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Journal of Virology, August 1999, p. 6618-6625, Vol. 73, No. 8
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Herpes Simplex Virus Latency-Associated Transcript Encodes a
Protein Which Greatly Enhances Virus Growth, Can Compensate
for Deficiencies in Immediate-Early Gene Expression, and Is
Likely To Function during Reactivation from Virus Latency
S. K.
Thomas,1
G.
Gough,2
D. S.
Latchman,1
R.
S. , and
Coffin1,*
The Windeyer Institute of Medical Sciences,
University College London, London,1 and
Glaxo-Wellcome Medicines Research Centre,
Stevenage,2 United Kingdom
Received 19 January 1999/Accepted 13 May 1999
Herpes simplex virus types 1 and 2 (HSV1 and HSV2) enter and
reactivate from latency in sensory neurons, although the events governing these processes are little understood. During latency, only
the latency-associated transcripts (LATs) are produced. However, although the LAT RNAs were described
10 years ago, their function remains ambiguous. Mutations affecting the LATs have minimal effects other than a small reduction in establishment of and reactivation from
latency in some cases. Mutations in putative LAT-contained open reading
frames (ORFs) have so far shown no effect. The LATs consist of a large
species from which smaller (
2 kb), nuclear, nonlinear LATs which are
abundant during latency are spliced. Thus, translation of ORFs in these
smaller LATs would not usually be expected to be possible, and if
expressed at all, their expression might be tightly regulated. Here we
show that deregulated expression of the largest HSV1 2-kb LAT-contained
ORF in various cells of neuronal and nonneuronal origin greatly
enhances virus growth in a manner specific to HSV1
the HSV1 LAT ORF
has no effect on the growth of HSV2. Similar results of enhanced growth
were found when the HSV1 LAT ORF was constitutively expressed from
within the HSV1 genome. The mechanism of LAT ORF action was strongly suggested to be by substituting for deficiencies in immediate-early (IE) gene expression (particularly ICP0), because deregulated LAT ORF
expression, as well as enhancing wild-type virus growth, was also found
to allow efficient growth of viruses with mutations in ICP0 or VMW65.
Such viruses otherwise exhibit considerable growth defects. IE gene
expression deficiencies are often the block to productive infection in
nonpermissive cells and are also evident during latency. These results,
which we show to be protein- rather than RNA-mediated effects, strongly
suggest a function of the tightly regulated expression of a LAT
ORF-encoded protein in the reactivation from HSV latency.
*
Corresponding author. Mailing address: The Windeyer
Institute of Medical Sciences, University College London, 46 Cleveland St., London W1P 6DB, United Kingdom. Phone: 0171-504-9230. Fax: 0171-387-3310. E-mail: r.coffin{at}ucl.ac.uk.
Journal of Virology, August 1999, p. 6618-6625, Vol. 73, No. 8
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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