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Review
. 2013 Feb 11;5(2):678-707.
doi: 10.3390/v5020678.

Directional spread of alphaherpesviruses in the nervous system

Tal Kramer  1 , Lynn W Enquist
Affiliations
Review

Directional spread of alphaherpesviruses in the nervous system

Tal Kramer et al. Viruses. .

Abstract

Alphaherpesviruses are pathogens that invade the nervous systems of their mammalian hosts. Directional spread of infection in the nervous system is a key component of the viral lifecycle and is critical for the onset of alphaherpesvirus-related diseases. Many alphaherpesvirus infections originate at peripheral sites, such as epithelial tissues, and then enter neurons of the peripheral nervous system (PNS), where lifelong latency is established. Following reactivation from latency and assembly of new viral particles, the infection typically spreads back out towards the periphery. These spread events result in the characteristic lesions (cold sores) commonly associated with herpes simplex virus (HSV) and herpes zoster (shingles) associated with varicella zoster virus (VZV). Occasionally, the infection spreads transsynaptically from the PNS into higher order neurons of the central nervous system (CNS). Spread of infection into the CNS, while rarer in natural hosts, often results in severe consequences, including death. In this review, we discuss the viral and cellular mechanisms that govern directional spread of infection in the nervous system. We focus on the molecular events that mediate long distance directional transport of viral particles in neurons during entry and egress.

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Figures

Figure 1
Figure 1
Directional spread of alphaherpesvirus infection in the mammalian nervous system. In their hosts, alphaherpesvirus infections typically initiate at peripheral sites, such as mucosal epithelia. Next, viral particles enter at the termini of sensory neurons of the peripheral nervous system (PNS). These particles are transported long distances along axons in the retrograde direction towards cell bodies, where the genomes are deposited in the nucleus to establish lifelong latency. Following reactivation from latency, new viral particles are assembled and transported towards sites of egress. Typically, infections spreads in the anterograde direction back out towards the periphery. This is essential for spread between hosts. Infection may also spread trans-neuronally, from the PNS to the central nervous system (CNS). Spread of alphaherpesvirus infection into the CNS is associated with lethal encephalitis.
Figure 2
Figure 2
The pseudorabies virus (PRV) replication cycle. Following virion attachment and entry, viral capsids and tegument proteins are released into the cytoplasm. Many of the tegument proteins previously contained within the virion are released into the cytoplasm. Viral capsids and a specific subset of tegument proteins are trafficked towards the nucleus, where the viral genome is deposited and replicated. Capsids containing newly replicated viral genomes are released from the nucleus into the cytoplasm, where they further mature by acquiring viral and host tegument proteins. Final maturation occurs by envelopment of viral particles into vesicles derived from the trans-Golgi network (TGN) that contain viral and host membrane proteins. This process, known as secondary envelopment, results in a mature virion that is contained within a transport vesicle. Enveloped virions are trafficked towards sites of egress along the cell surface. In neurons, enveloped virions are sorted into axons and transported long distances along microtubules towards distal egress sites. At the target membrane, the transport vesicle and plasma membrane fuse, releasing a mature, enveloped PRV virion from the cell.
Figure 3
Figure 3
PRV Us9 and gE/gI mediate anterograde spread of infection in neurons. PRV Us9 is essential for anterograde trans-neuronal spread in vivo and in vitro. In the absence of Us9, viral particles are assembled in the cell body, but are not sorted into axons. This neuron-specific phenotype suggests that Us9 functions by recruiting a molecular motor protein, either directly or indirectly, that facilitates axonal sorting of viral particles into axons. In contrast, gE/gI null mutants are defective for anterograde trans-neuronal spread in vivo, but are able to spread with reduced capacity in vitro. gE/gI null mutants display a small plaque phenotype in non-neuronal cell types.
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