Publication Date:
2008-07-04
Description:
Herpesviruses are characterized by their ability to maintain life-long latent infections in their animal hosts. However, the mechanisms that allow establishment and maintenance of the latent state remain poorly understood. Herpes simplex virus 1 (HSV-1) establishes latency in neurons of sensory ganglia, where the only abundant viral gene product is a non-coding RNA, the latency associated transcript (LAT). Here we show that LAT functions as a primary microRNA (miRNA) precursor that encodes four distinct miRNAs in HSV-1 infected cells. One of these miRNAs, miR-H2-3p, is transcribed in an antisense orientation to ICP0-a viral immediate-early transcriptional activator that is important for productive HSV-1 replication and thought to have a role in reactivation from latency. We show that miR-H2-3p is able to reduce ICP0 protein expression, but does not significantly affect ICP0 messenger RNA levels. We also identified a fifth HSV-1 miRNA in latently infected trigeminal ganglia, miR-H6, which derives from a previously unknown transcript distinct from LAT. miR-H6 shows extended seed complementarity to the mRNA encoding a second HSV-1 transcription factor, ICP4, and inhibits expression of ICP4, which is required for expression of most HSV-1 genes during productive infection. These results may explain the reported ability of LAT to promote latency. Thus, HSV-1 expresses at least two primary miRNA precursors in latently infected neurons that may facilitate the establishment and maintenance of viral latency by post-transcriptionally regulating viral gene expression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2666538/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2666538/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Umbach, Jennifer Lin -- Kramer, Martha F -- Jurak, Igor -- Karnowski, Heather W -- Coen, Donald M -- Cullen, Bryan R -- R01 AI067968/AI/NIAID NIH HHS/ -- R01 AI067968-02/AI/NIAID NIH HHS/ -- R01 AI067968-03/AI/NIAID NIH HHS/ -- T32 CA009111/CA/NCI NIH HHS/ -- England -- Nature. 2008 Aug 7;454(7205):780-3. doi: 10.1038/nature07103. Epub 2008 Jul 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Genetics and Microbiology and Center for Virology, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18596690" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Base Sequence
;
Cell Line
;
Down-Regulation
;
*Gene Expression Regulation, Viral
;
Genome, Viral/genetics
;
Herpesvirus 1, Human/*genetics/physiology
;
Humans
;
Immediate-Early Proteins/biosynthesis/genetics
;
Male
;
Mice
;
MicroRNAs/*genetics/*metabolism
;
RNA Processing, Post-Transcriptional
;
RNA, Messenger/genetics/metabolism
;
RNA, Viral/*genetics/*metabolism
;
Ubiquitin-Protein Ligases/biosynthesis/genetics
;
Virus Latency/*genetics/physiology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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