Disruption of tight junctions by cellulose sulfate facilitates HIV infection

Model of microbicide safety

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

Research output: Contribution to journalArticle

94 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)599-608
Number of pages10
JournalJournal of Infectious Diseases
Volume200
Issue number4
DOIs
StatePublished - Aug 15 2009

Fingerprint

Tight Junctions
Virus Diseases
Anti-Infective Agents
Safety
Tenofovir
Viruses
Electric Impedance
Nonoxynol
T-Lymphocytes
Adenine
Virus Replication
Blood Cells
Epithelium
Biomarkers
Epithelial Cells
cellulose sulfate
In Vitro Techniques

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 journalArticle

Mesquita, Pedro M M ; Cheshenko, Natalia V. ; Wilson, Sarah S. ; Mhatre, Mohak ; Guzman, Esmeralda ; Fakioglu, Esra ; Keller, Marla J. ; Herold, Betsy. / Disruption of tight junctions by cellulose sulfate facilitates HIV infection : Model of microbicide safety. In: Journal of Infectious Diseases. 2009 ; Vol. 200, No. 4. pp. 599-608.
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