Carl Gustav Figdor

Identification of different binding sites in the dendritic cell-specific receptor DC-SIGN for intercellular adhesion molecule 3 and HIV-1

The novel dendritic cell (DC)-specific human immunodeficiency virus type 1 (HIV-1) receptor DC-SIGN plays a key role in the dissemination of HIV-1 by DC. DC-SIGN is thought to capture HIV-1 at mucosal sites of entry, facilitating transport to lymphoid tissues, where DC-SIGN efficiently transmits HIV-1 to T cells. DC-SIGN is also important in the initiation of immune responses by regulating DC-T cell interactions through intercellular adhesion molecule 3 (ICAM-3). We have characterized the mechanism of ligand binding by DC-SIGN and identified the crucial amino acids involved in this process. Strikingly, the HIV-1 gp120 binding site in DC-SIGN is different from that of ICAM-3, consistent with the observation that glycosylation of gp120, in contrast to ICAM-3, is not crucial to the interaction with DC-SIGN. A specific mutation in DC-SIGN abrogated ICAM-3 binding, whereas the HIV-1 gp120 interaction was unaffected. This DC-SIGN mutant captured HIV-1 and infected T cells intrans as efficiently as wild-type DC-SIGN, demonstrating that ICAM-3 binding is not necessary for HIV-1 transmission. This study provides a basis for the design of drugs that inhibit or alter interactions of DC-SIGN with gp120 but not with ICAM-3 or vice versa and that have a therapeutic value in immunological diseases and/or HIV-1 infections.

Activation of LFA-1: Role of Cations

Several observations indicate that the affinity of integrin receptors for their ligands can be modulated. Resting leukocytes or platelets do not adhere spontaneously, but a variety of stimuli can induce β1- (VLA-4, VLA-5, VLA-6), β2- (LFA-1, CR3), and β3-integrin (IIb/IIIa)-mediated cell-cell interactions. Exposure of lymphocytes, myeloid cells, or platelets to phorbol ester (PMA) strongly induces cell aggregation (1,2). Similarly, FMLP can stimulate CR3-mediated adhesion of granulocytes to endothelial cells (3,4) and activation of platelets by thrombin or ADP causes IIb/IIIa-mediated aggregation (5). A prominent characteristic in all these observations is that adhesion is induced without an apparent increase in receptor expression. This suggests that changes in affinity of the receptor for its ligand, or changes in the avidity (for instance, by alteration of the organization of the adhesion receptors at the cell surface), directly affect cell adhesion. Second messengers play a pivotal role in integrin activation, although at present the precise intracellular circuits that regulate integrin-mediated cell adhesion are not completely understood.