Susceptibility to genital herpes as a biomarker predictive of increased HIV risk: Expansion of a murine model of microbicide safety

Sarah S. Wilson, Natalia V. Cheshenko, Esra Fakioglu, Pedro M M Mesquita, Marla J. Keller, Betsy Herold

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Background: A crucial gap in the development of microbicides for HIV prevention is the absence of models predictive of safety. Previous studies have demonstrated an increased susceptibility to genital herpes in mice following repeated applications of nonoxynol-9 (N-9). This study was designed to explore the underlying mechanisms, focusing on the effects that N-9 has on genital tract epithelium and to apply this expanded model to evaluate the safety of microbicides that have been advanced to clinical trials. Methods: Mice were treated intravaginally with formulated 3.5% N-9, 1% tenofovir, 0.5% or 2% PRO 2000, hydroxyethylcellulose (HEC) placebo or no treatment and the effect on herpes simplex virus 2 (HSV-2) susceptibility, epithelial cell architecture, junctional proteins and inflammation were assessed. Results: Mice treated with seven daily doses of N-9, but not tenofovir, PRO 2000 or HEC, were significantly more susceptible to challenge with low doses of HSV-2; confocal microscopy demonstrated increased numbers of viral particles deep within the genital tract. N-9 disrupted the epithelium with loss of tight and adherens junctional proteins. By contrast, the epithelium was relatively preserved following tenofovir, PRO 2000 and HEC exposure. Additionally, N-9, but not the other microbicides, triggered a significant inflammatory response relative to untreated mice. Conclusions: These findings indicate that disruption of the epithelium contributes to increased HSV-2 susceptibility and might provide a biomarker predictive of increased risk for HIV acquisition. The results are consistent with the safety outcomes of the recently completed Phase IIb clinical trial with 0.5% PRO 2000 gel, and predict that tenofovir gel will not adversely affect the genital tract.

Original languageEnglish (US)
Pages (from-to)1113-1124
Number of pages12
JournalAntiviral Therapy
Volume14
Issue number8
DOIs
StatePublished - 2009

Fingerprint

Tenofovir
Herpes Genitalis
Anti-Infective Agents
Human Herpesvirus 2
Epithelium
Biomarkers
HIV
Safety
Nonoxynol
Gels
Clinical Trials
Confocal Microscopy
Virion
Proteins
Epithelial Cells
Placebos
Inflammation
PRO 2000

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Susceptibility to genital herpes as a biomarker predictive of increased HIV risk : Expansion of a murine model of microbicide safety. / Wilson, Sarah S.; Cheshenko, Natalia V.; Fakioglu, Esra; Mesquita, Pedro M M; Keller, Marla J.; Herold, Betsy.

In: Antiviral Therapy, Vol. 14, No. 8, 2009, p. 1113-1124.

Research output: Contribution to journalArticle

@article{b96218c353644a01b31f2034e424f419,
title = "Susceptibility to genital herpes as a biomarker predictive of increased HIV risk: Expansion of a murine model of microbicide safety",
abstract = "Background: A crucial gap in the development of microbicides for HIV prevention is the absence of models predictive of safety. Previous studies have demonstrated an increased susceptibility to genital herpes in mice following repeated applications of nonoxynol-9 (N-9). This study was designed to explore the underlying mechanisms, focusing on the effects that N-9 has on genital tract epithelium and to apply this expanded model to evaluate the safety of microbicides that have been advanced to clinical trials. Methods: Mice were treated intravaginally with formulated 3.5{\%} N-9, 1{\%} tenofovir, 0.5{\%} or 2{\%} PRO 2000, hydroxyethylcellulose (HEC) placebo or no treatment and the effect on herpes simplex virus 2 (HSV-2) susceptibility, epithelial cell architecture, junctional proteins and inflammation were assessed. Results: Mice treated with seven daily doses of N-9, but not tenofovir, PRO 2000 or HEC, were significantly more susceptible to challenge with low doses of HSV-2; confocal microscopy demonstrated increased numbers of viral particles deep within the genital tract. N-9 disrupted the epithelium with loss of tight and adherens junctional proteins. By contrast, the epithelium was relatively preserved following tenofovir, PRO 2000 and HEC exposure. Additionally, N-9, but not the other microbicides, triggered a significant inflammatory response relative to untreated mice. Conclusions: These findings indicate that disruption of the epithelium contributes to increased HSV-2 susceptibility and might provide a biomarker predictive of increased risk for HIV acquisition. The results are consistent with the safety outcomes of the recently completed Phase IIb clinical trial with 0.5{\%} PRO 2000 gel, and predict that tenofovir gel will not adversely affect the genital tract.",
author = "Wilson, {Sarah S.} and Cheshenko, {Natalia V.} and Esra Fakioglu and Mesquita, {Pedro M M} and Keller, {Marla J.} and Betsy Herold",
year = "2009",
doi = "10.3851/IMP1463",
language = "English (US)",
volume = "14",
pages = "1113--1124",
journal = "Antiviral Therapy",
issn = "1359-6535",
publisher = "International Medical Press Ltd",
number = "8",

}

TY - JOUR

T1 - Susceptibility to genital herpes as a biomarker predictive of increased HIV risk

T2 - Expansion of a murine model of microbicide safety

AU - Wilson, Sarah S.

AU - Cheshenko, Natalia V.

AU - Fakioglu, Esra

AU - Mesquita, Pedro M M

AU - Keller, Marla J.

AU - Herold, Betsy

PY - 2009

Y1 - 2009

N2 - Background: A crucial gap in the development of microbicides for HIV prevention is the absence of models predictive of safety. Previous studies have demonstrated an increased susceptibility to genital herpes in mice following repeated applications of nonoxynol-9 (N-9). This study was designed to explore the underlying mechanisms, focusing on the effects that N-9 has on genital tract epithelium and to apply this expanded model to evaluate the safety of microbicides that have been advanced to clinical trials. Methods: Mice were treated intravaginally with formulated 3.5% N-9, 1% tenofovir, 0.5% or 2% PRO 2000, hydroxyethylcellulose (HEC) placebo or no treatment and the effect on herpes simplex virus 2 (HSV-2) susceptibility, epithelial cell architecture, junctional proteins and inflammation were assessed. Results: Mice treated with seven daily doses of N-9, but not tenofovir, PRO 2000 or HEC, were significantly more susceptible to challenge with low doses of HSV-2; confocal microscopy demonstrated increased numbers of viral particles deep within the genital tract. N-9 disrupted the epithelium with loss of tight and adherens junctional proteins. By contrast, the epithelium was relatively preserved following tenofovir, PRO 2000 and HEC exposure. Additionally, N-9, but not the other microbicides, triggered a significant inflammatory response relative to untreated mice. Conclusions: These findings indicate that disruption of the epithelium contributes to increased HSV-2 susceptibility and might provide a biomarker predictive of increased risk for HIV acquisition. The results are consistent with the safety outcomes of the recently completed Phase IIb clinical trial with 0.5% PRO 2000 gel, and predict that tenofovir gel will not adversely affect the genital tract.

AB - Background: A crucial gap in the development of microbicides for HIV prevention is the absence of models predictive of safety. Previous studies have demonstrated an increased susceptibility to genital herpes in mice following repeated applications of nonoxynol-9 (N-9). This study was designed to explore the underlying mechanisms, focusing on the effects that N-9 has on genital tract epithelium and to apply this expanded model to evaluate the safety of microbicides that have been advanced to clinical trials. Methods: Mice were treated intravaginally with formulated 3.5% N-9, 1% tenofovir, 0.5% or 2% PRO 2000, hydroxyethylcellulose (HEC) placebo or no treatment and the effect on herpes simplex virus 2 (HSV-2) susceptibility, epithelial cell architecture, junctional proteins and inflammation were assessed. Results: Mice treated with seven daily doses of N-9, but not tenofovir, PRO 2000 or HEC, were significantly more susceptible to challenge with low doses of HSV-2; confocal microscopy demonstrated increased numbers of viral particles deep within the genital tract. N-9 disrupted the epithelium with loss of tight and adherens junctional proteins. By contrast, the epithelium was relatively preserved following tenofovir, PRO 2000 and HEC exposure. Additionally, N-9, but not the other microbicides, triggered a significant inflammatory response relative to untreated mice. Conclusions: These findings indicate that disruption of the epithelium contributes to increased HSV-2 susceptibility and might provide a biomarker predictive of increased risk for HIV acquisition. The results are consistent with the safety outcomes of the recently completed Phase IIb clinical trial with 0.5% PRO 2000 gel, and predict that tenofovir gel will not adversely affect the genital tract.

UR - http://www.scopus.com/inward/record.url?scp=73449131509&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=73449131509&partnerID=8YFLogxK

U2 - 10.3851/IMP1463

DO - 10.3851/IMP1463

M3 - Article

C2 - 20032541

AN - SCOPUS:73449131509

VL - 14

SP - 1113

EP - 1124

JO - Antiviral Therapy

JF - Antiviral Therapy

SN - 1359-6535

IS - 8

ER -