Peptide Inhibitor of Complement C1, RLS-0071, Reduces Zosteriform Spread of Herpes Simplex Virus Type 1 Skin Infection and Promotes Survival in Infected Mice.

Maimoona Bhutta,Kirstin Reed,Elisa Gallo,Kenji Cunnion,Pamela Hair,Ronen Borenstein,Brittany Lassiter,Daniel Sausen,Neel Krishna

doi:10.3390/v13081422

Abstract

Herpes simplex virus type 1 (HSV-1) is a prevalent human pathogen primarily transmitted through skin-to-skin contact, especially on and around mucosal surfaces where there is contact with contaminated saliva during periods of viral shedding. It is estimated that 90% of adults worldwide have HSV-1 antibodies. Cutaneous HSV-1 infections are characterized by a sensation of tingling or numbness at the initial infection site followed by an eruption of vesicles and then painful ulcers with crusting. These symptoms can take ten days to several weeks to heal, leading to significant morbidity. Histologically, infections cause ballooning degeneration of keratinocytes and formation of multinucleated giant cells, ultimately resulting in a localized immune response. Commonly prescribed treatments against HSV-1 infections are nucleoside analogs, such as acyclovir (ACV). However, the emergence of ACV-resistant HSV (ACVR-HSV) clinical isolates has created an urgent need for the development of compounds to control symptoms of cutaneous infections. RLS-0071, also known as peptide inhibitor of complement C1 (PIC1), is a 15-amino-acid anti-inflammatory peptide that inhibits classical complement pathway activation and modulates neutrophil activation. It has been previously shown to aid in the healing of chronic diabetic wounds by inhibiting the excessive activation of complement component C1 and infiltration of leukocytes. Here, we report that treatment of cutaneous infections of HSV-1 and ACVR-HSV-1 in BALB/cJ mice with RLS-0071 significantly reduced the rate of mortality, decreased zosteriform spread, and enhanced the healing of the infection-associated lesions compared to control-treated animals. Therefore, RLS-0071 may work synergistically with other antiviral drugs to aid in wound healing of HSV-1 cutaneous infection and may potentially aid in rapid wound healing of other pathology not limited to HSV-1.

Highlights

An estimated 3.7 billion individuals live with herpes simplex virus 1 (HSV-1) infection worldwide [1]
We report that RLS-0071 has beneficial activity against Herpes simplex virus type 1 (HSV-1) skin infection in BALB/cJ mice
To test the antiviral activity of RLS-0071, 80–85% confluent Vero cells were pretreated with varying concentrations of RLS-0071 or HIS buffer and infected with 0.1 MOI of GFP-HSV-1 17+

Summary

Introduction

An estimated 3.7 billion individuals live with herpes simplex virus 1 (HSV-1) infection worldwide [1]. HSV-1 primarily infects the mucosal epithelial cells, causing the formation of painful, vesicular lesions [2]. Primary infection in the epithelium occurs as HSV-1 targets the basal keratinocytes, spreading into the supra-basal layers [3,4]. Cellular entry of HSV-1 requires the interaction of envelope glycoproteins and cell surface receptors. Glycoprotein D (gD) receptors, herpesvirus entry mediator (HVEM), nectin-1/nectin-2, and 3-O-sulfotransferase-generated heparan sulfate mediate viral entry in murine and human models of infection [3,5]. Murine models have been widely used to investigate cutaneous HSV-1 infection, as they contain HVEM and nectin-1 receptor homologs that support viral entry [3]. Cutaneous or zosteriform scarification models are utilized to infect mice efficiently

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