Herpes simplex virus type 1 latency-associated transcript expression protects trigeminal ganglion neurons from apoptosis.
Upon infection of murine trigeminal ganglia with herpes simplex virus type 1 (HSV-1), an immune response is initiated resulting in significant infiltration of CD8+ T cells. Previous investigators have observed a lack of apoptosis in HSV-1 trigeminal ganglia even in the presence of cytotoxic immune cells. To determine the role of the latency-associated transcript (LAT) in inhibiting apoptosis, we examined mice during acute and latent infection with HSV-1 (strain 17 or a LAT-negative deletion mutant strain 17 N/H) by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) and fluorescence-activated cell sorting (FACS). FACS analysis revealed CD8+ T cells in the trigeminal ganglia by day 7, with more being present in 17- than 17 N/H-infected trigeminal ganglia (6.22% versus 3.5%) and a decrease in number through day 30 (2.7% to 1.2%). To detect apoptotic CD8+ T cells, sections were assayed by TUNEL and stained for CD8+ T cells. By day 7, approximately 10% of CD8+ T cells in both 17- and 17 N/H-infected trigeminal ganglia had undergone apoptosis. By day 30, 58% and 74% of all T cells had undergone apoptosis in 17- and 17 N/H-infected trigeminal ganglia, respectively. Furthermore, no HSV strain 17-infected trigeminal ganglion neurons were apoptotic, but 0.087% of 17deltaSty and 0.98% of 17 N/H-infected neurons were apoptotic. We conclude that the antiapoptotic effect of LAT appears to require the LAT promoter, with most of the antiapoptotic effect mapping within the StyI (+447) to the HpaI (+1667) region and a minor contribution from the upstream StyI (+76) to StyI (+447) region.
Department of Microbiology, University of Pennsylvania School of Medicine, 3610 Hamilton Walk, Philadelphia, PA 19104, USA.
Francisco J
FJ
Branco
Nigel W
NW
Fraser
D000818:Animals; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D006561:Herpes Simplex / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs; D009474:Neurons / Q000821:virology; D012668:Trigeminal Ganglion / Q000473:pathology / Q000821:virology*; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*; D017735:Virus Latency
D035683:MicroRNAs; D014764:Viral Proteins; C477253:latency associated transcript, herpes simplex virus-1