In vitro selection of dextran sulfate-resistant strains of human immunodeficiency virus. Impact in the understanding of virus-cell binding and virus-cell fusion in the development of new anti-HIV agents.
Int Conf AIDS 1996 Jul 7-12; 11:213 (abstract no. Th.A.152) Este JA, Schols D, Desmyter J, De Clercq E; Rega Institute for Medical Research, Leuven, Belgium. Fax: 32-16-33.73.40.
Polyanions are potent inhibitors of Human Immunodeficiency Virus (HIV) types 1 and 2 in vitro. Polyanionic compounds are known to inhibit virus binding to CD4 positive cells or to inhibit the fusion step of viral infection. Compounds such as dextran sulfate (DS) and heparin have been the subject of detailed study for their anti-HIV-1 properties and serve as important tools for the study of the mechanism of virus binding and the subsequent fusion process. HIV-1 strains resistant to DS were raised. HIV-1 NL43 was cultured on MT-4 cells in the presence of DS (molecular weight 5,000) at an initial concentration that approximated 5 x the 50% effective concentration (EC50: 0.5 microgram/ml), which was then gradually raised during each subsequent passage, so that DS-resistant virus, growing in the presence of 5 mg/ml could be isolated after 20 passages (100 days). The DS-resistant strain was also up to 250-fold less sensitive to heparin than the wild-type strain. DS did not inhibit syncytium formation between MOLT-4 cells and HUT-78 cells persistently infected with the DS-resistant virus at concentrations up to 125 micrograms/ml. Furthermore, flow cytometric analysis revealed that a monoclonal antibody with specificity for the NTRKSIRIQRG region in the V3 loop of gp120 was recognized by the wild-type strain but not by the DS-resistant strain. DNA sequence analysis of DS-resistant strains will clarify which specific amino acid(s) are responsible for resistance to the polyanions. Although DS and heparin are at present not considered as antiviral agents due to their adverse effects in vivo, a clear understanding of their mechanism of action is relevant to the development of new anti-HIV agents. Compounds such as cosalane, GSPH-1, G-rich oligonucleotides (virus-binding inhibitors), and the bicyclams (fusion/uncoating inhibitors), among others, are being studied as drug candidates for anti-HIV therapy. These compounds share similarities with DS and heparin in their mechanism of action. Their resistance pattern and rate of resistance development might be crucial in determining the efficacy of such compounds as it has been shown with reverse transcriptase inhibitors. This is the first report of the development of HIV resistance to dextran sulfate.
Keywords: AEGIS, Anti-HIV Agents, HIV, Dextran Sulfate, Cell Fusion, HIV-1, Reverse Transcriptase Inhibitors, Antiviral Agents, HIV Envelope Protein gp120, HIV-1 Reverse Transcriptase, Giant Cells, Selection (Genetics), Antigens, CD4, Heterocyclic Compounds, Receptors, HIV, HIV Antibodies, HIV Integrase, JM 3100, Human, In Vitro, genetics, ICA11
