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J Virol. Aug 1992; 66(8): 4784–4793.
PMCID: PMC241306

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.

Abstract

The murine monoclonal antibody (MAb) 5A8, which is reactive with domain 2 of CD4, blocks human immunodeficiency virus type 1 (HIV-1) infection and syncytium formation of CD4+ cells (L. C. Burkly, D. Olson, R. Shapiro, G. Winkler, J. J. Rosa, D. W. Thomas, C. Williams, and P. Chisholm, J. Immunol., in press). Here we show that, in contrast to the CD4 domain 1 MAb 6H10, 5A8 and its Fab fragment do not block soluble CD4 (sCD4) binding to virions, whereas they do inhibit sCD4-induced exposure of cryptic epitopes on gp41 and dissociation of gp120 from virions. Two other MAbs, OKT4 and L120, which are reactive with domains 3 and 4 of CD4, have little or no effect on HIV-1 infection, syncytium formation, or sCD4-induced conformational changes in the envelope glycoproteins. The mechanisms of action of 5A8 and 6H10 can be further distinguished in syncytium inhibition assays: 6H10 blocks competitively, while 5A8 does not. We opine that 5A8 blocks HIV-1 infection and fusion by interfering with conformational changes in gp120/gp41 and/or CD4 that are necessary for virus-cell fusion.

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  • Allan JS. Receptor-mediated activation of immunodeficiency viruses in viral fusion. Science. 1991 May 31;252(5010):1322–1323. [PubMed]
  • Allan JS, Strauss J, Buck DW. Enhancement of SIV infection with soluble receptor molecules. Science. 1990 Mar 2;247(4946):1084–1088. [PubMed]
  • Ashorn PA, Berger EA, Moss B. Human immunodeficiency virus envelope glycoprotein/CD4-mediated fusion of nonprimate cells with human cells. J Virol. 1990 May;64(5):2149–2156. [PMC free article] [PubMed]
  • 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. [PubMed]
  • Celada F, Cambiaggi C, Maccari J, Burastero S, Gregory T, Patzer E, Porter J, McDanal C, Matthews T. Antibody raised against soluble CD4-rgp120 complex recognizes the CD4 moiety and blocks membrane fusion without inhibiting CD4-gp120 binding. J Exp Med. 1990 Oct 1;172(4):1143–1150. [PMC free article] [PubMed]
  • Clapham PR, Blanc D, Weiss RA. Specific cell surface requirements for the infection of CD4-positive cells by human immunodeficiency virus types 1 and 2 and by Simian immunodeficiency virus. Virology. 1991 Apr;181(2):703–715. [PubMed]
  • Clapham PR, McKnight A, Weiss RA. Human immunodeficiency virus type 2 infection and fusion of CD4-negative human cell lines: induction and enhancement by soluble CD4. J Virol. 1992 Jun;66(6):3531–3537. [PMC free article] [PubMed]
  • Clapham PR, Weber JN, Whitby D, McIntosh K, Dalgleish AG, Maddon PJ, Deen KC, Sweet RW, Weiss RA. Soluble CD4 blocks the infectivity of diverse strains of HIV and SIV for T cells and monocytes but not for brain and muscle cells. Nature. 1989 Jan 26;337(6205):368–370. [PubMed]
  • Dalgleish AG, Beverley PC, Clapham PR, Crawford DH, Greaves MF, Weiss RA. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature. 1984 Dec 20;312(5996):763–767. [PubMed]
  • Dimitrov DS, 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. [PubMed]
  • Dimitrov DS, Hillman K, Manischewitz J, Blumenthal R, Golding H. Kinetics of soluble CD4 binding to cells expressing human immunodeficiency virus type 1 envelope glycoprotein. J Virol. 1992 Jan;66(1):132–138. [PMC free article] [PubMed]
  • Grewe C, Beck A, Gelderblom HR. HIV: early virus-cell interactions. J Acquir Immune Defic Syndr. 1990;3(10):965–974. [PubMed]
  • Hart TK, Kirsh R, Ellens H, Sweet RW, Lambert DM, Petteway SR, Jr, Leary J, Bugelski PJ. 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. [PMC free article] [PubMed]
  • 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 Oct 1;172(4):1233–1242. [PMC free article] [PubMed]
  • Kirsh R, Hart TK, Ellens H, Miller J, Petteway SA, Jr, Lambert DM, Leary J, Bugelski PJ. 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. [PubMed]
  • Klasse PJ, Moore JP. Kinetics of the HIV-CD4 interactions and virus-cell fusion. AIDS. 1992 Mar;6(3):325–327. [PubMed]
  • Klatzmann D, Champagne E, Chamaret S, Gruest J, Guetard D, Hercend T, Gluckman JC, Montagnier L. T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature. 1984 Dec 20;312(5996):767–768. [PubMed]
  • Kowalski M, Potz J, Basiripour L, Dorfman T, Goh WC, Terwilliger E, Dayton A, Rosen C, Haseltine W, Sodroski J. Functional regions of the envelope glycoprotein of human immunodeficiency virus type 1. Science. 1987 Sep 11;237(4820):1351–1355. [PubMed]
  • Lasky LA, Nakamura G, Smith DH, Fennie C, Shimasaki C, Patzer E, Berman P, Gregory T, Capon DJ. Delineation of a region of the human immunodeficiency virus type 1 gp120 glycoprotein critical for interaction with the CD4 receptor. Cell. 1987 Sep 11;50(6):975–985. [PubMed]
  • Layne SP, Merges MJ, Dembo M, Spouge JL, Nara PL. HIV requires multiple gp120 molecules for CD4-mediated infection. Nature. 1990 Jul 19;346(6281):277–279. [PubMed]
  • Lifson JD, Rausch DM, Kalyanaraman VS, Hwang KM, Eiden LE. 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. [PubMed]
  • Maddon PJ, Dalgleish AG, McDougal JS, Clapham PR, Weiss RA, Axel R. The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell. 1986 Nov 7;47(3):333–348. [PubMed]
  • McClure MO, Marsh M, Weiss RA. Human immunodeficiency virus infection of CD4-bearing cells occurs by a pH-independent mechanism. EMBO J. 1988 Feb;7(2):513–518. [PMC free article] [PubMed]
  • McDougal JS, Kennedy MS, Sligh JM, Cort SP, Mawle A, Nicholson JK. Binding of HTLV-III/LAV to T4+ T cells by a complex of the 110K viral protein and the T4 molecule. Science. 1986 Jan 24;231(4736):382–385. [PubMed]
  • McDougal JS, Nicholson JK, Cross GD, Cort SP, Kennedy MS, Mawle AC. Binding of the human retrovirus HTLV-III/LAV/ARV/HIV to the CD4 (T4) molecule: conformation dependence, epitope mapping, antibody inhibition, and potential for idiotypic mimicry. J Immunol. 1986 Nov 1;137(9):2937–2944. [PubMed]
  • McKeating JA, McKnight A, Moore JP. Differential loss of envelope glycoprotein gp120 from virions of human immunodeficiency virus type 1 isolates: effects on infectivity and neutralization. J Virol. 1991 Feb;65(2):852–860. [PMC free article] [PubMed]
  • Moore JP. Simple methods for monitoring HIV-1 and HIV-2 gp120 binding to soluble CD4 by enzyme-linked immunosorbent assay: HIV-2 has a 25-fold lower affinity than HIV-1 for soluble CD4. AIDS. 1990 Apr;4(4):297–305. [PubMed]
  • Moore JP, Klasse PJ. Thermodynamic and kinetic analysis of sCD4 binding to HIV-1 virions and of gp120 dissociation. AIDS Res Hum Retroviruses. 1992 Apr;8(4):443–450. [PubMed]
  • Moore JP, McKeating JA, Huang YX, Ashkenazi A, Ho DD. Virions of primary human immunodeficiency virus type 1 isolates resistant to soluble CD4 (sCD4) neutralization differ in sCD4 binding and glycoprotein gp120 retention from sCD4-sensitive isolates. J Virol. 1992 Jan;66(1):235–243. [PMC free article] [PubMed]
  • Moore JP, McKeating JA, Norton WA, Sattentau QJ. 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. [PMC free article] [PubMed]
  • Allan JS. Receptor-mediated activation of immunodeficiency viruses in viral fusion. Science. 1991 May 31;252(5010):1322–1323. [PubMed]
  • Moore JP, McKeating JA, Weiss RA, Sattentau QJ. Dissociation of gp120 from HIV-1 virions induced by soluble CD4. Science. 1990 Nov 23;250(4984):1139–1142. [PubMed]
  • Sattentau QJ, Arthos J, Deen K, Hanna N, Healey D, Beverley PC, 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. [PMC free article] [PubMed]
  • Sattentau QJ, Moore JP. Conformational changes induced in the human immunodeficiency virus envelope glycoprotein by soluble CD4 binding. J Exp Med. 1991 Aug 1;174(2):407–415. [PMC free article] [PubMed]
  • Stein BS, Gowda SD, Lifson JD, Penhallow RC, Bensch KG, Engleman EG. pH-independent HIV entry into CD4-positive T cells via virus envelope fusion to the plasma membrane. Cell. 1987 Jun 5;49(5):659–668. [PubMed]
  • Thali M, Olshevsky U, Furman C, Gabuzda D, Li J, Sodroski J. Effects of changes in gp120-CD4 binding affinity on human immunodeficiency virus type 1 envelope glycoprotein function and soluble CD4 sensitivity. J Virol. 1991 Sep;65(9):5007–5012. [PMC free article] [PubMed]
  • Truneh A, Buck D, Cassatt DR, Juszczak R, Kassis S, Ryu SE, 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]
  • Watanabe M, Levine CG, Shen L, Fisher RA, Letvin NL. Immunization of simian immunodeficiency virus-infected rhesus monkeys with soluble human CD4 elicits an antiviral response. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4616–4620. [PMC free article] [PubMed]
  • Xu JY, Gorny MK, Palker T, Karwowska S, Zolla-Pazner S. Epitope mapping of two immunodominant domains of gp41, the transmembrane protein of human immunodeficiency virus type 1, using ten human monoclonal antibodies. J Virol. 1991 Sep;65(9):4832–4838. [PMC free article] [PubMed]

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