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Journal of Virology, July 2001, p. 6660-6675, Vol. 75, No. 14
Department of Molecular Genetics,
Biochemistry, and Microbiology, University of Cincinnati Medical
Center, Cincinnati, Ohio 45267-0524,1 and
Division of Infectious Diseases, Children's Hospital
Medical Center, Cincinnati, Ohio 45229-30392
Received 15 November 2000/Accepted 27 April 2001
A complex interaction has evolved between the host's peripheral
nervous system (PNS) and herpes simplex virus type 1 (HSV-1). Sensory
neurons are permissive for viral replication, yet the virus can also
enter a latent state in these cells. The interplay of viral and
neuronal signals that regulate the switch between the viral lytic and
latent states is not understood. The latency-associated transcript
(LAT) regulates the establishment of the latent state and is required
for >65% of the latent infections established by HSV-1 (R. L. Thompson and N. M. Sawtell, J. Virol. 71:5432-5440, 1997).
To further investigate how LAT functions, a 1.9-kb deletion that
includes the entire LAT promoter and 827 bp of the 5' end of the
primary LAT mRNA was introduced into strain 17syn+. The wild-type
parent, three independently derived deletion mutants, and two
independently derived genomically rescued variants of the mutants were
analyzed in a mouse ocular model. The number of latent sites
established in trigeminal ganglion (TG) neurons was determined using a
single-cell quantitative PCR assay for the viral genome on purified TG
neurons. It was found that the LAT null mutants established ~75%
fewer latent infections than the number established by the parental
strain or rescued variant. The reduced establishment phenotype of LAT
null mutants was due at least in part to a dramatic increase in the
loss of TG neurons in animals infected with the LAT mutants. Over half
of the neurons in the TG were destroyed following infection with the
LAT mutants, and this was significantly 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 result of increased apoptosis as
measured by a terminal deoxynucleotidyltransferase-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 was
established. Thus, one function of the LAT gene is to protect sensory
neurons and enhance the establishment of latency in the PNS.
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.14.6660-6675.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Herpes Simplex Virus Type 1 Latency-Associated
Transcript Gene Promotes Neuronal Survival
*
Corresponding author. Mailing address for Richard
Thompson: Department of Molecular Genetics, Biochemistry, and
Microbiology, University of Cincinnati Medical Center, 231 Albert Sabin
Way, Cincinnati, OH 45267-0524. Phone: (513) 558-0063. Fax: (513)
558-8474. E-mail: Richard.Thompson{at}UC.EDU.
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