title: Griffithsin protects mice from genital herpes by preventing cell-to-cell spread.
abstract: Griffithsin, which binds N-linked glycans on gp120 to prevent HIV entry, has the most potent HIV-1 inhibitory activity described for any antiviral lectin and is being developed for topical preexposure prophylaxis. The current studies were designed to further assess its potential by exploring its activity against herpes simplex virus 2 (HSV-2), a cofactor for HIV acquisition, in vitro and in a murine model. Safety was evaluated by examining its impact on epithelial barrier integrity in polarized cultures and testing whether repeated intravaginal dosing potentiates the susceptibility of mice to genital herpes. Griffithsin displayed modest inhibitory activity against HSV-2 if present during viral entry but completely blocked plaque formation if present postentry, reduced plaque size, and prevented cell-to-cell spread. These in vitro findings translated to significant protection against genital herpes in mice treated with 0.1% griffithsin gel. Griffithsin, but not placebo gel, prevented viral spread (visualized with a luciferase-expressing virus), significantly reduced disease scores, and resulted in greater survival (P < 0.05, log rank test). Protection persisted when HSV-2 was introduced in seminal plasma. Although griffithsin triggered a small decline in transepithelial electrical resistance in polarized cultures, this did not translate to any significant increase in the ability of HIV to migrate from the apical to the basolateral chamber nor to an increase in susceptibility to HSV-2 in mice treated with griffithsin gel for 7 days. These findings demonstrate that griffithsin inhibits HSV-2 by a unique mechanism of blocking cell-to-cell spread and support its further development for HIV and HSV-2 prevention.
authors.affiliation: Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Briana
authors.initials: B
authors.lastname: Nixon
authors.forename: Martha
authors.initials: M
authors.lastname: Stefanidou
authors.forename: Pedro M M
authors.initials: PM
authors.lastname: Mesquita
authors.forename: Esra
authors.initials: E
authors.lastname: Fakioglu
authors.forename: Theodore
authors.initials: T
authors.lastname: Segarra
authors.forename: Lisa
authors.initials: L
authors.lastname: Rohan
authors.forename: William
authors.initials: W
authors.lastname: Halford
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Palmer
authors.forename: Betsy C
authors.initials: BC
authors.lastname: Herold
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D005260:Female; D006558:Herpes Genitalis / Q000517:prevention & control* / Q000821:virology*; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D037121:Plant Lectins / Q000008:administration & dosage*; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D037121:Plant Lectins; C499654:griffithsin protein, Griffithsia
references.citation: J Virol. 2000 Aug;74(15):6712-9
references.pmid: 10888608
references.citation: Antimicrob Agents Chemother. 2012 Feb;56(2):805-15
references.pmid: 22083472
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 14;106(15):6099-104
references.pmid: 19332801
references.citation: PLoS One. 2007 Oct 03;2(10):e1001
references.pmid: 17912340
references.citation: J Virol. 2009 Dec;83(23):12559-68
references.pmid: 19793807
references.citation: PLoS One. 2011;6(11):e27675
references.pmid: 22096611
references.citation: J Virol. 2013 Feb;87(3):1443-53
references.pmid: 23152529
references.citation: J Virol. 2007 Jul;81(14):7636-46
references.pmid: 17494078
references.citation: Glycobiology. 2000 Dec;10(12):1259-69
references.pmid: 11159917
references.citation: Lancet. 2010 Oct 16;376(9749):1329-37
references.pmid: 20851460
references.citation: J Virol. 2010 Mar;84(5):2511-21
references.pmid: 20032190
references.citation: J Virol. 2004 Feb;78(4):1706-17
references.pmid: 14747536
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 3;107(31):13800-5
references.pmid: 20643940
references.citation: Antimicrob Agents Chemother. 2003 Aug;47(8):2518-25
references.pmid: 12878514
references.citation: N Engl J Med. 2012 Aug 2;367(5):411-22
references.pmid: 22784040
references.citation: Nat Rev Microbiol. 2007 Aug;5(8):583-97
references.pmid: 17632570
references.citation: J Virol. 2000 Dec;74(24):11437-46
references.pmid: 11090139
references.citation: Clin Exp Immunol. 2003 Jul;133(1):97-107
references.pmid: 12823283
references.citation: J Virol. 2005 Sep;79(18):11990-2001
references.pmid: 16140775
references.citation: Biol Reprod. 1997 Oct;57(4):847-55
references.pmid: 9314589
references.citation: Virology. 1983 Nov;131(1):59-70
references.pmid: 6316656
references.citation: Structure. 2010 Sep 8;18(9):1104-15
references.pmid: 20826337
references.citation: PLoS One. 2011 Mar 11;6(3):e17748
references.pmid: 21412438
references.citation: Clin Infect Dis. 2011 Dec;53(12):1265-70
references.pmid: 21976467
references.citation: PLoS One. 2011;6(8):e22635
references.pmid: 21829638
references.citation: J Virol. 1982 Oct;44(1):241-8
references.pmid: 6292487
references.citation: J Infect Dis. 2007 May 1;195(9):1332-9
references.pmid: 17397004
references.citation: Antiviral Res. 2009 Oct;84(1):67-75
references.pmid: 19665490
references.citation: Curr Opin Infect Dis. 2012 Feb;25(1):51-7
references.pmid: 22156901
references.citation: Virology. 2011 Sep 1;417(2):253-8
references.pmid: 21802104
references.citation: J Acquir Immune Defic Syndr. 2012 Oct 1;61(2):194-202
references.pmid: 22820806
references.citation: N Engl J Med. 2007 Feb 22;356(8):790-9
references.pmid: 17314338
references.citation: Antivir Ther. 2009;14(8):1113-24
references.pmid: 20032541
references.citation: J Med Primatol. 2007 Aug;36(4-5):244-53
references.pmid: 17669213
references.citation: J Infect Dis. 2009 Aug 15;200(4):599-608
references.pmid: 19586414
references.citation: J Virol. 2007 Dec;81(24):13315-24
references.pmid: 17913820
references.citation: J Virol. 2008 Jul;82(13):6576-84
references.pmid: 18434407
references.citation: PLoS One. 2011;6(8):e23521
references.pmid: 21858152
references.citation: N Engl J Med. 2012 Aug 2;367(5):399-410
references.pmid: 22784037
references.citation: J Infect Dis. 2007 Nov 1;196(9):1394-402
references.pmid: 17922405
references.citation: N Engl J Med. 2008 Jul 31;359(5):463-72
references.pmid: 18669425
references.citation: Virology. 1995 Feb 1;206(2):1108-16
references.pmid: 7856085
references.citation: Virology. 1995 Dec 1;214(1):29-39
references.pmid: 8525631
references.citation: AIDS Res Hum Retroviruses. 2012 Nov;28(11):1373-8
references.pmid: 22966871
references.citation: J Gen Virol. 1968 May;2(3):357-64
references.pmid: 4300104
references.citation: PLoS One. 2010 Jan 22;5(1):e8781
references.pmid: 20107502
references.citation: Science. 2010 Sep 3;329(5996):1168-74
references.pmid: 20643915
references.citation: Proteins. 2007 May 15;67(3):661-70
references.pmid: 17340634
references.citation: J Virol. 1991 Mar;65(3):1090-8
references.pmid: 1847438
references.citation: AIDS. 2006 Jan 2;20(1):73-83
references.pmid: 16327322
references.citation: Virology. 2000 May 25;271(1):155-62
references.pmid: 10814580
references.citation: Virology. 2010 Jun 20;402(1):187-96
references.pmid: 20392471
references.citation: Antimicrob Agents Chemother. 2004 Jun;48(6):2025-36
references.pmid: 15155195
references.citation: Scand J Infect Dis. 1991;23(4):425-30
references.pmid: 1659737