow cytometry	ic50	0.8300	uM
13-ethyl-6-methylidene-4,8-bis-(4-methylphenyl)sulfonyl-4,8,15-triazabicyclo[9.3.1]pentadeca-1(14),11(15),12-triene;hydrochloride	1682741: Binding affinity to signal peptide of human CD4-YFP expressed in CHO-K1 cells assessed down-modulation of CD4 surface expression incubated for 24 hrs by flow cytometry	ic50	0.8600	uM
13-tert-butyl-6-methylidene-4,8-bis-(4-methylphenyl)sulfonyl-4,8,15-triazabicyclo[9.3.1]pentadeca-1(14),11(15),12-triene;hydrochloride	1682741: Binding affinity to signal peptide of human CD4-YFP expressed in CHO-K1 cells assessed down-modulation of CD4 surface expression incubated for 24 hrs by flow cytometry	ic50	0.9500	uM
13-ethoxy-6-methylidene-4,8-bis-(4-methylphenyl)sulfonyl-4,8,15-triazabicyclo[9.3.1]pentadeca-1(14),11(15),12-triene;hydrochloride	1682741: Binding affinity to signal peptide of human CD4-YFP expressed in CHO-K1 cells assessed down-modulation of CD4 surface expression incubated for 24 hrs by flow cytometry	ic50	1.5000	uM
13-methyl-6-methylidene-4,8-bis-(4-methylphenyl)sulfonyl-4,8,15-triazabicyclo[9.3.1]pentadeca-1(14),11(15),12-triene;hydrochloride	1682741: Binding affinity to signal peptide of human CD4-YFP expressed in CHO-K1 cells assessed down-modulation of CD4 surface expression incubated for 24 hrs by flow cytometry	ic50	1.6700	uM
13-methoxy-6-methylidene-4,8-bis-(4-methylphenyl)sulfonyl-4,8,15-triazabicyclo[9.3.1]pentadeca-1(14),11(15),12-triene;hydrochloride	1682741: Binding affinity to signal peptide of human CD4-YFP expressed in CHO-K1 cells assessed down-modulation of CD4 surface expression incubated for 24 hrs by flow cytometry	ic50	1.8800	uM
6-methylidene-4,8-bis-(4-methylphenyl)sulfonyl-4,8,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene	1682741: Binding affinity to signal peptide of human CD4-YFP expressed in CHO-K1 cells assessed down-modulation of CD4 surface expression incubated for 24 hrs by flow cytometry	ic50	2.8100	uM
5-[1-(3-carboxy-5-chloro-4-hydroxyphenyl)-4-[(3S,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl]but-1-enyl]-3-chloro-2-hydroxybenzoic acid	104279: In vitro inhibition of cytopathic effect was determined against HIV-2 ROD in MT-4 cells using MTS cytoprotection assay	ec50	4.0000	uM
[(2S)-1-[(2S,3S)-2-[[2-[[(2S)-2-[[(2S)-6-amino-2-[(2-naphthalen-2-yloxyacetyl)amino]hexanoyl]amino]-3-methylbutanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]pyrrolidin-2-yl]methyl N-tert-butylcarbamate	292376: Binding affinity to CD4 by SPR assay	kd	6.0000	uM
6-methylidene-4,8-bis-(4-methylphenyl)sulfonyl-4,8,15-triazabicyclo[9.3.1]pentadeca-1(14),11-dien-13-one;hydrobromide	1682741: Binding affinity to signal peptide of human CD4-YFP expressed in CHO-K1 cells assessed down-modulation of CD4 surface expression incubated for 24 hrs by flow cytometry	ic50	9.3000	uM

CTD chemical–gene interactions

35 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
(+)-JQ1 compound	decreases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Dexamethasone	decreases reaction, decreases expression	2
Nickel	increases expression	2
Tretinoin	increases expression	2
triphenyl phosphate	affects expression	1
rimexolone	decreases reaction, decreases expression	1
dienogest	affects cotreatment, decreases expression	1
sulindac sulfide	increases expression	1
ethinyl estradiol-desogestrel combination	increases expression	1
N-(6-methylamino-3-nitrophenyl)-3-(3-indolyl)acrylamide	affects binding	1
licochalcone B	increases expression	1
Decitabine	increases expression	1
Glyphosate	increases expression	1
Adjuvants, Immunologic	affects response to substance	1
Aluminum Hydroxide	affects response to substance	1
Asbestos	decreases expression	1
Cisplatin	affects cotreatment, decreases reaction, increases expression	1
Ethinyl Estradiol	affects cotreatment, decreases expression	1
Lead	affects methylation	1
Methotrexate	decreases expression	1
Naled	affects expression	1
Nicotine	decreases expression	1
Tetradecanoylphorbol Acetate	affects cotreatment, affects expression	1
Theophylline	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Zinc	affects cotreatment, affects expression	1
2-Naphthylamine	increases expression	1
Mifepristone	decreases expression, decreases reaction	1

ChEMBL screening assays

38 unique, capped per target: 30 binding, 8 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2351019	Binding	Inhibition of anti-CD4 mAb sim-2 binding to CD4 in PHA-induced human T cells at 0.1 to 10 uM incubated for 20 mins prior to mAb sim-2 addition measured after 1 hr by flow cytometric analysis	Improved guanide compounds which bind the CXCR4 co-receptor and inhibit HIV-1 infection. — Bioorg Med Chem Lett
CHEMBL712351	Functional	In vitro inhibition of cytopathic effect was determined against HIV-2 ROD in MT-4 cells using MTS cytoprotection assay	Correlation of anti-HIV activity with anion spacing in a series of cosalane analogues with extended polycarboxylate pharmacophores. — J Med Chem

Cellosaurus cell lines

69 cell lines: 57 cancer cell line, 6 transformed cell line, 6 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1D94	HOS-CD4-CCR1	Cancer cell line	Female
CVCL_1D95	HOS-CD4-CCR2b	Cancer cell line	Female
CVCL_1D96	HOS-CD4-CCR3	Cancer cell line	Female
CVCL_1D97	HOS-CD4-CCR4	Cancer cell line	Female
CVCL_1D98	HOS-CD4-CCR5	Cancer cell line	Female
CVCL_1D99	HOS-CD4-Fusin	Cancer cell line	Female
CVCL_1E00	HOS-CD4-pBABE-puro	Cancer cell line	Female
CVCL_1E11	3T3.T4	Transformed cell line	Male
CVCL_1E12	3T3.T4.BOB	Transformed cell line	Male
CVCL_1E13	3T3.T4.Bonzo	Transformed cell line	Male

Clinical trials (associated diseases)

2 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02135003	Not specified	COMPLETED	Non-enrolment and Non-adherence to HIV Care in a Community-based Program, Rakai, Uganda
NCT06044792	Not specified	NOT_YET_RECRUITING	The Influence of Primary HIV-1 Drug Resistance Mutations on Immune Reconstruction in PLWH