P12.06
Background: Studies on HIV-resistant women (exposed uninfected) from the Punwami Sex Worker cohort have shed light on putative protective mechanisms, suggesting that mucosal immunological factors, such as serpins, could be mediating HIV-resistance. This project aims to assess the activity of a panel of serpins against HIV-1 in a preclinical mucosal tissue explant model.
Methods: Antiviral efficacy of nine blinded serpins was assessed in TZM-bl cells, ecto-cervical tissue explants and migratory cells. Incubation of cells or tissue with serpins for 1 h was followed by addition of an R5-tropic virus, BaL. Tissue was exposed to virus for 2 h and then washed. Following overnight incubation of tissue, migratory cells were harvested and co-cultured with PM-1 CD4+ T cells without drug. Infection was determined by measurement of luciferase expression (in TZM-bl cells) or p24 viral antigen in culture supernatants.
Results: Following screening in TZM-bl cells where dose-response curves were measured for two serpins, antiviral activity in ecto-cervical explants was detected for five serpins allowing us to establish an order of inhibitory potency when mimicking pre-coital use of a serpin-based microbicide. In addition, the migration of cells out of the explants was blocked by certain serpins, indicating potential prevention of viral dissemination following amplification of the founder population.
Conclusions: These results constitute the base for further development of these mucosal proteins as microbicides. Serpin combinations and sustained exposure of explants to serpins mimicking repeated dosing strategies will inform the dosing and formulation of these antiproteases which have shown potential as effective microbicides able to inhibit HIV-1 transmission in pre-clinical assays.
