Ginkgolic Acid Inhibits Herpes Simplex Virus Type 1 Skin Infection and Prevents Zosteriform Spread in Mice.

Maimoona Bhutta,Gustavo Doncel,Elisa Gallo,Stephen Martin,Esther Jones,Oren Shechter,Ronen Borenstein

doi:10.3390/v13010086

Maimoona Bhutta, Gustavo Doncel + Show 5 more

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https://doi.org/10.3390/v13010086

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Abstract

Herpes simplex virus type 1 (HSV-1) causes a lifelong latent infection with an estimated global prevalence of 66%. Primary and recurrent HSV infections are characterized by a tingling sensation, followed by an eruption of vesicles, which can cause painful erosions. Commonly used antiviral drugs against HSV infection are nucleoside analogues including acyclovir (ACV), famciclovir, and valacyclovir. Although these nucleoside analogues reduce morbidity and mortality in immunocompetent individuals, ACV-resistant HSV strains (ACVR-HSV) have been isolated from immunocompromised patients. Thus, ACVR-HSV infection poses a critical emerging public health concern. Recently, we reported that ginkgolic acid (GA) inhibits HSV-1 by disrupting viral structure, blocking fusion, and inhibiting viral protein synthesis. Additionally, we showed GA affords a broad spectrum of fusion inhibition of all three classes of fusion proteins, including those of HIV, Ebola, influenza A and Epstein Barr viruses. Here we report GA’s antiviral activity against HSV-1 skin infection in BALB/cJ mice. GA-treated mice demonstrated a significantly reduced mortality rate and decreased infection scores compared to controls treated with dimethylsulfoxide (DMSO)-vehicle. Furthermore, GA efficiently inhibited ACVR-HSV-1 strain 17+ in vitro and in vivo. Since GA’s mechanism of action includes virucidal activity and fusion inhibition, it is expected to work alone or synergistically with other anti-viral drugs, and we anticipate it to be effective against additional cutaneous and potentially systemic viral infections.

Highlights

Herpes simplex virus type 1 (HSV-1) is a prevalent human pathogen with an estimated global prevalence of 66% (3752 million people) [1,2]
We report for the first time that Ginkgolic acid (GA) has antiviral activity against HSV-1 skin infection in BALB/cJ mice
Exposure of nucleoside analogues, such as acyclovir, in cell culture can provide selective pressure that can lead to enrichment of drug-resistant thymidine kinase (TK) variants [33]

Summary

Introduction

Herpes simplex virus type 1 (HSV-1) is a prevalent human pathogen with an estimated global prevalence of 66% (3752 million people) [1,2]. HSV-1 causes a lifelong latent infection, and it is primarily transmitted through fluids or droplets from cutaneous or mucosal lesions [2,3]. The virus enters the sensory nerve endings and neural ganglia, where it establishes a lifelong latency, and with reactivation, recurs at the mucosal and cutaneous sites. The primary mechanism of viral entry occurs through the fusion of the viral envelope with the host cell’s plasma membrane, which is followed by transport of the viral capsid to the nucleus [6]. Regulation of HSV-1 transcription occurs in sequential three phases of gene expression, beginning with the production of immediate-early (IE) or α-genes, early (E)

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