Journal
VIRUSES-BASEL
Volume 14, Issue 5, Pages -Publisher
MDPI
DOI: 10.3390/v14051015
Keywords
varicella zoster virus; latency; reactivation; human neuron culture; non-coding RNA
Categories
Funding
- Israel-US Binational Science Foundation [2017259]
- National Institutes of Health from NIAID [AI122640, AI156527]
- Israel Science Foundation [613/20]
- Direct For Computer & Info Scie & Enginr
- Office of Advanced Cyberinfrastructure (OAC) [2017259] Funding Source: National Science Foundation
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By altering the non-coding RNA of varicella zoster virus, we found that these RNA may play important roles in the latency of the virus.
Locked-nucleotide analog antagonists (LNAA) to four varicella zoster virus small non-coding RNA (VZVsncRNA 10-13) derived from the mRNA of the open reading frame (ORF) 61 gene individually reduce VZV replication in epithelial cells and fibroblasts. To study the potential roles VZVsncRNA 10-13 have in neuronal infection we generated two recombinant VZV; one in which 8 nucleotides were changed in VZVsncRNA10 without altering the encoded residues of ORF61 (VZVsnc10MUT) and a second containing a 12-nucleotide deletion of the sequence common to VZVsncRNA12 and 13, located in the ORF61 mRNA leader sequence (VZVsnc12-13DEL). Both were developed from a VZV BAC with a green fluorescent protein (GFP) reporter fused to the N terminal of the capsid protein encoded by ORF23. The growth of both mutant VZV in epithelial cells and fibroblasts was similar to that of the parental recombinant virus. Both mutants established productive infections and experimental latency in neurons derived from human embryonic stem cells (hESC). However, neurons that were latently infected with both VZV mutant viruses showed impaired ability to reactivate when given stimuli that successfully reactivated the parental virus. These results suggest that these VZVsncRNA may have a role in VZV latency maintenance and/or reactivation. The extension of these studies and confirmation of such roles could potentially inform the development of a non-reactivating, live VZV vaccine.
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