Herpes Simplex Virus 1 MicroRNA miR-H28 Exported to Uninfected Cells in Exosomes Restricts Cell-to-Cell Virus Spread by Inducing Gamma Interferon mRNA

Abstract

An earlier report showed that herpes simplex virus 1 (HSV-1) expresses two microRNAs (miRNAs), miR-H28 and miR-H29, late in the infectious cycle. The miRNAs are packed in exosomes and, in recipient cells, restrict the transmission of virus from infected cells to uninfected cells. We now report that (i) miR-H28 induced the synthesis of gamma interferon (IFN-γ) in both infected cells and cells transfected with miR-H28, (ii) IFN-γ accumulated concurrently with viral proteins in infected cells, (iii) IFN-γ was produced in HEp-2 cells derived from cancer tissue and in HEK293T cells derived from normal tissue, and (iv) HSV-1 replication was affected by exposure to IFN-γ before infection but not during or after infection. The results presented in this report support the growing body of evidence indicating that HSV-1 encodes functions designed to reduce the spread of infection from infected cells to uninfected cells, possibly in order to maximize the transmission of virus from infected individuals to uninfected individuals. IMPORTANCE In this report, we show that IFN-γ is produced by HSV-1 viral miR-H28 and viral replication is blocked in cells exposed to IFN-γ before infection but not during or after infection. The inevitable conclusion is that HSV-1 induces IFN-γ to curtail its spread from infected cells to uninfected cells. In essence, this report supports the hypothesis that HSV-1 encodes functions that restrict the transmission of virus from cell to cell.

MicroRNA Involvement in Signaling Pathways During Viral Infection

“…They showed that both miR-H28 overexpression and IFNγ induction happen at the same time, at the end of the reproductive cycle. Their study found increased levels of IFNγ at 7 h and, most notably, at 18 h after transfection with miR-H28 (Huang et al, 2019). Han et al had previously suggested that IFN could be activated at the hand of the stimulator of interferon genes (STING) member of the signaling pathways, which is exported through exosomes from infected cells to healthy ones (Han et al, 2016).…”

Exosomal miR‐145‐5p derived from orthohantavirus‐infected endothelial cells inhibits HTNV infection

“…17 Exosome-HSV containing miR-H28 can restrict cell to cell virus spread by inducing IFNγ mRNA. 18 Accumulative evidences demonstrated that parental exosomes can transport miRNAs to immune cells enabling a dialog between parental cells and immune cells. Exosome from hepatitis B virus (HBV) containing immunoregulatory miRNA suppressed IL-12p35 mRNA expression and offset innate immune response in THP-1 derived macrophages.…”

Alphaherpesvirus gB Homologs Are Targeted to Extracellular Vesicles, but They Differentially Affect MHC Class II Molecules

“…It is a subject that needs to be further investigated for alphaherpesvirus gB. HSV-1 EVs have been already reported to mediate innate immunity by transferring the stimulator of interferon genes (STING) and viral microRNA miR-H28 to uninfected cells, sensitizing the recipient cells to forthcoming infection [4,78]. It would be interesting to check if during BoHV-1 or PRV infection, EVs can also shape the immune response.…”