Disruption of tight junctions by cellulose sulfate facilitates HIV infection: model of microbicide safety.
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.
Mesquita
Pedro M M
PM
Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Cheshenko
Natalia
N
Wilson
Sarah S
SS
Mhatre
Mohak
M
Guzman
Esmeralda
E
Fakioglu
Esra
E
Keller
Marla J
MJ
Herold
Betsy C
BC
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002460:Cell Line; D002482:Cellulose / Q000031:analogs & derivatives* / Q000494:pharmacology; D017097:Electric Impedance; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D006678:HIV / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009282:Naphthalenesulfonates / Q000494:pharmacology; D063065:Organophosphonates / Q000494:pharmacology; D011108:Polymers / Q000494:pharmacology; D000068698:Tenofovir; D019108:Tight Junctions / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D016328:NF-kappa B; D009282:Naphthalenesulfonates; D063065:Organophosphonates; C120231:PRO 2000; D011108:Polymers; D002482:Cellulose; C020254:cellulose sulfate; D000068698:Tenofovir; D000225:Adenine