Following virus transmission, cell-cell contacts are downregulated. Initial transient contacts are stabilized, and virus assembly was observed to be redirected toward sites of cell-cell contact after an ∼30-min delay. MLV-infected fibroblasts were observed to establish contact with uninfected cells in a reaction driven by Env-receptor interactions. (C) Establishment of adhesion between infected and uninfected cells using MLV as the model system (56, 112). Virus-infected cells are blue, and the receptor-expressing target cells are labeled as green. Extracellular matrix components (ECM) have also been observed to play a role in a peripheral mode of transmission (92). The association of viruses with the cell-cell interface could be the consequence of either de novo assembly or surface transmission (55, 56). (B) Several distinct mechanisms can contribute to the accumulation of viruses at the synapse. Interestingly, all three structural elements have been associated with the accumulation and transmission of viruses from infected to uninfected cells (43, 51, 102). Exocytosis of secretory lysosomes can be observed in the cSMAC zone. The antigen-presenting cell is shown in green, and the effector cell is shown in blue. The architecture of the immunological synapse consists of central and peripheral supermolecular adhesion complexes, cSMAC and pSMAC, respectively (84). (A) Utilization of structural elements of immunological synapses for viral spreading. Viruses can either utilize existing synaptic contacts or establish contact between infected and uninfected cells to promote viral spreading. An understanding of viral cell-to-cell spreading will enhance our ability to intervene in the efficient spreading of viral infections. In this review, we will present support for this model, illustrate the ability of viruses to utilize and manipulate cell adhesion molecules, and discuss the mechanism and driving forces of directional spreading. This implies that virus release and entry are efficiently coordinated to sites of cell-cell contact, resulting in a process that is distinct from its individual components. Central to the excitement in the field of virus cell-to-cell transmission is the idea that cell-to-cell spread is more than the sum of the processes of virus release and entry. While there are fundamental differences between these types of transmissions, it has emerged that the ability of viruses to utilize and manipulate cell-cell contact contributes to the success of viral infections. Viral infections spread based on the ability of viruses to overcome multiple barriers and move from cell to cell, tissue to tissue, and person to person and even across species.
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