Herpes simplex virus-1 utilizes the host actin cytoskeleton for its release from axonal growth cones

Herpes simplex virus type 1 (HSV-1) has evolved mechanisms to exploit the host cytoskeleton during entry, replication and exit from cells. In this study, we determined the role of actin and the molecular motor proteins, myosin II and myosin V, in the transport and release of HSV-1 from axon termini, or growth cones. Using compartmentalized neuronal devices, we showed that inhibition of actin polymerization, but not actin branching, significantly reduced the release of HSV-1 from axons. Furthermore, we showed that inhibition of myosin V, but not myosin II, also significantly reduced the release of HSV-1 from axons. Using confocal and electron microscopy, we determined that viral components are transported along axons to growth cones, despite actin or myosin inhibition. Overall, our study supports the role of actin in virus release from axonal growth cones and suggests myosin V as a likely candidate involved in this process.
Author summary Herpes simplex virus type 1 (HSV-1) is a ubiquitous human pathogen causing cold sores and genital herpes. HSV-1 infects sensory neurons of the peripheral nervous system where it establishes a lifelong infection and cannot be cured. Reactivation is common, with the virus transported back along sensory nerves, forming new lesions, or is shed asymptomatically. Antiviral resistance is emerging to current antivirals that target viral replication, indicating the need to identify new targets for future treatment. The host cell cytoskeleton plays an important role during transport of the virus. HSV-1 is transported along axons via microtubules; however, how the virus is released from axon termini, where actin predominates, is unknown. Here we show that an intact actin cytoskeleton is required for efficient virus release from axon termini. Furthermore, we show that myosin V, an actin based molecular motor that drives transport, is essential in virus release from axon termini. Together, this study defines the mechanisms behind HSV-1 release from axon termini which will guide future directions in identifying possible therapeutic targets for HSV-1.