The requirements for herpes simplex virus type 1 cell–cell spread via nectin-1 parallel those for virus entry

Herpes simplex virus type 1 (HSV-1) spreads from an infected cell to an uninfected cell by virus entry, virus-induced cell fusion, and cell–cell spread. The three forms of virus spread require the viral proteins gB, gD, and gH-gL, as well as a cellular gD receptor. The mutual requirement for the fusion glycoproteins and gD receptor suggests that virus entry, cell fusion, and cell–cell spread occur by a similar mechanism. The goals of this study were to examine the role of the nectin-1α transmembrane domain and cytoplasmic tail in cell–cell spread and to obtain a better understanding of the receptor-dependent events occurring at the plasma membrane during cell–cell spread. We determined that an intact nectin-1α V-like domain was required for cell–cell spread, while a membrane-spanning domain and cytoplasmic tail were not. Chimeric forms of nectin-1 that were non-functional for virus entry did not mediate cell–cell spread regardless of whether they could mediate cell fusion. Also, cell–cell spread of syncytial isolates was dependent upon nectin-1α expression and occurred through a nectin-1-dependent mechanism. Taken together, our results indicate that nectin-1-dependent events occurring at the plasma membrane during cell–cell spread were equivalent to those for virus entry.