Disruption of tight junctions by cellulose sulfate facilitates HIV infection: model of microbicide safety.

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 immunodeficiency 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 kappaB activation in peripheral blood mononuclear cells and increased HIV replication in chronically infected U1 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.

• Authors: Pedro M M Mesquita, Natalia Cheshenko, Sarah S Wilson, Mohak Mhatre, Esmeralda Guzman, Esra Fakioglu, Marla J Keller, Betsy C Herold
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 200 Issue 4 Pg. 599-608 (Aug 15 2009) ISSN: 0022-1899 [Print] United States
• PMID: 19586414 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anti-HIV Agents
• Anti-Infective Agents
• NF-kappa B
• Naphthalenesulfonates
• Organophosphonates
• PRO 2000
• Polymers
• Cellulose
• cellulose sulfate
• Tenofovir
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology)
• Anti-HIV Agents (pharmacology)
• Anti-Infective Agents (pharmacology)
• Cell Line
• Cellulose (analogs & derivatives, pharmacology)
• Electric Impedance
• Epithelial Cells (cytology, drug effects)
• HIV (drug effects, physiology)
• Humans
• Inflammation (metabolism)
• NF-kappa B (metabolism)
• Naphthalenesulfonates (pharmacology)
• Organophosphonates (pharmacology)
• Polymers (pharmacology)
• Tenofovir
• Tight Junctions (drug effects)
• Virus Replication (drug effects)