Abstract
Exposure of HIV-1 to dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)-expressing B-lymphoblast Raji cells (Raji/DC-SIGN) but not to wild-type Raji/0 cells results in the capture of HIV-1 particles to the cells as measured by the quantification of cell-associated p24 antigen. Cocultivation of HIV-1-captured Raji/DC-SIGN cells with uninfected CD4+ T lymphocyte C8166 cells results in abundant formation of syncytia within 36 h after cocultivation. Short preexposure of HIV-1 to carbohydrate-binding agents (CBA) dose dependently prevents the Raji/DC-SIGN cells from efficiently binding the virus particles, and no syncytia formation occurs upon subsequent cocultivation with C8166 cells. Thus, the mannose-specific [i.e., the plant lectins Hippeastrum hybrid agglutinin (HHA), Galanthus nivalis agglutinin (GNA), Narcissus pseudonarcissus agglutinin; and Cymbidium agglutinin (CA); the procaryotic cyanovirin-N (CV-N); and the monoclonal antibody 2G12) and N-acetylglucosamine-specific (i.e., the plant lectin Urtica dioica agglutinin) CBAs efficiently abrogate the DC-SIGN-directed HIV-1 capture and subsequent transmission to T lymphocytes. In this assay, the CD4-down-regulating cyclotriazodisulfonamide derivative, the CXCR4 and CCR5 coreceptor antagonists 1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl] - 1,4,8,11 - tetrazacyclotetradecane (AMD3100) and maraviroc, the gp41-binding enfuvirtide, and the polyanionic substances dextran sulfate (Mr 5000), sulfated polyvinyl alcohol, and the naphthalene sulfonate polymer PRO-2000 were markedly less efficient or even completely ineffective. Similar observations were made in primary monocyte-derived dendritic cell cultures that were infected with HIV-1 particles that had been shortly pre-exposed to the CBAs CV-N, CA, HHA, and GNA and the polyanions DS-5000 and PRO-2000. The potential of CBAs, but not polyanions and other structural/functional classes of entry inhibitors, to impair DC-SIGN-expressing cells in their capacity of transmitting HIV to T lymphocytes might be an important property to be taken into consideration in the eventual choice to move microbicide candidate drugs to the clinical setting.
Footnotes
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The research was supported by the Geconcerteerde Onderzoeksacties (GOA 05/19), the Flemish Foundation for Scientific Research (no. G-0267-04), the European Commission (René Descartes Prize-2001 HPAW-2002-90001, and EMPRO 503558 of the 6th Frame Work Programme), the Agence Nationale de Recherches sur le SIDA, and the Centers of Excellence from the Katholieke Universiteit Leuven (EF/05/15).
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ABBREVIATIONS: DC, dendritic cell; ICAM, intercellular adhesion molecule; DC-SIGN, dendritic cell-specific ICAM-3-grabbing nonintegrin; CBA, carbohydrate-binding agent; GNA, Galanthus nivalis agglutinin; HHA, Hippeastrum hybrid agglutinin; NPA, Narcissus pseudonarcissus agglutinin; CA, Cymbidium hybrid agglutinin; UDA, Urtica dioica agglutinin; UC-781, N-[4-chloro-3-(3-methylbut-2-enoxy)phenyl]-2-methyl-furan-3-carbothioamide; CV-N, cyanovirin; PRO-2000, naphthalene sulfonate polymer; PVAS, sulfated polyvinyl alcohol; MO, monocyte-derived; mAb, monoclonal antibody; DS-5000, dextran sulfate (Mr 5000); CADA, cyclotriazodisulfonamide; Ag, antigen.
- Received August 25, 2006.
- Accepted October 20, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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