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Journal of Virology, May 2004, p. 5147-5156, Vol. 78, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.10.5147-5156.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

{theta} Defensins Protect Cells from Infection by Herpes Simplex Virus by Inhibiting Viral Adhesion and Entry

Bushra Yasin,1 Wei Wang,2 Mabel Pang,1 Natalia Cheshenko,3 Teresa Hong,2 Alan J. Waring,2 Betsy C. Herold,3 Elizabeth A. Wagar,1 and Robert I. Lehrer2*

Departments of Pathology and Laboratory Medicine,1 Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-1731,2 Department of Pediatrics and Microbiology, Mount Sinai Medical School, New York, New York 100293

Received 13 October 2003/ Accepted 22 January 2004

We tested the ability of 20 synthetic {theta} defensins to protect cells from infection by type 1 and type 2 herpes simplex viruses (HSV-1 and -2, respectively). The peptides included rhesus {theta} defensins (RTDs) 1 to 3, originally isolated from rhesus macaque leukocytes, and three peptides (retrocyclins 1 to 3) whose sequences were inferred from human {theta}-defensin (DEFT) pseudogenes. We also tested 14 retrocyclin analogues, including the retro, enantio, and retroenantio forms of retrocyclin 1. Retrocyclins 1 and 2 and RTD 3 protected cervical epithelial cells from infection by both HSV serotypes, but only retrocyclin 2 did so without causing cytotoxicity or requiring preincubation with the virus. Surface plasmon resonance studies revealed that retrocyclin 2 bound to immobilized HSV-2 glycoprotein B (gB2) with high affinity (Kd, 13.3 nM) and that it did not bind to enzymatically deglycosylated gB2. Temperature shift experiments indicated that retrocyclin 2 and human {alpha} defensins human neutrophil peptide 1 (HNP 1) to HNP 3 protected human cells from HSV-2 by different mechanisms. Retrocyclin 2 blocked viral attachment, and its addition during the binding or penetration phases of HSV-2 infection markedly diminished nuclear translocation of VP16 and expression of ICP4. In contrast, HNPs 1 to 3 had little effect on binding but reduced both VP16 transport and ICP4 expression if added during the postbinding (penetration) period. We recently reported that {theta} defensins are miniature lectins that bind gp120 of human immunodeficiency virus type 1 (HIV-1) with high affinity and inhibit the entry of R5 and X4 isolates of HIV-1. Given its small size (18 residues), minimal cytotoxicity, lack of activity against vaginal lactobacilli, and effectiveness against both HSV-2 and HIV-1, retrocyclin 2 provides an intriguing prototype for future topical microbicide development.

* Corresponding author. Mailing address: Department of Medicine, CHS 37-062, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095. Phone: (310) 825-5340. Fax: (310) 206-8766. E-mail: rlehrer{at}mednet.ucla.edu.

Journal of Virology, May 2004, p. 5147-5156, Vol. 78, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.10.5147-5156.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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