Skip to main content
Journal of Virology logoLink to Journal of Virology
. 1993 Jun;67(6):3656–3659. doi: 10.1128/jvi.67.6.3656-3659.1993

A monoclonal antibody to the CDR-3 region of CD4 inhibits soluble CD4 binding to virions of human immunodeficiency virus type 1.

J P Moore 1
PMCID: PMC237720  PMID: 8497074

Abstract

The CDR-3 region of CD4 has been proposed to be involved in the fusion reaction between human immunodeficiency virus type 1 (HIV-1) and CD4+ cells, either at a stage involving virus binding or subsequent to virus binding. Part of the evidence for this has been the observation that monoclonal antibodies (MAbs) to CDR-3 block HIV infection potently without strongly inhibiting the binding of monomeric gp120 to CD4. Here I show that, in a system using oligomeric, virion-bound gp120, a MAb to CDR-3 resembles those to CDR-2 in that it inhibits soluble CD4 binding to virions. Consequently, ternary complexes of MAb-soluble CD4-gp120 cannot be detected with CDR-2 MAbs and are detectable only at a very low level with a CDR-3 MAb, but they clearly form when a control MAb to CD4 domain 4 is used. Although not in direct conflict with previously published data on the role of CDR-3 MAbs in the inhibition of HIV-1 infection, these experiments do not support the hypothesis that the CDR-3 region is specifically involved in virus entry at a postbinding stage.

Full text

PDF

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arthos J., Deen K. C., Chaikin M. A., Fornwald J. A., Sathe G., Sattentau Q. J., Clapham P. R., Weiss R. A., McDougal J. S., Pietropaolo C. Identification of the residues in human CD4 critical for the binding of HIV. Cell. 1989 May 5;57(3):469–481. doi: 10.1016/0092-8674(89)90922-7. [DOI] [PubMed] [Google Scholar]
  2. Ashkenazi A., Presta L. G., Marsters S. A., Camerato T. R., Rosenthal K. A., Fendly B. M., Capon D. J. Mapping the CD4 binding site for human immunodeficiency virus by alanine-scanning mutagenesis. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7150–7154. doi: 10.1073/pnas.87.18.7150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Batinić D., Robey F. A. The V3 region of the envelope glycoprotein of human immunodeficiency virus type 1 binds sulfated polysaccharides and CD4-derived synthetic peptides. J Biol Chem. 1992 Apr 5;267(10):6664–6671. [PubMed] [Google Scholar]
  4. Berger E. A., Lifson J. D., Eiden L. E. Stimulation of glycoprotein gp120 dissociation from the envelope glycoprotein complex of human immunodeficiency virus type 1 by soluble CD4 and CD4 peptide derivatives: implications for the role of the complementarity-determining region 3-like region in membrane fusion. Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):8082–8086. doi: 10.1073/pnas.88.18.8082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bugelski P. J., Ellens H., Hart T. K., Kirsh R. L. Soluble CD4 and dextran sulfate mediate release of gp120 from HIV-1: implications for clinical trials. J Acquir Immune Defic Syndr. 1991;4(9):923–924. [PubMed] [Google Scholar]
  6. Callahan L. N., Phelan M., Mallinson M., Norcross M. A. Dextran sulfate blocks antibody binding to the principal neutralizing domain of human immunodeficiency virus type 1 without interfering with gp120-CD4 interactions. J Virol. 1991 Mar;65(3):1543–1550. doi: 10.1128/jvi.65.3.1543-1550.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Camerini D., Seed B. A CD4 domain important for HIV-mediated syncytium formation lies outside the virus binding site. Cell. 1990 Mar 9;60(5):747–754. doi: 10.1016/0092-8674(90)90089-w. [DOI] [PubMed] [Google Scholar]
  8. Capon D. J., Ward R. H. The CD4-gp120 interaction and AIDS pathogenesis. Annu Rev Immunol. 1991;9:649–678. doi: 10.1146/annurev.iy.09.040191.003245. [DOI] [PubMed] [Google Scholar]
  9. Choe H. R., Sodroski J. Contribution of charged amino acids in the CDR2 region of CD4 to HIV-1 gp120 binding. J Acquir Immune Defic Syndr. 1992;5(2):204–210. [PubMed] [Google Scholar]
  10. Corbeau P., Benkirane M., Weil R., David C., Emiliani S., Olive D., Mawas C., Serre A., Devaux C. Ig CDR3-like region of the CD4 molecule is involved in HIV-induced syncytia formation but not in viral entry. J Immunol. 1993 Jan 1;150(1):290–301. [PubMed] [Google Scholar]
  11. Dimitrov D. S., Golding H., Blumenthal R. Initial stages of HIV-1 envelope glycoprotein-mediated cell fusion monitored by a new assay based on redistribution of fluorescent dyes. AIDS Res Hum Retroviruses. 1991 Oct;7(10):799–805. doi: 10.1089/aid.1991.7.799. [DOI] [PubMed] [Google Scholar]
  12. Eiden L. E., Lifson J. D. HIV interactions with CD4: a continuum of conformations and consequences. Immunol Today. 1992 Jun;13(6):201–206. doi: 10.1016/0167-5699(92)90154-Y. [DOI] [PubMed] [Google Scholar]
  13. Hart T. K., Kirsh R., Ellens H., Sweet R. W., Lambert D. M., Petteway S. R., Jr, Leary J., Bugelski P. J. Binding of soluble CD4 proteins to human immunodeficiency virus type 1 and infected cells induces release of envelope glycoprotein gp120. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2189–2193. doi: 10.1073/pnas.88.6.2189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kalyanaraman V. S., Rausch D. M., Osborne J., Padgett M., Hwang K. M., Lifson J. D., Eiden L. E. Evidence by peptide mapping that the region CD4(81-92) is involved in gp120/CD4 interaction leading to HIV infection and HIV-induced syncytium formation. J Immunol. 1990 Dec 15;145(12):4072–4078. [PubMed] [Google Scholar]
  15. Kirsh R., Hart T. K., Ellens H., Miller J., Petteway S. A., Jr, Lambert D. M., Leary J., Bugelski P. J. Morphometric analysis of recombinant soluble CD4-mediated release of the envelope glycoprotein gp120 from HIV-1. AIDS Res Hum Retroviruses. 1990 Oct;6(10):1209–1212. doi: 10.1089/aid.1990.6.1209. [DOI] [PubMed] [Google Scholar]
  16. Lifson J. D., Hwang K. M., Nara P. L., Fraser B., Padgett M., Dunlop N. M., Eiden L. E. Synthetic CD4 peptide derivatives that inhibit HIV infection and cytopathicity. Science. 1988 Aug 5;241(4866):712–716. doi: 10.1126/science.2969619. [DOI] [PubMed] [Google Scholar]
  17. Lifson J. D., Rausch D. M., Kalyanaraman V. S., Hwang K. M., Eiden L. E. Synthetic peptides allow discrimination of structural features of CD4(81-92) important for HIV-1 infection versus HIV-1-induced syncytium formation. AIDS Res Hum Retroviruses. 1991 Jun;7(6):521–527. doi: 10.1089/aid.1991.7.521. [DOI] [PubMed] [Google Scholar]
  18. McDonnell J. M., Blank K. J., Rao P. E., Jameson B. A. Direct involvement of the CDR3-like domain of CD4 in T helper cell activation. J Immunol. 1992 Sep 1;149(5):1626–1630. [PubMed] [Google Scholar]
  19. Moore J. P., McKeating J. A., Norton W. A., Sattentau Q. J. Direct measurement of soluble CD4 binding to human immunodeficiency virus type 1 virions: gp120 dissociation and its implications for virus-cell binding and fusion reactions and their neutralization by soluble CD4. J Virol. 1991 Mar;65(3):1133–1140. doi: 10.1128/jvi.65.3.1133-1140.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Moore J. P., McKeating J. A., Weiss R. A., Sattentau Q. J. Dissociation of gp120 from HIV-1 virions induced by soluble CD4. Science. 1990 Nov 23;250(4984):1139–1142. doi: 10.1126/science.2251501. [DOI] [PubMed] [Google Scholar]
  21. Moore J. P., Sattentau Q. J., Klasse P. J., Burkly L. C. A monoclonal antibody to CD4 domain 2 blocks soluble CD4-induced conformational changes in the envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) and HIV-1 infection of CD4+ cells. J Virol. 1992 Aug;66(8):4784–4793. doi: 10.1128/jvi.66.8.4784-4793.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nara P. L., Hwang K. M., Rausch D. M., Lifson J. D., Eiden L. E. CD4 antigen-based antireceptor peptides inhibit infectivity of human immunodeficiency virus in vitro at multiple stages of the viral life cycle. Proc Natl Acad Sci U S A. 1989 Sep;86(18):7139–7143. doi: 10.1073/pnas.86.18.7139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ohki K., Kimura T., Ohmura K., Kato S., Ikuta K. Blocking of HIV-1 infection, but not HIV-1-induced syncytium formation, by a CD4 peptide derivative partly corresponding to an immunoglobulin CDR3. AIDS. 1990 Nov;4(11):1160–1161. doi: 10.1097/00002030-199011000-00020. [DOI] [PubMed] [Google Scholar]
  24. Olshevsky U., Helseth E., Furman C., Li J., Haseltine W., Sodroski J. Identification of individual human immunodeficiency virus type 1 gp120 amino acids important for CD4 receptor binding. J Virol. 1990 Dec;64(12):5701–5707. doi: 10.1128/jvi.64.12.5701-5707.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Repke H., Gabuzda D., Palù G., Emmrich F., Sodroski J. Effects of CD4 synthetic peptides on HIV type I envelope glycoprotein function. J Immunol. 1992 Sep 1;149(5):1809–1816. [PubMed] [Google Scholar]
  26. Ryu S. E., Kwong P. D., Truneh A., Porter T. G., Arthos J., Rosenberg M., Dai X. P., Xuong N. H., Axel R., Sweet R. W. Crystal structure of an HIV-binding recombinant fragment of human CD4. Nature. 1990 Nov 29;348(6300):419–426. doi: 10.1038/348419a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sattentau Q. J., Arthos J., Deen K., Hanna N., Healey D., Beverley P. C., Sweet R., Truneh A. Structural analysis of the human immunodeficiency virus-binding domain of CD4. Epitope mapping with site-directed mutants and anti-idiotypes. J Exp Med. 1989 Oct 1;170(4):1319–1334. doi: 10.1084/jem.170.4.1319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sattentau Q. J., Weiss R. A. The CD4 antigen: physiological ligand and HIV receptor. Cell. 1988 Mar 11;52(5):631–633. doi: 10.1016/0092-8674(88)90397-2. [DOI] [PubMed] [Google Scholar]
  29. Schockmel G. A., Somoza C., Davis S. J., Williams A. F., Healey D. Construction of a binding site for human immunodeficiency virus type 1 gp120 in rat CD4. J Exp Med. 1992 Jan 1;175(1):301–304. doi: 10.1084/jem.175.1.301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Shapira-Nahor O., Golding H., Vujcic L. K., Resto-Ruiz S., Fields R. L., Robey F. A. CD4-derived synthetic peptide blocks the binding of HIV-1 GP120 to CD4-bearing cells and prevents HIV-1 infection. Cell Immunol. 1990 Jun;128(1):101–117. doi: 10.1016/0008-8749(90)90010-o. [DOI] [PubMed] [Google Scholar]
  31. Sweet R. W., Truneh A., Hendrickson W. A. CD4: its structure, role in immune function and AIDS pathogenesis, and potential as a pharmacological target. Curr Opin Biotechnol. 1991 Aug;2(4):622–633. doi: 10.1016/0958-1669(91)90089-n. [DOI] [PubMed] [Google Scholar]
  32. Thali M., Furman C., Helseth E., Repke H., Sodroski J. Lack of correlation between soluble CD4-induced shedding of the human immunodeficiency virus type 1 exterior envelope glycoprotein and subsequent membrane fusion events. J Virol. 1992 Sep;66(9):5516–5524. doi: 10.1128/jvi.66.9.5516-5524.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Truneh A., Buck D., Cassatt D. R., Juszczak R., Kassis S., Ryu S. E., Healey D., Sweet R., Sattentau Q. A region in domain 1 of CD4 distinct from the primary gp120 binding site is involved in HIV infection and virus-mediated fusion. J Biol Chem. 1991 Mar 25;266(9):5942–5948. [PubMed] [Google Scholar]
  34. Wang J. H., Yan Y. W., Garrett T. P., Liu J. H., Rodgers D. W., Garlick R. L., Tarr G. E., Husain Y., Reinherz E. L., Harrison S. C. Atomic structure of a fragment of human CD4 containing two immunoglobulin-like domains. Nature. 1990 Nov 29;348(6300):411–418. doi: 10.1038/348411a0. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES