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- and 
-Defensins Block Multiple Steps in Herpes Simplex Virus Infection1
* Department of Pediatrics and
Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029;
Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, MD 21201; and
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
This study examined the ability of nine human defensins (HD) to protect against herpes simplex virus infection. Noncytotoxic concentrations of all six 
-defensins (HNP1–4, HD5, and HD6) and human 
-defensin (hBD) 3 inhibited HSV infection. Two other -defensins, hBD1 and 2, lacked this protective activity. Synchronized assays revealed that HNP-4, HD6, and hBD3 acted primarily by preventing binding and entry, whereas HNP1–3 and HD5 also inhibited postentry events. Even when added several hours after entry, substantial reduction in viral gene expression ensued. Human cervical epithelial cells incubated with HNP-1 or HD5 accumulated the peptides intracellularly. Surface plasmon resonance studies revealed that HNPs 1, 2, 3, and HD5 bound HSV glycoprotein B (gB) with high affinity, but showed minimal binding to heparan sulfate, the receptor for attachment. In contrast, HNP-4 and HD6 bound heparan sulfate, but not gB. HBD3 bound both gB and heparan sulfate, but hBD1 and hBD2 bound neither. Admixture of HD5 with hydroxyethylcellulose significantly protected mice from a viral challenge lethal to controls receiving an inactive peptide or hydroxyethylcellulose alone. These findings demonstrate that HDs act at multiple steps in the HSV life cycle and support the development of defensins or defensin-like peptides as microbicides.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by U.S. Public Health Service Grants AI065309 (to B.C.H.) and AI061482 (to W.L.).
2 Address correspondence and reprint requests to Dr. Betsy C. Herold, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1657, New York, NY 10029. E-mail address: betsy.herold{at}mssm.edu
3 Abbreviations used in this paper: SLPI, secretory leukocyte protease inhibitor; STI, sexually transmitted infection; MOI, multiplicity of infection; HNP, human neutrophil peptide; HD, human defensin; hBD, human -defensin; HPV, human papillomavirus; HEC, hydroxyethylcellulose; gB, glycoprotein B; VP16, viral protein 16; ICP, infected cell protein; HR, heptad repeat; PKC, protein kinase C; RU, resonance unit.
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