Viral transmission from an infected cell to a target cell has been long appreciated to be more efficient than infection with a cell-free virus. New work using high-resolution, live-cell microscopy techniques provides important insights into the mechanisms underlying the efficiency of retrovirus transmission between cells.

The spread of retroviruses between cells is estimated to be 2–3 orders of magnitude more efficient when cells can physically interact with each other1, 2. The underlying mechanism is largely unknown, but transfer is believed to occur through large-surface interfaces, called virological or infectious synapses3, 4, 5, 6. Here, we report the direct visualization of cell-to-cell transmission of retroviruses in living cells. Our results reveal a mechanism of virus transport from infected to non-infected cells, involving thin filopodial bridges. These filopodia originate from non-infected cells and interact, through their tips, with infected cells. A strong association of the viral envelope glycoprotein (Env) in an infected cell with the receptor molecules in a target cell generates a stable bridge. Viruses then move along the outer surface of the filopodial bridge toward the target cell. Our data suggest that retroviruses spread by exploiting an inherent ability of filopodia to transport ligands from cell to cell.

Curiosity may kill the cell, based on findings from Nathan Sherer, Walther Mothes (Yale University, New Haven, CT), and colleagues. The exploratory filopodia that cells send out can be caught by infected cells and used to spread viruses. Mothes's group had already shown that viruses surf along the outer surface of filopodia toward the cell body. Now they find that infected fibroblasts deposit retroviral particles onto their neighbors' filopodia. Infected cells grab filopodia using contacts between a transmembrane retroviral protein and its receptor in the uninfected cell. At the meeting point, the already infected cell tears off and takes in chunks of filopodial membrane by endocytosis. "The infected cell pulls the target cell into itself," explains Mothes. "The forces must be gigantic." These forces lengthen and stabilize the structure into a bridge that resembles cytonemes, the actin-filled communication tubes that connect fly epithelial cells. Retroviral particles assembled at the endocytic hot spots, which abutted the filopodial tips. The particles then budded out onto the filopodia. A mutant version of the viral budding protein blocked their escape. By linking to the filopodial actin network, the particles then moved against the membrane tide toward the uninfected cell, where they were eventually internalized.