title: Bridging the gap between preclinical and clinical microbicide trials: blind evaluation of candidate gels in murine models of efficacy and safety.
abstract: BACKGROUND
  Despite significant protection in preclinical studies, cellulose sulfate (CS) failed to protect women against HIV-1/2 and was associated with a trend toward increased HIV-1 acquisition in one of the clinical trials. These results highlight the need for preclinical tests more predictive of clinical outcomes. The objective of this study was to test coded vaginal gels, including CS, in murine models of safety and efficacy to determine the models' utility for evaluating future products.
  
  
  METHODS
  Four coded formulations, including 6% CS, 2% PRO 2000 and two placebo gels, were administered intravaginally to medroxyprogesterone-treated mice and their ability to prevent genital herpes (efficacy) or to alter the susceptibility to low dose HSV challenge (safety) was determined. Nonoyxnol-9 served as a positive toxicity control.
  
  
  RESULTS
  CS and PRO 2000 significantly protected mice from genital herpes following infection with a laboratory or clinical isolate of HSV-2 introduced in buffer (p<0.001). However, protection was reduced when virus was introduced in seminal plasma. Moreover, mice were significantly more susceptible to infection with low doses of HSV-2 when challenged 12 h after the 7th daily dose of CS or nonoxynol-9 (p<0.05). The increased susceptibility was associated with alterations in epithelial architecture.
  
  
  CONCLUSIONS
  CS prevented genital herpes when present at the time of viral challenge, but increased the rate of infection when gel was applied daily for 7 days with a vaginal wash prior to viral inoculation. The findings presumably reflect altered epithelial architecture, which may have contributed to the trend towards increased HIV observed clinically.
authors.affiliation: Department of Pediatrics and Microbiology-Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Segarra
authors.forename: Esra
authors.initials: E
authors.lastname: Fakioglu
authors.forename: Natalia
authors.initials: N
authors.lastname: Cheshenko
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Wilson
authors.forename: Pedro M M
authors.initials: PM
authors.lastname: Mesquita
authors.forename: Gustavo F
authors.initials: GF
authors.lastname: Doncel
authors.forename: Betsy C
authors.initials: BC
authors.lastname: Herold
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002482:Cellulose / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D006558:Herpes Genitalis / Q000517:prevention & control*; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000472:pathogenicity; D051379:Mice; D009282:Naphthalenesulfonates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D011108:Polymers / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000890:Anti-Infective Agents; D009282:Naphthalenesulfonates; C120231:PRO 2000; D011108:Polymers; D014622:Vaginal Creams, Foams, and Jellies; D002482:Cellulose; C020254:cellulose sulfate
references.citation: PLoS One. 2008 Sep 08;3(9):e3162
references.pmid: 18776937
references.citation: AIDS. 2009 Jan 28;23(3):309-17
references.pmid: 19114868
references.citation: J Virol. 2004 Mar;78(5):2530-6
references.pmid: 14963155
references.citation: AIDS. 2001 Aug 17;15(12):1563-8
references.pmid: 11504989
references.citation: Sex Transm Dis. 2009 May;36(5):312-8
references.pmid: 19295469
references.citation: Retrovirology. 2011 Aug 11;8:65
references.pmid: 21835012
references.citation: AIDS. 2000 Jan 7;14(1):85-8
references.pmid: 10714571
references.citation: Antivir Ther. 2009;14(8):1113-24
references.pmid: 20032541
references.citation: Lancet. 2002 Sep 28;360(9338):971-7
references.pmid: 12383665
references.citation: Lancet. 2008 Dec 6;372(9654):1977-87
references.pmid: 19059048
references.citation: Genes Immun. 2005 May;6(3):203-10
references.pmid: 15772680
references.citation: Lancet. 2010 Oct 16;376(9749):1329-37
references.pmid: 20851460
references.citation: Am J Pathol. 2005 Feb;166(2):409-19
references.pmid: 15681825
references.citation: Mol Cell Biol. 2011 Feb;31(4):756-65
references.pmid: 21135124
references.citation: Physiol Genomics. 2007 Aug 20;30(3):213-22
references.pmid: 17456736
references.citation: J Immunol. 2006 Dec 15;177(12):8658-66
references.pmid: 17142766
references.citation: Contraception. 2004 Sep;70(3):233-40
references.pmid: 15325893
references.citation: Contraception. 2004 Nov;70(5):415-22
references.pmid: 15504382
references.citation: Am J Reprod Immunol. 2011 Mar;65(3):325-33
references.pmid: 21143689
references.citation: Am J Obstet Gynecol. 1995 Aug;173(2):534-43
references.pmid: 7645632
references.citation: J Virol. 2009 Oct;83(20):10358-65
references.pmid: 19656878
references.citation: Contraception. 2006 Aug;74(2):133-40
references.pmid: 16860051
references.citation: PLoS One. 2008 Jan 23;3(1):e1474
references.pmid: 18213382
references.citation: J Infect Dis. 2007 May 1;195(9):1332-9
references.pmid: 17397004
references.citation: J Immunol. 2008 Apr 15;180(8):5653-61
references.pmid: 18390750
references.citation: mBio. 2011 Oct 25;2(6):e00168-11
references.pmid: 22027006
references.citation: Sex Transm Dis. 2008 Mar;35(3):269-75
references.pmid: 18091028
references.citation: Sex Transm Dis. 2008 Oct;35(10):889-97
references.pmid: 18607310
references.citation: Am J Reprod Immunol. 2011 Mar;65(3):308-16
references.pmid: 21214660
references.citation: J Infect Dis. 2009 Aug 15;200(4):599-608
references.pmid: 19586414
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: 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: Antimicrob Agents Chemother. 1997 Dec;41(12):2776-80
references.pmid: 9420059
references.citation: Virology. 2000 May 25;271(1):155-62
references.pmid: 10814580
references.citation: PLoS One. 2007 Dec 19;2(12):e1312
references.pmid: 18091987
references.citation: AIDS. 2010 Jul 17;24(11):1778-81
references.pmid: 20588106