Direct cell-to-cell spread of animal viruses in solid tissues is a complex, poorly understood process. A number of viruses have become very adept at moving from an infected cell to an adjoining uninfected cell, specifically at sites of cell-cell contact, moving across epithelial cell or neuronal junctions. Directed cell-to-cell spread is typically rapid and efficient, in part because viruses and their cell surface receptors are in close proximity, and viruses can move across the narrow spaces between cells, protected from the effects of neutralizing antibodies and other immune system components by tight and adherens junctions. Virus cell-to-cell spread and entry of extracellular or cell-free virus particles frequently share mechanistic details, eg, the use of similar fusion machinery, but cell-to-cell spread can involve intracellular and extracellular events that determine virus delivery to cell junctions and the use of receptors found exclusively at cell junctions. Here, we focus on cell-to-cell spread as defined above and do not discuss virus-induced formation of syncytia, ie, fusion of infected and uninfected cells.

Three interesting examples of how animal viruses have organized their egress strategies to promote cell-to-cell spread are described here. The alphaherpesviruses provide fascinating examples of viruses that replicate in polarized cells, epithelial cells, and neurons and mimic intracellular sorting pathways to direct nascent virions to cell junctions, promoting infection of adjacent epithelial cells and directed spread within the nervous system. Human immunodeficiency virus (HIV) is a virus that normally replicates in lymphocytes and macrophages, cells that are not usually considered polarized. However, HIV can specifically assemble progeny at sites of transient contact between lymphocytes and macrophages, thereby promoting virus spread. Poxviruses can induce the formation of actin tails that launch virus particles from the cell surface on the tips of microvilli toward neighboring cells.