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Anti-human immunodeficiency virus (HIV) drug HOE/BAY 946 increases membrane hydrophobicity of human lymphocytes and specifically suppresses HIV-protein synthesis

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Abstract

The polysulfated polyxylan HOE/BAY 946, which has been tested in two pilot studies in ARC/AIDS patients and in asymptomatic HIV carriers in Germany, was believed to act by inhibiting virus attachment to the cell. However, the drug was also found to reduce the amount of HIV particles released from infected peripheral blood mononuclear cells (PBMC) in vitro. Furthermore, preincubation of PBMC with the drug led to a partial inhibition of a following HIV infection, suggesting that the drug also affects virus entry. Electron Paramagnetic Resonance (EPR) measurements on uninfected human lymphocytes using 5-proxyl-nonane as spin label demonstrated smaller hyperfine coupling constant (aN) values in the presence of HOE/BAY 946 or dextran sulfate 5000. Accordingly, h-1P/h-1H ratios were decreased, indicating increased plasma membrane hydrophobicity and a membrane-stabilizing effect of the drugs. Culture of the chronically HIV-infected monocytic cell line U937/HIV-2D194 in the presence of HOE/BAY 946 specifically and drastically reduced the release of virions and the intracellular synthesis of viral proteins as determined by radioimmunoprecipitation and reverse transcriptase assays. In conclusion, although the EPR studies showed a physico-chemical effect on membrane polarity, HOE/BAY 946 and dextran sulfate clearly affect processes beyond the cell membrane. Thus, in contrast to previous reports suggesting that polysulfated sugars affect HIV only by inhibiting virus binding to uninfected cells, they clearly inhibit HIV in infected cells as well and appear to have a pleiotropic mode of action. Such drugs may be less likely to result in viral resistance after prolonged application than substances acting only on one step in the life cycle of the virus.

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Authors and Affiliations

  1. Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 70, Frankfurt, Federal Republic of Germany

    Lothar Biesert, Michalina Adamski, Hary Suhartono & Helga Rübsamen-Waigmann

  2. Zentrum der Biologischen Chemie, Arbeitsgruppe Membranstruktur, Theodor-Stern-Kai 7, 70, Frankfurt, Federal Republic of Germany

    Guido Zimmer

  3. Zentrum der Dermatologie und Venerologie, Abteilung II, Theodor-Stern-Kai 7, 70, Frankfurt, Federal Republic of Germany

    Jürgen Fuchs & Rainer Milbradt

  4. Zentrum der Inneren Medizin, Zentrallabor, Klinikum der Johann-Wolfgang-Goethe-Universität, Theodor-Stern-Kai 7, 70, Frankfurt, Federal Republic of Germany

    Uwe Unkelbach

  5. Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA

    Rolf J. Mehlhorn

  6. Central Laboratory Chemistry, University of Pécs, Pécs, Hungary

    Katman Hideg

Authors
  1. Lothar Biesert
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  2. Michalina Adamski
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  3. Guido Zimmer
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  4. Hary Suhartono
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  5. Jürgen Fuchs
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  6. Uwe Unkelbach
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  7. Rolf J. Mehlhorn
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  8. Katman Hideg
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  9. Rainer Milbradt
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  10. Helga Rübsamen-Waigmann
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Biesert, L., Adamski, M., Zimmer, G. et al. Anti-human immunodeficiency virus (HIV) drug HOE/BAY 946 increases membrane hydrophobicity of human lymphocytes and specifically suppresses HIV-protein synthesis. Med Microbiol Immunol 179, 307–321 (1990). https://doi.org/10.1007/BF00189609

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  • DOI: https://doi.org/10.1007/BF00189609

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