Infection and Transport of Herpes Simplex Virus Type 1 in Neurons: Role of the Cytoskeleton

Abstract

Herpes simplex virus type 1 (HSV-1) is a neuroinvasive human pathogen that has the ability to infect and replicate within epithelial cells and neurons and establish a life-long latent infection in sensory neurons. HSV-1 depends on the host cellular cytoskeleton for entry, replication, and exit. Therefore, HSV-1 has adapted mechanisms to promote its survival by exploiting the microtubule and actin cytoskeletons to direct its active transport, infection, and spread between neurons and epithelial cells during primary and recurrent infections. This review will focus on the currently known mechanisms utilized by HSV-1 to harness the neuronal cytoskeleton, molecular motors, and the secretory and exocytic pathways for efficient virus entry, axonal transport, replication, assembly, and exit from the distinct functional compartments (cell body and axon) of the highly polarized sensory neurons.

Keywords: actin; axonal transport; cytoskeleton; herpes simplex virus; microtubules; neurons.

Figure 1

Herpes simplex virus type 1 (HSV-1) life cycle in the human host. After primary infection in the epidermis, HSV-1 enters sensory nerves innervating the skin or mucosa and undergoes retrograde axonal transport to the neuronal cell body where it establishes a life-long latent infection within sensory neurons. During reactivation, HSV-1 travels via anterograde axonal transport towards the peripheral epidermis to cause recurrent herpes or to be asymptomatically shed.

Figure 2

Entry of HSV-1 into neurons. HSV-1 enters neuronal cells by attachment and fusion of the viral envelope with the plasma membrane and this process is mediated by viral glycoproteins gB, gD, and gH/gL. During membrane fusion, the HSV-1 envelope and its glycoproteins remain associated with the plasma membrane while most tegument proteins dissociate from the incoming capsid. The capsid with associated inner tegument pUL36, pUL37, and pUS3 traverses the actin cortex and is transported along microtubules towards the MTOC to the nucleus in the cell body. The retrograde transport of incoming capsids to the nucleus is mediated by the cellular motor dynein and requires pUL36 and pUL37. MTOC, microtubule organizing center.

Figure 3

HSV-1 assembly, transport and exit from neurons. In the cell body, following nuclear egress, naked capsids acquire inner tegument proteins predominantly in the cytoplasm followed by the acquisition of outer tegument and envelope proteins as capsids invaginate vesicles derived from the TGN. The fully enveloped virion is transported to the plasma membrane where it can exit the cell body. Viral capsids containing inner tegument proteins with or without an envelope and vesicles associated with glycoproteins and tegument proteins are also targeted for active transport along microtubules in axons utilizing the neuronal secretory pathway (involving Rab3A, Gap43, SNAP25, and kinesin) and this process is mediated by the envelope proteins pUS9, gE/gI and possibly (?) pUL20. Viral capsids acquire a final envelope by invagination of vesicles with associated tegument and envelope proteins prior to exit from axonal growth cones.