Effects of herpes simplex virus type-1 latency: Associated transcript on sympathetic and sensory neurons

Abstract

Herpes simplex virus type-1 (HSV-1) primarily infects mucoepithelial tissues of the eye, the orofacial region and to a lesser extent the genitalia. Subsequently, the virus is transported in a retrograde fashion through the axons of the sensory and sympathetic neurons to their nuclei, where the virus establishes a life-long latent infection. During this latency period, the viral genome is transcriptionally silent except for a single region encoding the latency associated transcript (LAT). The function of LAT is still largely unknown. To understand how HSV-1 latency might affect neurons, we transfected primary cultures of sympathetic neurons and sensory neurons obtained from rat embryos, with LAT expressing plasmids. LAT increased the survival of both sympathetic and sensory neurons after induction of cell death by NGF deprivation. Since HSV-1 is transported through axons both after initial infection and during reactivation, we considered the possibility that LAT may affect axonal growth. We found that LAT expression increased axonal regeneration by two-fold in both types of neurons. Inhibition of the MAPK pathway reverses stimulation of both neuronal survival and axonal regeneration, which indicates that these effects are mediated through the MAPK pathway. Our data provide evidence that HSV-1 LAT promotes survival of sympathetic as well as trigeminal neurons. To understand how HSV-1 latency might affect dendrites in sympathetic neurons, we transfected primary cultures of sympathetic neurons obtained from rat embryos, with LAT expressing plasmids. LAT inhibited initial dendritic growth and induced dendritic retraction in sympathetic neurons. Latent HSV-1 infection of cultured sympathetic neurons inhibited dendritic growth indicating that this is likely also a consequence of natural infection. To determine if HSV-1 latency might affect calcitonin gene-related peptide (CGRP) expression in trigeminal sensory neurons, we transfected primary neuronal cultures of trigeminal ganglia from rat embryos with plasmids expressing LAT. In the presence of Bone Morphogenetic Protein-7 (BMP7), CGRP was expressed in 49% of sensory neurons. However, this percentage was reduced to 19% in neurons transfected with LAT expressing plasmids. We also found that transfection of the IE63 gene of varicella-zoster virus (VZV) reduced the percentage of trigeminal neurons containing CGRP. However, the observed effect of IE63 in contrast to that of LAT, was completely reversed by treatment of cultures with MgCl 2 , which indicates that the effect of IE63 was due to increased release of CGRP from trigeminal neurons. (Abstract shortened by UMI.)