{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:06:20Z","timestamp":1790924780163,"version":"4.1.0"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Retrovirology"],"published-print":{"date-parts":[[2006,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Human immunodeficiency virus (HIV) enters target cells by a membrane fusion process that involves a series of sequential interactions between its envelope glycoproteins, the CD4 receptor and CXCR4\/CCR5 coreceptors. CD4 molecules are expressed at the cell surface of lymphocytes and monocytes mainly as monomers, but basal levels of CD4 dimers are also present at the cell surface of these cells. Previous evidence indicates that the membrane distal and proximal extracellular domains of CD4, respectively D1 and D4, are involved in receptor dimerization.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here, we have used A201 cell lines expressing two CD4 mutants, CD4-E91K, E92K (D1 mutant) and CD4-Q344E (D4 mutant), harboring dimerization defects to analyze the role of CD4 dimerization in HIV-1 entry. Using entry assays based on \u03b2-lactamase-Vpr or luciferase reporter activities, as well as virus encoding envelope glycoproteins derived from primary or laboratory-adapted strains, we obtained evidence suggesting an association between disruption of CD4 dimerization and increased viral entry efficiency.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Taken together, our results suggest that monomeric forms of CD4 are preferentially used by HIV-1 to gain entry into target cells, thus implying that the dimer\/monomer ratio at the cell surface of HIV-1 target cells may modulate the efficiency of HIV-1 entry.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1742-4690-3-31","type":"journal-article","created":{"date-parts":[[2006,6,8]],"date-time":"2006-06-08T18:32:10Z","timestamp":1149791530000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Association between disruption of CD4 receptor dimerization and increased human immunodeficiency virus type 1 entry"],"prefix":"10.1186","volume":"3","author":[{"given":"Rachel","family":"Bourgeois","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanne","family":"Mercier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Paquette-Brooks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9ric A","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2006,6,8]]},"reference":[{"key":"473_CR1","doi-asserted-by":"publisher","first-page":"2677","DOI":"10.1101\/gad.833300","volume":"14","author":"RW Doms","year":"2000","unstructured":"Doms RW, Trono D: The plasma membrane as a combat zone in the HIV battlefield. Genes Dev. 2000, 14: 2677-2688. 10.1101\/gad.833300.","journal-title":"Genes Dev"},{"key":"473_CR2","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/S0065-2776(08)60498-8","volume":"53","author":"MC Miceli","year":"1993","unstructured":"Miceli MC, Parnes JR: Role of CD4 and CD8 in T cell activation and differentiation. Adv Immunol. 1993, 53: 59-122.","journal-title":"Adv Immunol"},{"key":"473_CR3","doi-asserted-by":"publisher","first-page":"2590","DOI":"10.1002\/(SICI)1521-4141(199908)29:08<2590::AID-IMMU2590>3.0.CO;2-R","volume":"29","author":"GW Lynch","year":"1999","unstructured":"Lynch GW, Sloane AJ, Raso V, Lai A, Cunningham AL: Direct evidence for native CD4 oligomers in lymphoid and monocytoid cells. Eur J Immunol. 1999, 29: 2590-2602. 10.1002\/(SICI)1521-4141(199908)29:08<2590::AID-IMMU2590>3.0.CO;2-R.","journal-title":"Eur J Immunol"},{"key":"473_CR4","doi-asserted-by":"publisher","first-page":"6261","DOI":"10.4049\/jimmunol.169.11.6261","volume":"169","author":"MC Moldovan","year":"2002","unstructured":"Moldovan MC, Yachou A, Levesque K, Wu H, Hendrickson WA, Cohen EA, S\u00e9kaly RP: CD4 dimers constitute the functional component required for T cell activation. J Immunol. 2002, 169: 6261-6268.","journal-title":"J Immunol"},{"key":"473_CR5","doi-asserted-by":"publisher","first-page":"5438","DOI":"10.4049\/jimmunol.176.9.5438","volume":"176","author":"MC Moldovan","year":"2006","unstructured":"Moldovan MC, Sabbagh L, Breton G, S\u00e9kaly RP, Krummel MF: Triggering of T Cell Activation via CD4 Dimers. J Immunol. 2006, 176: 5438-5445.","journal-title":"J Immunol"},{"key":"473_CR6","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/ni815","volume":"3","author":"LJ Matthias","year":"2002","unstructured":"Matthias LJ, Yam PT, Jiang XM, Vandegraaff N, Li P, Poumbourios P, Donoghue N, Hogg PJ: Disulfide exchange in domain 2 of CD4 is required for entry of HIV-1. Nat Immunol. 2002, 3: 727-732.","journal-title":"Nat Immunol"},{"key":"473_CR7","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1034\/j.1600-0625.2003.00078.x","volume":"12","author":"GW Lynch","year":"2003","unstructured":"Lynch GW, Slaytor EK, Elliott FD, Saurajen A, Turville SG, Sloane AJ, Cameron PU, Cunningham AL, Halliday GM: CD4 is expressed by epidermal Langerhans' cells predominantly as covalent dimers. Exp Dermatol. 2003, 12: 700-711. 10.1034\/j.1600-0625.2003.00078.x.","journal-title":"Exp Dermatol"},{"key":"473_CR8","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/S0167-5699(98)01325-5","volume":"19","author":"S Li","year":"1998","unstructured":"Li S, Satoh T, Korngold R, Huang Z: CD4 dimerization and oligomerization: implications for T-cell function and structure-based drug design. Immunol Today. 1998, 19: 455-462. 10.1016\/S0167-5699(98)01325-5.","journal-title":"Immunol Today"},{"key":"473_CR9","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1038\/338257a0","volume":"338","author":"A Veillette","year":"1989","unstructured":"Veillette A, Bookman MA, Horak EM, Samelson LE, Bolen JB: Signal transduction through the CD4 receptor involves the activation of the internal membrane tyrosine-protein kinase p56lck. Nature. 1989, 338: 257-259. 10.1038\/338257a0.","journal-title":"Nature"},{"key":"473_CR10","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.4049\/jimmunol.160.4.1875","volume":"160","author":"L Briant","year":"1998","unstructured":"Briant L, Robert-Hebmann V, Sivan V, Brunet A, Pouyssegur J, Devaux C: Involvement of extracellular signal-regulated kinase module in HIV-mediated CD4 signals controlling activation of nuclear factor-kappa B and AP-1 transcription factors. J Immunol. 1998, 160: 1875-1885.","journal-title":"J Immunol"},{"key":"473_CR11","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1038\/387527a0","volume":"387","author":"H Wu","year":"1997","unstructured":"Wu H, Kwong PD, Hendrickson WA: Dimeric association and segmental variability in the structure of human CD4. Nature. 1997, 387: 527-530. 10.1038\/387527a0.","journal-title":"Nature"},{"key":"473_CR12","doi-asserted-by":"crossref","first-page":"16875","DOI":"10.1016\/S0021-9258(19)85274-2","volume":"268","author":"JP Langedijk","year":"1993","unstructured":"Langedijk JP, Puijk WC, van Hoorn WP, Meloen RH: Location of CD4 dimerization site explains critical role of CDR3-like region in HIV-1 infection and T-cell activation and implies a model for complex of coreceptor-MHC. J Biol Chem. 1993, 268: 16875-16878.","journal-title":"J Biol Chem"},{"key":"473_CR13","doi-asserted-by":"publisher","first-page":"19441","DOI":"10.1074\/jbc.272.31.19441","volume":"272","author":"L Briant","year":"1997","unstructured":"Briant L, Signoret N, Gaubin M, Robert-Hebmann V, Zhang X, Murali R, Greene MI, Piatier-Tonneau D, Devaux C: Transduction of activation signal that follows HIV-1 binding to CD4 and CD4 dimerization involves the immunoglobulin CDR3-like region in domain 1 of CD4. J Biol Chem. 1997, 272: 19441-19450. 10.1074\/jbc.272.31.19441.","journal-title":"J Biol Chem"},{"key":"473_CR14","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1126\/science.3003906","volume":"231","author":"T Folks","year":"1986","unstructured":"Folks T, Powell DM, Lightfoote MM, Benn S, Martin MA, Fauci AS: Induction of HTLV-III\/LAV from a nonvirus-producing T-cell line: implications for latency. Science. 1986, 231: 600-602.","journal-title":"Science"},{"key":"473_CR15","doi-asserted-by":"publisher","first-page":"6776","DOI":"10.1128\/JVI.75.15.6776-6785.2001","volume":"75","author":"K Tokunaga","year":"2001","unstructured":"Tokunaga K, Greenberg ML, Morse MA, Cumming RI, Lyerly HK, Cullen BR: Molecular basis for cell tropism of CXCR4-dependent human immunodeficiency virus type 1 isolates. J Virol. 2001, 75: 6776-6785. 10.1128\/JVI.75.15.6776-6785.2001.","journal-title":"J Virol"},{"key":"473_CR16","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1038\/nbt745","volume":"20","author":"M Cavrois","year":"2002","unstructured":"Cavrois M, De Noronha C, Greene WC: A sensitive and specific enzyme-based assay detecting HIV-1 virion fusion in primary T lymphocytes. Nat Biotechnol. 2002, 20: 1151-1154. 10.1038\/nbt745.","journal-title":"Nat Biotechnol"},{"key":"473_CR17","doi-asserted-by":"crossref","first-page":"5559","DOI":"10.1002\/j.1460-2075.1994.tb06893.x","volume":"13","author":"M Benkirane","year":"1994","unstructured":"Benkirane M, Jeang KT, Devaux C: The cytoplasmic domain of CD4 plays a critical role during the early stages of HIV infection in T-cells. Embo J. 1994, 13: 5559-5569.","journal-title":"Embo J"},{"key":"473_CR18","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/S0014-5793(02)02566-8","volume":"516","author":"G Bossis","year":"2002","unstructured":"Bossis G, Salinas S, Cartier C, Devaux C, Briant L: NF-kappaB activation upon interaction of HIV-1 envelope glycoproteins with cell surface CD4 involves IkappaB kinases. FEBS Lett. 2002, 516: 257-264. 10.1016\/S0014-5793(02)02566-8.","journal-title":"FEBS Lett"},{"key":"473_CR19","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1006\/viro.2000.0612","volume":"276","author":"RW Doms","year":"2000","unstructured":"Doms RW: Beyond receptor expression: the influence of receptor conformation, density, and affinity in HIV-1 infection. Virology. 2000, 276: 229-237. 10.1006\/viro.2000.0612.","journal-title":"Virology"},{"key":"473_CR20","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1084\/jem.20030648","volume":"199","author":"C Jolly","year":"2004","unstructured":"Jolly C, Kashefi K, Hollinshead M, Sattentau QJ: HIV-1 cell to cell transfer across an Env-induced, actin-dependent synapse. J Exp Med. 2004, 199: 283-293. 10.1084\/jem.20030648.","journal-title":"J Exp Med"},{"key":"473_CR21","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1016\/j.yexcr.2004.11.022","volume":"304","author":"DH Nguyen","year":"2005","unstructured":"Nguyen DH, Giri B, Collins G, Taub DD: Dynamic reorganization of chemokine receptors, cholesterol, lipid rafts, and adhesion molecules to sites of CD4 engagement. Exp Cell Res. 2005, 304: 559-569. 10.1016\/j.yexcr.2004.11.022.","journal-title":"Exp Cell Res"},{"key":"473_CR22","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1124\/jpet.103.064956","volume":"310","author":"PT Toth","year":"2004","unstructured":"Toth PT, Ren D, Miller RJ: Regulation of CXCR4 receptor dimerization by the chemokine SDF-1alpha and the HIV-1 coat protein gp120: a fluorescence resonance energy transfer (FRET) study. J Pharmacol Exp Ther. 2004, 310: 8-17. 10.1124\/jpet.103.064956.","journal-title":"J Pharmacol Exp Ther"},{"key":"473_CR23","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1089\/aid.1996.12.1001","volume":"12","author":"N Signoret","year":"1996","unstructured":"Signoret N, Blanc-Zouaoui D, Kwong PD, Sattentau QJ: Selective effects of electrostatic changes in the CD4 CDR-3-like loop on infection by different human immunodeficiency virus type 1 isolates. AIDS Res Hum Retroviruses. 1996, 12: 1001-1013.","journal-title":"AIDS Res Hum Retroviruses"},{"key":"473_CR24","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1084\/jem.172.4.1233","volume":"172","author":"D Healey","year":"1990","unstructured":"Healey D, Dianda L, Moore JP, McDougal JS, Moore MJ, Estess P, Buck D, Kwong PD, Beverley PC, Sattentau QJ: Novel anti-CD4 monoclonal antibodies separate human immunodeficiency virus infection and fusion of CD4+ cells from virus binding. J Exp Med. 1990, 172: 1233-1242. 10.1084\/jem.172.4.1233.","journal-title":"J Exp Med"},{"key":"473_CR25","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1038\/312159a0","volume":"312","author":"D Celander","year":"1984","unstructured":"Celander D, Haseltine WA: Tissue-specific transcription preference as a determinant of cell tropism and leukaemogenic potential of murine retroviruses. Nature. 1984, 312: 159-162.","journal-title":"Nature"},{"key":"473_CR26","doi-asserted-by":"publisher","first-page":"28346","DOI":"10.1074\/jbc.M300327200","volume":"278","author":"K Levesque","year":"2003","unstructured":"Levesque K, Zhao YS, Cohen EA: Vpu exerts a positive effect on HIV-1 infectivity by down-modulating CD4 receptor molecules at the surface of HIV-1-producing cells. J Biol Chem. 2003, 278: 28346-28353. 10.1074\/jbc.M300327200.","journal-title":"J Biol Chem"},{"key":"473_CR27","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1097\/00042560-199501000-00004","volume":"8","author":"J Friborg","year":"1995","unstructured":"Friborg J, Ladha A, Gottlinger H, Haseltine WA, Cohen EA: Functional analysis of the phosphorylation sites on the human immunodeficiency virus type 1 Vpu protein. J Acquir Immune Defic Syndr Hum Retrovirol. 1995, 8: 10-22.","journal-title":"J Acquir Immune Defic Syndr Hum Retrovirol"}],"container-title":["Retrovirology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1742-4690-3-31.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,7]],"date-time":"2023-05-07T17:28:02Z","timestamp":1683480482000},"score":1,"resource":{"primary":{"URL":"https:\/\/retrovirology.biomedcentral.com\/articles\/10.1186\/1742-4690-3-31"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,6,8]]},"references-count":27,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2006,12]]}},"alternative-id":["473"],"URL":"https:\/\/doi.org\/10.1186\/1742-4690-3-31","relation":{},"ISSN":["1742-4690"],"issn-type":[{"value":"1742-4690","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,6,8]]},"assertion":[{"value":"24 April 2006","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 June 2006","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 June 2006","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"31"}}