{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:12:04Z","timestamp":1760235124376,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T00:00:00Z","timestamp":1626912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/v13081422","type":"journal-article","created":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T22:37:14Z","timestamp":1626993434000},"page":"1422","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Peptide Inhibitor of Complement C1, RLS-0071, Reduces Zosteriform Spread of Herpes Simplex Virus Type 1 Skin Infection and Promotes Survival in Infected Mice"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0057-8094","authenticated-orcid":false,"given":"Maimoona","family":"Bhutta","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23507, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Sausen","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23507, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirstin","family":"Reed","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23507, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Gallo","sequence":"additional","affiliation":[{"name":"Board-Certified Dermatologist and Independent Researcher, Norfolk, VA 23507, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pamela","family":"Hair","sequence":"additional","affiliation":[{"name":"ReAlta Life Sciences, Inc., Norfolk, VA 23502, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brittany","family":"Lassiter","sequence":"additional","affiliation":[{"name":"ReAlta Life Sciences, Inc., Norfolk, VA 23502, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neel","family":"Krishna","sequence":"additional","affiliation":[{"name":"ReAlta Life Sciences, Inc., Norfolk, VA 23502, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Cunnion","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23507, USA"},{"name":"ReAlta Life Sciences, Inc., Norfolk, VA 23502, USA"},{"name":"Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA 23507, USA"},{"name":"Children\u2019s Specialty Group, 811 Redgate Avenue, Norfolk, VA 23507, USA"},{"name":"Children\u2019s Hospital of The King\u2019s Daughters, Norfolk, VA 23507, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronen","family":"Borenstein","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23507, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,22]]},"reference":[{"key":"ref_1","unstructured":"WHO (2021, May 27). Massive Proportion of World\u2019s Population Are Living with Herpes Infection. Available online: https:\/\/www.who.int\/news\/item\/01-05-2020-massive-proportion-world-population-living-with-herpes-infection#:~:text=An%20estimated%203.7%20billion%20people,the%20mouth%20(oral%20herpes)."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Waisner, H., and Kalamvoki, M. (2019). The ICP0 Protein of Herpes Simplex Virus 1 (HSV-1) Downregulates Major Autophagy Adaptor Proteins Sequestosome 1 and Optineurin during the Early Stages of HSV-1 Infection. J. Virol., 93.","DOI":"10.1128\/JVI.01258-19"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.jdermsci.2018.09.006","article-title":"Cell-to-cell transmission of HSV-1 in differentiated keratinocytes promotes multinucleated giant cell formation","volume":"93","author":"Yamamoto","year":"2019","journal-title":"J. Dermatol. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3009","DOI":"10.1038\/jid.2015.290","article-title":"Invasion of Herpes Simplex Virus Type 1 into Murine Epidermis: An Ex Vivo Infection Study","volume":"135","author":"Rahn","year":"2015","journal-title":"J. Investig. Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1128\/JVI.02917-14","article-title":"Entry Mechanisms of Herpes Simplex Virus 1 into Murine Epidermis: Involvement of Nectin-1 and Herpesvirus Entry Mediator as Cellular Receptors","volume":"89","author":"Petermann","year":"2014","journal-title":"J. Virol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1007\/s007050200024","article-title":"The ability of an HSV strain to initiate zosteriform spread correlates with its neuroinvasive disease potential","volume":"147","author":"Goel","year":"2002","journal-title":"Arch. Virol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8315","DOI":"10.1128\/JVI.00633-09","article-title":"Anterograde Spread of Herpes Simplex Virus Type 1 Requires Glycoprotein E and Glycoprotein I but Not Us9","volume":"83","author":"McGraw","year":"2009","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1128\/AAC.49.3.1055-1059.2005","article-title":"Herpes Simplex Virus Thymidine Kinase Mutations Associated with Resistance to Acyclovir: A Site-Directed Mutagenesis Study","volume":"49","author":"Frobert","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1097\/QCO.0000000000000288","article-title":"Antiviral resistance in herpes simplex virus and varicella-zoster virus infections","volume":"29","author":"Piret","year":"2016","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.4049\/jimmunol.1402354","article-title":"Complement Deficiency Promotes Cutaneous Wound Healing in Mice","volume":"194","author":"Rafail","year":"2015","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"534291","DOI":"10.1155\/2012\/534291","article-title":"Complement Activation and Inhibition in Wound Healing","volume":"2012","author":"Cazander","year":"2012","journal-title":"Clin. Dev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Sharp, J.A., Hair, P.S., Pallera, H.K., Kumar, P.S., Mauriello, C.T., Nyalwidhe, J.O., Phelps, C.A., Park, D., Thielens, N.M., and Pascal, S.M. (2015). Peptide Inhibitor of Complement C1 (PIC1) Rapidly Inhibits Complement Activation after Intravascular Injection in Rats. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132446"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"406","DOI":"10.3389\/fimmu.2014.00406","article-title":"Peptide Inhibitor of Complement C1, a Novel Suppressor of Classical Pathway Activation: Mechanistic Studies and Clinical Potential","volume":"5","author":"Sharp","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"558","DOI":"10.3389\/fimmu.2018.00558","article-title":"Inhibition of Immune Complex Complement Activation and Neutrophil Extracellular Trap Formation by Peptide Inhibitor of Complement C1","volume":"9","author":"Hair","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hair, P.S., Sass, L.A., Krishna, N.K., and Cunnion, K.M. (2017). Inhibition of Myeloperoxidase Activity in Cystic Fibrosis Sputum by Peptide Inhibitor of Complement C1 (PIC1). PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0170203"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Cunnion, K.M., Krishna, N.K., Pallera, H.K., Pineros-Fernandez, A., Rivera, M.G., Hair, P.S., Lassiter, B.P., Huyck, R., Clements, M.A., and Hood, A.F. (2017). Complement Activation and STAT4 Expression Are Associated with Early Inflammation in Diabetic Wounds. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0170500"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4110","DOI":"10.1128\/JVI.73.5.4110-4119.1999","article-title":"Live-Cell Analysis of a Green Fluorescent Protein-Tagged Herpes Simplex Virus Infection","volume":"73","author":"Elliott","year":"1999","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Bhutta, M.S., Shechter, O., Gallo, E.S., Martin, S.D., Jones, E., Doncel, G.F., and Borenstein, R. (2021). Ginkgolic Acid Inhibits Herpes Simplex Virus Type 1 Skin Infection and Prevents Zosteriform Spread in Mice. Viruses, 13.","DOI":"10.3390\/v13010086"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4746","DOI":"10.1038\/s41598-020-61700-0","article-title":"Ginkgolic acid inhibits fusion of enveloped viruses","volume":"10","author":"Borenstein","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s10989-017-9651-z","article-title":"Peptide Inhibitor of Complement C1 (PIC1) Inhibits Growth of Pathogenic Bacteria","volume":"25","author":"Hair","year":"2019","journal-title":"Int. J. Pept. Res. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1126\/science.1193748","article-title":"Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women","volume":"329","author":"Karim","year":"2010","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1089\/aid.2005.21.845","article-title":"In Vitroandin VivoCharacterization of a Potential Universal Placebo Designed for Use in Vaginal Microbicide Clinical Trials","volume":"21","author":"Tien","year":"2005","journal-title":"AIDS Res. Hum. Retroviruses"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1111\/j.1365-2141.2011.08988.x","article-title":"Management of multidrug-resistant viruses in the immunocompromised host","volume":"156","author":"Sellar","year":"2011","journal-title":"Br. J. Haematol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.3851\/IMP1870","article-title":"Novel resistance-associated mutations of thymidine kinase and DNA polymerase genes of herpes simplex virus type 1 and type 2","volume":"16","author":"Sauerbrei","year":"2011","journal-title":"Antivir. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1093\/jac\/dkv285","article-title":"Database on natural polymorphisms and resistance-related non-synonymous mutations in thymidine kinase and DNA polymerase genes of herpes simplex virus types 1 and 2","volume":"71","author":"Sauerbrei","year":"2015","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1128\/AAC.46.6.1766-1772.2002","article-title":"Potent in Vivo Antiviral Activity of the Herpes Simplex Virus Primase-Helicase Inhibitor BAY 57-1293","volume":"46","author":"Betz","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_27","first-page":"143","article-title":"Type I IFN suppresses Cxcr2 driven neutrophil recruitment into the sensory ganglia during viral infection","volume":"11","author":"Stock","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/nri2937","article-title":"Recognition of herpesviruses by the innate immune system","volume":"11","author":"Paludan","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-021-22841-6","article-title":"Nociceptive sensory neurons promote CD8 T cell responses to HSV-1 infection","volume":"12","author":"Filtjens","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"srep41091","DOI":"10.1038\/srep41091","article-title":"Neutrophils are dispensable in the modulation of T cell immunity against cutaneous HSV-1 infection","volume":"7","author":"Hor","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2791","DOI":"10.3389\/fimmu.2020.593901","article-title":"Skin Viral Infections: Host Antiviral Innate Immunity and Viral Immune Evasion","volume":"11","author":"Lei","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wang, L., Wang, R., Xu, C., and Zhou, H. (2020). Pathogenesis of Herpes Stromal Keratitis: Immune Inflammatory Response Mediated by Inflammatory Regulators. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00766"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.virol.2010.08.001","article-title":"Gr-1+ cells, but not neutrophils, limit virus replication and lesion development following flank infection of mice with herpes simplex virus type-1","volume":"407","author":"Wojtasiak","year":"2010","journal-title":"Virology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1111\/j.1600-0765.2012.01476.x","article-title":"Effects of herpes simplex virus type 1 infection on immune functions of human neutrophils","volume":"47","author":"Hung","year":"2012","journal-title":"J. Periodontal Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1086\/515626","article-title":"Phenotypic and Genotypic Characterization of Acyclovir-Resistant Herpes Simplex Viruses from Immunocompromised Patients","volume":"178","author":"Gaudreau","year":"1998","journal-title":"J. Infect. Dis."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/8\/1422\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:33:07Z","timestamp":1760164387000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/8\/1422"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,22]]},"references-count":35,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["v13081422"],"URL":"https:\/\/doi.org\/10.3390\/v13081422","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2021,7,22]]}}}