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 CD4ϩ 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 (M r 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.Dendritic cells (DC) function as antigen-presenting cells that capture microorganisms that enter the peripheral mucosal tissues. After antigen uptake, the immature DCs migrate to the T cell areas of secondary lymphoid organs. During this migration, DCs mature and tend to form clusters with T cells, initiating adaptive immune responses (Banchereau and Steinman, 1998). The 2 integrins LFA-1 and ␣D2 present at DC are believed to bind to ICAM-3, which is expressed at high levels on resting T cells. However, this is clearly not the sole interaction between DC and T cell populations. It has indeed been shown that the ICAM-3 binding C-type lectin [designated dendritic cell-specific ICAM-3 grab-