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The C‐type lectin DC‐SIGN internalizes soluble antigens and HIV‐1 virions via a clathrin‐dependent mechanism

Dendritic cells (DC), professional Ag‐presenting cells located in mucosae and lymphoid organs, operate at the interface of innate and adaptive immunity and are likely the first cells to encounter invading HIV‐1. Although the C‐type lectin DC‐Specific ICAM‐3‐grabbing non‐integrin (DC‐SIGN) binds to several viruses, including HIV‐1, its direct involvement in viral entry remains controversial. Despite its central role in DC function, little is known about the underlying molecular mechanism(s) of DC‐SIGN‐mediated Ag uptake. Here, we analyzed the early stages of DC‐SIGN‐mediated endocytosis and demonstrate that both membrane cholesterol and dynamin are required. Confocal microscopy and clathrin RNAi showed that DC‐SIGN‐mediated internalization occurs via clathrin‐coated pits. Electron microscopy of ultrathin sections showed the involvement of DC‐SIGN in clathrin‐dependent HIV‐1 internalization by DC. Currently, DC‐specific C‐type lectins are considered potential target in anti‐tumor clinical trials. Detailed information about how different Ag are internalized via these receptors will facilitate the rational design of targeted therapeutic strategies.