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

Abstract

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.

The anti-apoptotic function of HSV-1 LAT in neuronal cell cultures but not its function during reactivation correlates with expression of two small non-coding RNAs, sncRNA1&2

“…Our data also suggests that the absence of both sncRNA1 and sncRNA2 protects the mice mortality in comparison to control viruses as we have shown recently that absence of sncRNA1 leads to more mice mortality [ 38 ]. Previously we reported that mice ocularly infected with ΔsncRNA1 virus were more susceptible to ocular infection than mice infected with WT McKrae virus suggesting that the sncRNA1 sequence has a protective role during ocular infection [ 38 ]. In contrast, deletion of both sncRNA1&2 in ΔsncRNA1&2 virus did not affect survival in ocularly infected mice compared with WT McKrae or dLAT2903 virus.…”

“…They further showed that expression of TTG mutant sncRNA1, but not sncRNA2, restored virus production, suggesting that this ATG is necessary for the sncRNA1 inhibition of viral replication. We have also shown that TTG mutations within the sncRNAs reduced virus replication, apoptosis, and HVEM promoter activity in transfected cells [ 38 ]. Thus, some or most of the functions associated with LAT could be mediated by these two sncRNAs.…”

“…Recently we reported construction of a recombinant virus lacking the 62 bp sncRNA1 sequence in HSV-1 strain McKrae and creating recombinant virus ΔsncRNA1 [ 38 ]. Replication of ΔsncRNA1 virus in tissue culture or in the eyes of infected mice was similar to that of HSV-1 strain McKrae and dLAT2903 viruses.…”

Multi-targeted loss of the antigen presentation molecule MR1 during HSV-1 and HSV-2 infection

“… 109 Unexpectedly, deletion of the short non-coding RNA sequence sncRNA1 from the HSV-1 genome drives increased MR1 transcript levels in the trigeminal ganglia of mice after ocular infection. 110 Currently, there is an extremely limited understanding of the factors affecting regulation of the ubiquitously expressed MR1 gene, although it has been shown to vary between cell types, 111 is upregulated by inflammatory cytokines associated with type 1 diabetes, 112 and the ratio of MR1A to MR1B isoforms varies between tissues and individuals. 76 One publication that has examined MR1 transcripts during viral infection detected elevated MR1 transcripts in hepatocytes infected with hepatitis B virus, with an associated increase in cytotoxicity of MAIT cells.…”

A Comparison of Pseudorabies Virus Latency to Other α-Herpesvirinae Subfamily Members

“…Meanwhile, ocular virus titers, eye disease, and levels of latency and reactivation were similar in mice infected with either McKrae or the mutant virus. However, absence of sncRNA1 significantly decreased the ocularly infected mice survival and led to virus increased virulence [ 29 ]. These suggest that sncRNA1 has a protective function during acute ocular infection, although the presence of sncRNA1 sequence has no significant effect on virus latency or reactivation.…”