Herpes simplex virus (HSV) enters cells by fusion at plasma membranes or endosomes. Cellular factors route the virus to different pathways. αVβ3-integrin directs HSV to a lipid raft and acidic endosome pathway. We report that infection mediated by nectin1 plus αVβ3-integrin exhibits the same characteristics as entry mediated by raft-located forms of nectin. αVβ3-integrin relocalizes nectin1 to lipid rafts, independently of virus. Thus, HSV routing to the lipid raft-dependent pathway is consequent to the integrin-induced relocalization of nectin1. Inhibition by the Na+/H+ exchanger 5-(N-ethyl-N-isopropyl)amirolide suggests that αVβ3-integrin overexpression favors HSV macropinocytic uptake in some cells but not in others.