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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. [ABSTRACT FROM AUTHOR]

Skin mononuclear phagocytes (MNPs) provide the first interactions of invading viruses with the immune system. In addition to Langerhans cells (LCs), we recently described a second epidermal MNP population, Epi-cDC2s, in human anogenital epidermis that is closely related to dermal conventional dendritic cells type 2 (cDC2) and can be preferentially infected by HIV. Here we show that in epidermal explants topically infected with herpes simplex virus (HSV-1), both LCs and Epi-cDC2s interact with HSV-1 particles and infected keratinocytes. Isolated Epi-cDC2s support higher levels of infection than LCs in vitro, inhibited by acyclovir, but both MNP subtypes express similar levels of the HSV entry receptors nectin-1 and HVEM, and show similar levels of initial uptake. Using inhibitors of endosomal acidification, actin and cholesterol, we found that HSV-1 utilises different entry pathways in each cell type. HSV-1 predominantly infects LCs, and monocyte-derived DCs, via a pH-dependent pathway. In contrast, Epi-cDC2s are mainly infected via a pH-independent pathway which may contribute to the enhanced infection of Epi-cDC2s. Both cells underwent apoptosis suggesting that Epi-cDC2s may follow the same dermal migration and uptake by dermal DCs that we have previously shown for LCs. Thus, we hypothesize that the uptake of HSV and infection of Epi-cDC2s will stimulate immune responses via a different pathway to LCs, which in future may help guide HSV vaccine development and adjuvant targeting. Author summary: Here we describe the first interactions of herpes simplex virus type 1 (HSV-1) with the human immune system as it enters the human genital skin. It was previously thought that this initial interaction of HSV-1 was only with 'Langerhans cells' (LCs) but we describe another important interaction with a new immune cell, Epi-cDC2s, which can also be infected by HIV and much more efficiently than LCs. Thus, there are now two of these types of immune cells resident in human epidermis. Therefore the way in which sexually transmitted and skin infecting viruses establish infection needs to be re-examined, including for HSV. We compared how these two cell types interacted with HSV-1 and showed Epi-cDC2s are more susceptible to HSV-1 infection than LCs and take up the virus via a different entry pathway. We speculate these cells may then carry HSV fragments to the dermis and then to lymph nodes to stimulate a protective immune response. These findings suggest similar routes may apply for chickenpox and cowpox viruses which also enter via the skin. Studying this pathway to establishment of natural immunity to HSV, may help guide the development of a successful vaccine. [ABSTRACT FROM AUTHOR]

The interferon (IFN) system is one of the first lines of defense activated against invading viral pathogens. Upon secretion, IFNs activate a signaling cascade resulting in the production of several interferon stimulated genes (ISGs), which work to limit viral replication and establish an overall anti-viral state. Herpes simplex virus type 1 is a ubiquitous human pathogen that has evolved to downregulate the IFN response and establish lifelong latent infection in sensory neurons of the host. This review will focus on the mechanisms by which the host innate immune system detects invading HSV-1 virions, the subsequent IFN response generated to limit viral infection, and the evasion strategies developed by HSV-1 to evade the immune system and establish latency in the host. [ABSTRACT FROM AUTHOR]