Viral UL8 Is Involved in the Antiviral Activity of Oleanolic Acid Against HSV-1 Infection.

Tianhao Shan,Yuzhou Jiang,Kai Zheng,Zhaoyang Wang,Jiaoyan Jia,Yifei Wang,Ju Ye,Yiliang Wang,Zhe Ren

doi:10.3389/fmicb.2021.689607

Abstract

Herpes simplex virus type 1 (HSV-1) is highly prevalent in humans and can cause severe diseases, especially in immunocompromised adults and newborns, such as keratitis and herpes simplex encephalitis. At present, the clinical therapeutic drug against HSV-1 infection is acyclovir (ACV), and its extensive usage has led to the emergence of ACV-resistant strains. Therefore, it is urgent to explore novel therapeutic targets and anti-HSV-1 drugs. This study demonstrated that Oleanolic acid, a pentacyclic triterpenoid widely existing in natural product, had strong antiviral activity against both ACV-sensitive and -resistant HSV-1 strains in different cells. Mechanism studies showed that Oleanolic acid exerted its anti-HSV-1 activity in the immediate early stage of infection, which involved the dysregulation of viral UL8, a component of viral helicase-primase complex critical for viral replication. In addition, Oleanolic acid significantly ameliorated the skin lesions in an HSV-1 infection mediated zosteriform model. Together, our study suggested that Oleanolic acid could be a potential candidate for clinical therapy of HSV-1 infection-related diseases.

Highlights

Herpes simplex virus type 1 (HSV-1) is an enveloped DNA virus belonging to alphaherpesvirinae subfamily (Midak-Siewirska et al, 2010)
These results suggest that Oleanolic acid has significant potential for the treatment of HSV-1 infection-induced skin lesions, such as H. gladiatorum
HaCaT cells were transfected with plasmids overexpressing UL5/UL8/UL52 before the cells were infected with HSV-1 (MOI = 5) in the presence or absence of Oleanolic acid (20 μM)

Summary

INTRODUCTION

Herpes simplex virus type 1 (HSV-1) is an enveloped DNA virus belonging to alphaherpesvirinae subfamily (Midak-Siewirska et al, 2010). The clinical drug against HSV-1 infection is acyclovir (ACV), which targets HSV-1 DNA polymerase to inhibit viral replication (Hassan et al, 2015). HSV-1 DNA replication requires the primase activity of the helicase-primase complex, which is a heterotrimer consisting of the protein products of viral UL5, UL8, and UL52 genes (Crute et al, 1989; Boehmer and Lehman, 1997). 15 derivatives of Oleanolic acid triterpenoids showed moderate anti-HSV-1 activities (Ikeda et al, 2005). We systematically evaluated the antiviral activity of Oleanolic acid against common HSV-1 and ACV-resistant HSV1 strains in vivo and in vitro. We explored its potential molecular mechanism, which involved the deregulation of viral UL8 These results suggest that Oleanolic acid has significant potential for the treatment of HSV-1 infection-induced skin lesions, such as H. gladiatorum

MATERIALS AND METHODS

RESULTS

DISCUSSION

Findings

DATA AVAILABILITY STATEMENT