Human alpha- and beta-defensins block multiple steps in herpes simplex virus infection.
This study examined the ability of nine human defensins (HD) to protect against herpes simplex virus infection. Noncytotoxic concentrations of all six alpha-defensins (HNP1-4, HD5, and HD6) and human beta-defensin (hBD) 3 inhibited HSV infection. Two other beta-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.
Hazrati
Ehsan
E
Department of Pediatrics, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029, USA.
Galen
Benjamin
B
Lu
Wuyuan
W
Wang
Wei
W
Ouyang
Yan
Y
Keller
Marla J
MJ
Lehrer
Robert I
RI
Herold
Betsy C
BC
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells; D006493:Heparin / Q000378:metabolism; D006561:Herpes Simplex / Q000276:immunology*; D006801:Humans; D051379:Mice; D011485:Protein Binding; D020349:Surface Plasmon Resonance; D014759:Viral Envelope Proteins / Q000378:metabolism; D023084:alpha-Defensins / Q000276:immunology* / Q000378:metabolism; D023083:beta-Defensins / Q000276:immunology* / Q000378:metabolism
C422950:DEFB103A protein, human; C465593:DEFB105A protein, human; C465592:DEFB106A protein, human; D014759:Viral Envelope Proteins; D023084:alpha-Defensins; D023083:beta-Defensins; C040495:glycoprotein B, Simplexvirus; C406413:human neutrophil peptide 1; C406416:human neutrophil peptide 2; C406427:human neutrophil peptide 3; C406428:human neutrophil peptide 4; D006493:Heparin