544. DISRUPTION OF TIGHT JUNCTIONS BY CELLULOSE SULFATE FACILITATES HIV INFECTION: MODEL OF MICROBICIDE SAFETY.

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Mesquita¹, P.M.M., Cheshenko¹, N., Wilson¹, S.S., Mhatre¹, M., Guzman¹, E., Fakioglu¹, E., Keller³, M.J., and Herold^1,2, B.C. Department of ¹Pediatrics, ²Microbiology-Immunology, and ³Medicine, Albert Einstein College of Medicine, Bronx, New York. J Infectious Diseases, 200, 599–608 (2009).

Summary:
This study by researchers in the Departments of Pediatrics, Microbiology-Immunology and Medicine at Albert Einstein College of Medicine demonstrated that MatTek’s EpiVaginal in vitro 3-D human cervico-vaginal tissue equivalent can be used to model potential epithelial barrier disruption caused by microbicide candidate formulations, and how epithelial barrier disruption leads to increased risk of HIV infection.

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 kappa-B 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.

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EpiVaginal Technical References

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Applications: Biomarker research, HIV/AIDS, Microbicides

Keywords: Adherens junction protein, Confocal microscopy, EpiVaginal, Epithelial disruption, HIV infection, HIV-1, Human immunodeficiency viruse type 1, Microbicide, Syndecan desmoglein, Syndecan proteoglycans, VLC-100, p24

Materials Tested: 9-[2-(phosphonomethoxy)pro-pyl]adenine, Cellulose sulfate , Nonoxynol-9 (N-9, PRO2000, Tenofovir

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