Herpes simplex virus type 1 latency-associated transcript gene promotes neuronal survival

A complex interaction has evolved between the host's peripheral nervous sys tem (PNS) and herpes simplex virus type 1 (HSV-1). Sensory neurons are perm issive for viral replication, yet the virus can also enter a latent state i n these cells. The interplay of viral and neuronal signals that regulate th e switch between the viral lytic and latent states is not understood. The l atency-associated transcript (LAT) regulates the establishment of the laten t state and is required for > 65% of the latent infections established by H SV-1 (R. L. Thompson and N, M. Sawtell, J. Virol. 71:5432-5440, 1997). To f urther investigate how LAT functions, a 1.9-kb deletion that includes the e ntire LAT promoter and 827 bp of the 5' end of the primary LAT mRNA was int roduced into strain 17syn+. The wild-type parent, three independently deriv ed deletion mutants, and two independently derived genomically rescued vari ants of the mutants were analyzed in a mouse ocular model. The number of la tent sites established in trigeminal ganglion (TG) neurons was determined u sing a single-cell quantitative PCR assay for the viral genome on purified TG neurons. It was found that the WT null mutants established similar to 75 % fewer latent infections than the number established by the parental strai n or rescued variant. The reduced establishment phenotype of LAT null mutan ts was due at least in part to a dramatic increase in the loss of TG neuron s in animals infected with the LAT mutants. Over half of the neurons in the TG were destroyed following infection with the WT mutants, and this was si gnificantly more than were lost following infection with wild type. This is the first demonstration that the HSV LAT locus prevents the destruction of sensory neurons. The death of these neurons did not appear to be the resul t of increased apoptosis as measured by a terminal deoxynucleotidyltransfer ase-mediated dUTP-biotin nick end labeling assay. Animals latently infected with the LAT null mutants reactivated less frequently in vivo and this was consistent with the reduction in the number of neurons in which latency wa s established. Thus, one function of the WT gene is to protect sensory neur ons and enhance the establishment of latency in the PNS.