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A synthetic globotriaosylceramide analogue inhibits HIV-1 infection in vitro by two mechanisms

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Author

  • Amanda L. Harrison
  • Martin L Olsson
  • R. Brad Jones
  • Stephanie Ramkumar
  • Darinka Sakac
  • Beth Binnington
  • Stephen Henry
  • Clifford A. Lingwood
  • Donald R. Branch

Summary, in English

Previously, it was shown that the cell-membrane-expressed glycosphingolipid, globotriaosylceramide (Gb(3)/P-k/CD77), protects against HIV-1 infection and may be a newly described natural resistance factor against HIV infection. We have now investigated the potential of a novel, water soluble, non-toxic and completely synthetic analogue of Gb(3)/P-k (FSL-Gb(3)) to inhibit HIV-1 infection in vitro. A uniquely designed analogue, FSL-Gb(3), of the natural Gb(3)/P-k molecule was synthesized. HIV-1(IIIB) (X4 virus) and HIV-1(Ba-L) (R5 virus) infection of PHA/interleukin-2-activated, peripheral blood mononuclear cells (PBMCs) and Jurkat T cells in vitro was assessed, as well as infection of U87.CD4.CCR5 by various clinical R5 tropic viruses after treatment with FSL-Gb(3). We monitored Gb(3), CD4 and CXCR4 expression by fluorescent antibody cell sorting and viral replication by p24 (gag) ELISA. Total cellular Gb(3) was examined by glycosphingolipid extraction and thin layer chromatography. In vivo toxicity was monitored in mice by histological assessment of vital organs and lymphoid tissue. FSL-Gb(3) blocked X4 and R5 of both lab and clinical viral strains in activated PBMCs or the U87.CD4.CCR5 cell line with a 50% inhibitory concentration (IC50) of approximately 200-250 mu M. FACS and TLC overlay showed that FSL-Gb(3) can insert itself into cellular plasma membranes and that cellular membrane-absorbed FSL-Gb(3) is able to inhibit subsequent HIV-1 infection. There was no effect of FSL-Gb(3) on cell surface levels of CD4 or CXCR4. Thus, FSL-Gb(3) can inhibit HIV-1 by two mechanisms: direct inhibition of virus and inhibition of viral entry. Infusion of FSL-Gb(3) into laboratory mice at doses well in excess of theoretical therapeutic doses was tolerated with no untoward reactions. Our results demonstrate the potential utility of using a completely synthetic, water soluble globotriaosylceramide analogue, FSL-Gb(3), having low toxicity, for possible future use as a novel therapeutic approach for the systemic treatment of HIV/AIDS.

Publishing year

2010

Language

English

Pages

515-524

Publication/Series

Glycoconjugate Journal

Volume

27

Issue

5

Document type

Journal article

Publisher

Springer

Topic

  • Hematology

Keywords

  • HIV
  • HIV infection
  • antigen
  • P-k blood group
  • Gb(3)
  • Glycosphingolipids
  • Globotriaosylceramide

Status

Published

Research group

  • Transfusion Medicine

ISBN/ISSN/Other

  • ISSN: 1573-4986