Abstract
Background. The lack of biomarkers that are predictive of safety is a critical gap in the development of microbicides. The present experiments were designed to evaluate the predictive value of in vitro models of microbicide safety. Methods. Changes in the epithelial barrier were evaluated by measuring transepithelial electrical resistance (TER) after exposure of human epithelial cells to candidate microbicides in a dual-chamber system. The significance of observed changes was addressed by challenging cultures with human immuodeficiency virus (HIV) and measuring the ability of virus to cross the epithelium and infect target T cells cultured in the lower chamber. Results. Exposure to nonoxynol-9 (N-9) or cellulose sulfate (CS), but not 9-[2-(phosphonomethoxy)propyl] adenine (also referred to as tenofovir) or PRO2000, resulted in a rapid and sustained reduction in TER and a marked increase in HIV infection of T cells cultured in the lower chamber. Moreover, CS triggered nuclear factor KB activation in peripheral blood mononuclear cells and increased HIV replication in chronically infected Ul cells. Conclusions. Epithelial barrier disruption and enhanced viral replication may have contributed to the increased risk of HIV acquisition observed in phase 3 trials of N-9 and CS. Expansion of in vitro safety testing to include these models would provide a more stringent preclinical assessment of microbicide safety and may prove to be more predictive of clinical outcomes.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 599-608 |
| Number of pages | 10 |
| Journal | Journal of Infectious Diseases |
| Volume | 200 |
| Issue number | 4 |
| DOIs | |
| State | Published - Aug 15 2009 |
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ASJC Scopus subject areas
- Infectious Diseases
- Immunology and Allergy
Cite this
Disruption of tight junctions by cellulose sulfate facilitates HIV infection : Model of microbicide safety. / Mesquita, Pedro M M; Cheshenko, Natalia V.; Wilson, Sarah S.; Mhatre, Mohak; Guzman, Esmeralda; Fakioglu, Esra; Keller, Marla J.; Herold, Betsy.
In: Journal of Infectious Diseases, Vol. 200, No. 4, 15.08.2009, p. 599-608.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Disruption of tight junctions by cellulose sulfate facilitates HIV infection
T2 - Model of microbicide safety
AU - Mesquita, Pedro M M
AU - Cheshenko, Natalia V.
AU - Wilson, Sarah S.
AU - Mhatre, Mohak
AU - Guzman, Esmeralda
AU - Fakioglu, Esra
AU - Keller, Marla J.
AU - Herold, Betsy
PY - 2009/8/15
Y1 - 2009/8/15
N2 - Background. The lack of biomarkers that are predictive of safety is a critical gap in the development of microbicides. The present experiments were designed to evaluate the predictive value of in vitro models of microbicide safety. Methods. Changes in the epithelial barrier were evaluated by measuring transepithelial electrical resistance (TER) after exposure of human epithelial cells to candidate microbicides in a dual-chamber system. The significance of observed changes was addressed by challenging cultures with human immuodeficiency virus (HIV) and measuring the ability of virus to cross the epithelium and infect target T cells cultured in the lower chamber. Results. Exposure to nonoxynol-9 (N-9) or cellulose sulfate (CS), but not 9-[2-(phosphonomethoxy)propyl] adenine (also referred to as tenofovir) or PRO2000, resulted in a rapid and sustained reduction in TER and a marked increase in HIV infection of T cells cultured in the lower chamber. Moreover, CS triggered nuclear factor KB activation in peripheral blood mononuclear cells and increased HIV replication in chronically infected Ul cells. Conclusions. Epithelial barrier disruption and enhanced viral replication may have contributed to the increased risk of HIV acquisition observed in phase 3 trials of N-9 and CS. Expansion of in vitro safety testing to include these models would provide a more stringent preclinical assessment of microbicide safety and may prove to be more predictive of clinical outcomes.
AB - Background. The lack of biomarkers that are predictive of safety is a critical gap in the development of microbicides. The present experiments were designed to evaluate the predictive value of in vitro models of microbicide safety. Methods. Changes in the epithelial barrier were evaluated by measuring transepithelial electrical resistance (TER) after exposure of human epithelial cells to candidate microbicides in a dual-chamber system. The significance of observed changes was addressed by challenging cultures with human immuodeficiency virus (HIV) and measuring the ability of virus to cross the epithelium and infect target T cells cultured in the lower chamber. Results. Exposure to nonoxynol-9 (N-9) or cellulose sulfate (CS), but not 9-[2-(phosphonomethoxy)propyl] adenine (also referred to as tenofovir) or PRO2000, resulted in a rapid and sustained reduction in TER and a marked increase in HIV infection of T cells cultured in the lower chamber. Moreover, CS triggered nuclear factor KB activation in peripheral blood mononuclear cells and increased HIV replication in chronically infected Ul cells. Conclusions. Epithelial barrier disruption and enhanced viral replication may have contributed to the increased risk of HIV acquisition observed in phase 3 trials of N-9 and CS. Expansion of in vitro safety testing to include these models would provide a more stringent preclinical assessment of microbicide safety and may prove to be more predictive of clinical outcomes.
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U2 - 10.1086/600867
DO - 10.1086/600867
M3 - Article
VL - 200
SP - 599
EP - 608
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
SN - 0022-1899
IS - 4
ER -