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

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.

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

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