title: Theta defensins protect cells from infection by herpes simplex virus by inhibiting viral adhesion and entry.
abstract: 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 (K(d), 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1731, USA.
authors.forename: Bushra
authors.initials: B
authors.lastname: Yasin
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Mabel
authors.initials: M
authors.lastname: Pang
authors.forename: Natalia
authors.initials: N
authors.lastname: Cheshenko
authors.forename: Teresa
authors.initials: T
authors.lastname: Hong
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Waring
authors.forename: Betsy C
authors.initials: BC
authors.lastname: Herold
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Wagar
authors.forename: Robert I
authors.initials: RI
authors.lastname: Lehrer
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D023082:Defensins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D015497:HIV-1 / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000502:physiology; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007778:Lactobacillus / Q000187:drug effects; D008969:Molecular Sequence Data; D014621:Vagina / Q000382:microbiology; D023084:alpha-Defensins / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D023082:Defensins; D023084:alpha-Defensins; C450142:theta-defensin