Herpes simplex virus triggers activation of calcium-signaling pathways

Abstract

The cellular pathways required for herpes simplex virus (HSV) invasion have not been defined. To test the hypothesis that HSV entry triggers activation of Ca²⁺-signaling pathways, the effects on intracellular calcium concentration ([Ca²⁺]_i) after exposure of cells to HSV were examined. Exposure to virus results in a rapid and transient increase in [Ca²⁺]_i. Pretreatment of cells with pharmacological agents that block release of inositol 1,4,5-triphosphate (IP₃)–sensitive endoplasmic reticulum stores abrogates the response. Moreover, treatment of cells with these pharmacological agents inhibits HSV infection and prevents focal adhesion kinase (FAK) phosphorylation, which occurs within 5 min after viral infection. Viruses deleted in glycoprotein L or glycoprotein D, which bind but do not penetrate, fail to induce a [Ca²⁺]_i response or trigger FAK phosphorylation. Together, these results support a model for HSV infection that requires activation of IP₃-responsive Ca²⁺-signaling pathways and that is associated with FAK phosphorylation. Defining the pathway of viral invasion may lead to new targets for anti-viral therapy.