The Role of Herpes Simplex Virus Type 1 Infection in Demyelination of the Central Nervous System

Abstract

Herpes simplex type 1 (HSV-1) is a neurotropic virus that infects the peripheral and central nervous systems. After primary infection in epithelial cells, HSV-1 spreads retrogradely to the peripheral nervous system (PNS), where it establishes a latent infection in the trigeminal ganglia (TG). The virus can reactivate from the latent state, traveling anterogradely along the axon and replicating in the local surrounding tissue. Occasionally, HSV-1 may spread trans-synaptically from the TG to the brainstem, from where it may disseminate to higher areas of the central nervous system (CNS). It is not completely understood how HSV-1 reaches the CNS, although the most accepted idea is retrograde transport through the trigeminal or olfactory tracts. Once in the CNS, HSV-1 may induce demyelination, either as a direct trigger or as a risk factor, modulating processes such as remyelination, regulation of endogenous retroviruses, or molecular mimicry. In this review, we describe the current knowledge about the involvement of HSV-1 in demyelination, describing the pathways used by this herpesvirus to spread throughout the CNS and discussing the data that suggest its implication in demyelinating processes.

Keywords: HSV-1; central nervous system; demyelination; endogenous retroviruses; molecular mimicry; oligodendrocytes; peripheral nervous system.

Figure 1

Spread of HSV-1 to the CNS via the trigeminal nerve. (A) HSV-1 may pass from the epithelia to the peripheral nervous system (PNS) by cell-to-cell spread between epithelial cells and nerve endings of sensory neurons that innervate them (1). The virus travels along the axon by retrograde transport to the cell soma of the sensory neuron, located in the trigeminal ganglion (TG). Conversely, HSV-1 can travel back by anterograde transport to the epithelial cells where the primary infection took place (2). The virus can also spread trans-synaptically, crossing the synaptic cleft (3). (B) After infection of epithelial cells, HSV-1 spreads to the PNS, entering sensory neurons by fusion with the plasma membrane of its nerve terminals. Then, HSV-1 travels retrogradely to the cell body and establishes a latent infection in the TG. Afterwards, the virus may enter the central nervous system (CNS) if it spreads trans-synaptically to the brainstem, from where it might spread to higher brain areas. (C) Spread to the CNS may take place through the three branches of the trigeminal nerve: ophthalmic, maxillary and mandibular. From here, the virus can access the trigeminal nucleus and other brain structures. (Structures are schematically represented and they are not drawn to scale).

Figure 2

Spread of herpes simplex virus type 1 (HSV-1) to the central nervous system (CNS) via the olfactory nerve. (A) HSV-1 may enter the CNS via the olfactory neuroepithelium. From there, the virus may reach the olfactory bulb and then spread through the olfactory tract to reach limbic structures, such as the hippocampus, amygdala, or orbitofrontal cortex. (B) HSV-1 may reach the olfactory bulb infecting olfactory sensory cells, whose axons cross the ethmoid bone through the cribriform plate. These neurons form synapses with mitral and tufted cells in the glomeruli. The virus may infect these cells trans-synaptically at the glomeruli and spread towards the olfactory projection pathways. (C) Once in the olfactory tract, the virus may access the ipsilateral projection areas, such as the orbitofrontal cortex, via the lateral olfactory stria (in blue), or they may reach the contralateral olfactory structures through the anterior commissure via the medial olfactory stria (in red). (Structures are schematically represented and are not drawn to scale).