Ganglioside modulation of CD4 does not block T-helper cell function as compared to antagonism by anti-CD4 antibody

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Abstract

Gangliosides (GM1) modulate CD4 from the surface of T-helper lymphocytes and have been shown to block CD4-mediated HIV-1 infection in vitro. However, the effects of GM1 on CD4 are neutralized in the presence of serum. We sought to make a GM1 derivative which would resist serum neutralization and to determine whether modulation of CD4 by GM1 would affect T-helper lymphocyte function. Study of GM1 and GM1-derivatives in the presence of serum indicated that the active conformation involves intact sialic acid hydroxyl groups and intermolecular ganglioside interactions. All chemical modifications directed toward the sialic acid moiety reduced the ability of GM1 to modulate CD4. Elution profiles of GM1 in the presence and absence of albumin indicate that the active form of GM1 is represented by micelles that are disrupted by albumin. Function studies show that CD4 T-helper cells made CD- by GM1 treatment continue to proliferate in culture and recognize antigen (Ag) through the T cell receptor (TcR). Moreover, T-helper cell mediated inflammation assessed by Ag-specific, delayed type hypersensitivity (DTH) was enhanced after passive transfer of GM1-treated T-helper cells to naive animals. In comparison, CD4 blockade by anti-CD4 antibody decreased Ag-stimulated T-helper cell proliferation and DTH reactions. These results demonstrate that 1) CD4 modulation involves an active conformation that arises from sialic acid effector molecules organized by micellar GM1 conformations; and 2) the mechanism by which GM1 modulates CD4 is different from CD4 antagonism seen with anti-CD4 antibody treatment.

Original languageEnglish (US)
Pages (from-to)315-323
Number of pages9
JournalDrug Development Research
Volume25
Issue number4
Publication statusPublished - 1992

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Keywords

  • CD4 molecule
  • Gangliosides
  • T-helper cells

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Pharmacology

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