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Molecular Pharmacology

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Research ArticleArticle

Development of Resistance of Human Immunodeficiency Virus Type 1 to Dextran Sulfate Associated with the Emergence of Specific Mutations in the Envelope gp120 Glycoprotein

José A. Esté, Dominique Schols, Karen De Vreese, Kristel Van Laethem, Anne-Mieke Vandamme, Jan Desmyter and Erik De Clercq
Molecular Pharmacology July 1997, 52 (1) 98-104; DOI: https://doi.org/10.1124/mol.52.1.98
José A. Esté
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
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Dominique Schols
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
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Karen De Vreese
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
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Kristel Van Laethem
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
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Anne-Mieke Vandamme
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
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Jan Desmyter
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
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Erik De Clercq
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
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Abstract

Polyanionic compounds are known to inhibit the binding of human immunodeficiency virus (HIV) to CD4+ cells and the subsequent fusion step between the virus and cells. We selected an HIV-1 strain resistant to dextran sulfate (DS) by cultivation of HIV-1 (NL4–3)-infected MT-4 cells in the presence of DSM r 5000. DS did not inhibit the binding of DS-resistant virus to MT-4 cells or syncytium formation between MOLT cells and HUT-78 cells persistently infected with the DS-resistant virus. In addition, a monoclonal antibody with specificity for the V3 loop of envelope gp120 glycoprotein did not recognize the DS-resistant HIV-1 gp120 V3 loop. The following mutations were found in the gp120 molecule of the DS-resistant HIV-1 strain but not in the wild-type strain: S114N in the V1 loop region; S134N in the V2 loop region; K269E, Q278H, and N293D in the V3 loop region; N323S in the C3 region; a deletion of five amino acids (Phe-Asn-Ser-Thr-Trp) at positions 364–368 in the V4 loop; and R387I in the CD4 binding domain. Our results suggest that (i) DS interacts with specific amino acid residues in the gp120 molecule, (ii) the virus is able to overcome the inhibitory effect of DS on viral infectivity, (iii) cross-resistance developed against those polyanionic compounds that are structurally related to DS, and (iv) the molecular determinants of HIV cell tropism, syncytium-inducing ability, coreceptor (fusin/CC-CKR5) utilization, and polyanion resistance seem to be located in the envgenome of HIV and specifically in the V3 loop domain.

Footnotes

    • Received December 4, 1996.
    • Accepted February 10, 1997.
  • Send reprint requests to: Dr. José A. Esté, Fundació IRSI-CAIXA, Hospital Universitari Germans Trias i Pujol, Lab of Retrovirology, CTRA del Canyet s/n, 08916 Badalona, Spain. E-mail:jaeste{at}ns.hugtip.scs.es

  • ↵1 Current affiliation: Fundació IRSI-CAIXA, Retrovirology Laboratory, 08916 Badalona, Spain.

  • This work was supported in part by the Biomedical Research Program of the European Commission and Janssen Research Foundation and by grants from the Belgian Geconcerteerde Onderzoeksacties and Nationaal Fonds voor Wetenschappelijk Onderzoek. J.A.E. is a Fellow from Banco Interamericano de Desarrolio-Consejo Nacional de Ciencia y Tecnologica (Venezuela).

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Molecular Pharmacology: 52 (1)
Molecular Pharmacology
Vol. 52, Issue 1
1 Jul 1997
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Research ArticleArticle

Development of Resistance of Human Immunodeficiency Virus Type 1 to Dextran Sulfate Associated with the Emergence of Specific Mutations in the Envelope gp120 Glycoprotein

José A. Esté, Dominique Schols, Karen De Vreese, Kristel Van Laethem, Anne-Mieke Vandamme, Jan Desmyter and Erik De Clercq
Molecular Pharmacology July 1, 1997, 52 (1) 98-104; DOI: https://doi.org/10.1124/mol.52.1.98

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Research ArticleArticle

Development of Resistance of Human Immunodeficiency Virus Type 1 to Dextran Sulfate Associated with the Emergence of Specific Mutations in the Envelope gp120 Glycoprotein

José A. Esté, Dominique Schols, Karen De Vreese, Kristel Van Laethem, Anne-Mieke Vandamme, Jan Desmyter and Erik De Clercq
Molecular Pharmacology July 1, 1997, 52 (1) 98-104; DOI: https://doi.org/10.1124/mol.52.1.98
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