Herpes simplex virus type 1 modifies the protein composition of extracellular vesicles to promote neurite outgrowth and facilitate neuroinfection

Herpes simplex virus type 1 (HSV-1) is a highly contagious and prevalent human pathogen that causes many diseases, including encephalitis. During primary infection, HSV-1 infects epithelial cells and then neurites of peripheral neurons, establishing lifelong infection in the neuronal cell body. Neurites are highly dynamic structures that grow or retract in the presence of attractive or repulsive cues, respectively. Whether HSV-1 modulates these cues and thereby neurite outgrowth was not known. Here, we show that HSV-1 glycoprotein G (gG) reduces the inhibitory effect of epithelial cells on neurite outgrowth, facilitating viral infection of neurons through neurite ends. The mechanism of action involves the modification of the protein composition of extracellular vesicles (EV), including increased amount of galectin-1. We show that galectin-1 located in EV produced during HSV-1 infection of epithelial cells promotes neurite outgrowth, and this activity can be partially neutralized by antibodies. This study provides new insights into the neurotropism of HSV-1, identifying for the first time a viral protein that modifies the protein composition of EV to increase neurite outgrowth and neuronal infection.