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

  1. José A. Esté1,
  2. Dominique Schols,
  3. Karen De Vreese,
  4. Kristel Van Laethem,
  5. Anne-Mieke Vandamme,
  6. Jan Desmyter and
  7. Erik De Clercq
  1. Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium

    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

    • 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.

    • ↵2 J. A. Esté, D. Schols, P. Proust, S. Struyf, A. Wuyts, J. Van Damme, J. Desmyter, and E. De Clercq. Interaction of polyanions with β-chemokine receptors, manuscript in preparation.

    • 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).

    • Abbreviations:
      HIV
      human immunodeficiency virus
      mAb
      monoclonal antibody
      SI
      syncytium-inducing
      HSA
      human serum albumin
      DS
      dextran sulfate
      DSr
      dextran sulfate resistant
      CDS
      cyclodextrin sulfate
      PCR
      polymerase chain reaction
      CPE
      cytopathic effect
      MT
      macrophage-tropic
      MTT
      3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
      ATA
      aurintricarboxylic acid
      PBS
      phosphate-buffered saline
      • Received December 4, 1996.
      • Accepted February 10, 1997.
    « Previous | Next Article »Table of Contents

    This Article

    1. Molecular Pharmacology July 1, 1997 vol. 52 no. 1 98-104
    1. » Abstract
    2. Full Text
    3. Full Text (PDF)

    Classifications

    Responses

    1. Submit a response
    2. No responses published

    Current Issue

    1. November 2009, 76 (5)
    1. Current Issue
    1. Alert me to new issues of Molecular Pharmacology