PMID- 35254102 OWN - NLM STAT- MEDLINE DCOM- 20220415 LR - 20220910 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 96 IP - 7 DP - 2022 Apr 13 TI - Small Noncoding RNA (sncRNA1) within the Latency-Associated Transcript Modulates Herpes Simplex Virus 1 Virulence and the Host Immune Response during Acute but Not Latent Infection. PG - e0005422 LID - 10.1128/jvi.00054-22 [doi] LID - e00054-22 AB - The HSV-1 latency-associated transcript (LAT) locus contains two small noncoding RNA (sncRNA) sequences (sncRNA1 and sncRNA2) that are not microRNAs (miRNAs). We recently reported that sncRNA1 is more important for in vitro activation of the herpesvirus entry mediator than sncRNA2, but its in vivo function is not known. To determine the role, if any, of sncRNA1 during herpes simplex virus 1 (HSV-1) infection in vivo, we deleted the 62-bp sncRNA1 sequence in HSV-1 strain McKrae using dLAT2903 (LAT-minus) virus, creating DeltasncRNA1 recombinant virus. Deletion of the sncRNA1 in DeltasncRNA1 virus was confirmed by complete sequencing of DeltasncRNA1 virus and its parental virus (i.e., McKrae). Replication of DeltasncRNA1 virus in tissue culture or in the eyes of infected mice was similar to that of HSV-1 strain McKrae and dLAT2903 viruses. However, the absence of sncRNA1 significantly reduced the levels of ICP0, ICP4, and gB but not LAT transcripts in infected rabbit skin cells in vitro. In contrast, the absence of sncRNA1 did reduce LAT expression in trigeminal ganglia (TG), but not in corneas, by day 5 postinfection (p.i.) in infected mice. Levels of eye disease in mice infected with DeltasncRNA1 or McKrae virus were similar, and despite reduced LAT levels in TG during acute DeltasncRNA1 infection, McKrae and DeltasncRNA1 viruses did not affect latency or reactivation on day 28 p.i. However, mice infected with DeltasncRNA1 virus were more susceptible to ocular infection than their wild-type (WT) counterparts. Expression of host immune response genes in corneas and TG of infected mice during primary infection showed reduced expression of beta interferon (IFNbeta) and IFNgamma and altered activation of key innate immune pathways, such as the JAK-STAT pathway in DeltasncRNA1 virus compared with parental WT virus. Our results reveal novel functions for sncRNA1 in upregulating the host immune response and suggest that sncRNA1 has a protective role during primary ocular HSV-1 infection. IMPORTANCE HSV-1 latency-associated transcript (LAT) plays a major role in establishing latency and reactivation; however, the mechanism by which LAT controls these processes is largely unknown. In this study, we sought to establish the role of the small noncoding RNA1 (sncRNA1) encoded within LAT during HSV-1 ocular infection. Our results suggest that sncRNA1 has a protective role during acute ocular infection by modulating the innate immune response to infection. FAU - Tormanen, Kati AU - Tormanen K AD - Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, CSMC-SSB3, Los Angeles, California, USA. FAU - Matundan, Harry H AU - Matundan HH AD - Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, CSMC-SSB3, Los Angeles, California, USA. FAU - Wang, Shaohui AU - Wang S AD - Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, CSMC-SSB3, Los Angeles, California, USA. FAU - Jaggi, Ujjaldeep AU - Jaggi U AD - Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, CSMC-SSB3, Los Angeles, California, USA. FAU - Mott, Kevin R AU - Mott KR AD - Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, CSMC-SSB3, Los Angeles, California, USA. FAU - Ghiasi, Homayon AU - Ghiasi H AUID- ORCID: 0000-0003-3291-1995 AD - Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, CSMC-SSB3, Los Angeles, California, USA. LA - eng GR - R01 EY024649/EY/NEI NIH HHS/United States GR - R01 EY029160/EY/NEI NIH HHS/United States PT - Journal Article DEP - 20220307 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (RNA, Small Untranslated) SB - IM MH - Animals MH - Cells, Cultured MH - *Eye Infections/immunology/virology MH - Gene Expression Regulation/immunology MH - *Herpes Simplex/immunology/virology MH - *Herpesvirus 1, Human/genetics/pathogenicity MH - *Immunity/genetics MH - Mice MH - *RNA, Small Untranslated/metabolism MH - Rabbits MH - Signal Transduction/genetics MH - *Virulence/genetics MH - Virus Activation/genetics MH - Virus Latency/genetics PMC - PMC9006899 OTO - NOTNLM OT - cornea OT - eye disease OT - gene expression OT - immune responses OT - latency reactivation OT - recombinant virus OT - survival OT - virus replication COIS- The authors declare no conflict of interest. EDAT- 2022/03/08 06:00 MHDA- 2022/04/16 06:00 PMCR- 2022/09/07 CRDT- 2022/03/07 12:15 PHST- 2022/03/08 06:00 [pubmed] PHST- 2022/04/16 06:00 [medline] PHST- 2022/03/07 12:15 [entrez] PHST- 2022/09/07 00:00 [pmc-release] AID - 00054-22 [pii] AID - jvi.00054-22 [pii] AID - 10.1128/jvi.00054-22 [doi] PST - ppublish SO - J Virol. 2022 Apr 13;96(7):e0005422. doi: 10.1128/jvi.00054-22. Epub 2022 Mar 7.