A neuron-specific host microRNA targets herpes simplex virus-1 ICP0 expression and promotes latency.
After infecting peripheral sites, herpes simplex virus (HSV) invades the nervous system and initiates latent infection in sensory neurons. Establishment and maintenance of HSV latency require host survival, and entail repression of productive cycle ("lytic") viral gene expression. We find that a neuron-specific microRNA, miR-138, represses expression of ICP0, a viral transactivator of lytic gene expression. A mutant HSV-1 (M138) with disrupted miR-138 target sites in ICP0 mRNA exhibits enhanced expression of ICP0 and other lytic proteins in infected neuronal cells in culture. Following corneal inoculation, M138-infected mice have higher levels of ICP0 and lytic transcripts in trigeminal ganglia during establishment of latency, and exhibit increased mortality and encephalitis symptoms. After full establishment of latency, the fraction of trigeminal ganglia harboring detectable lytic transcripts is greater in M138-infected mice. Thus, miR-138 is a neuronal factor that represses HSV-1 lytic gene expression, promoting host survival and viral latency.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Dongli
D
Pan
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Omar
O
Flores
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Jennifer L
JL
Umbach
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Jean M
JM
Pesola
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Peris
P
Bentley
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
Pamela C
PC
Rosato
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
David A
DA
Leib
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Bryan R
BR
Cullen
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: don_coen@hms.harvard.edu.
Donald M
DM
Coen
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D003315:Cornea / Q000473:pathology / Q000821:virology; D004279:DNA, Viral / Q000235:genetics; D004660:Encephalitis / Q000821:virology; D015967:Gene Expression Regulation, Viral; D057809:HEK293 Cells; D006561:Herpes Simplex / Q000401:mortality / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D012668:Trigeminal Ganglion / Q000473:pathology / Q000821:virology*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000235:genetics*; D014709:Vero Cells; D017735:Virus Latency
D004279:DNA, Viral; D017874:Immediate-Early Proteins; C546110:MIRN138 microRNA, human; D035683:MicroRNAs; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1