Session 82Poster Presentations Microbicides Session Day and Time: Tuesday 1:30 - 3:30 pm Room: Hall A
677 Candidate Microbicide Formulations of the HIV-1 Inhibitor UC-781 Block Localized HIV-1 Infection and Dendritic Cell Dissemination Pathways within Human Cervical Tissue P. Watts*2, J. Romano1, G. Wallace2, M. Aydelotte1, G. Cohl1, R. Schnaare1, B. Burruano1, R. Shattock2 1Biosyn, Inc, Huntingdon Valley, PA and 2St George's Hosp Med Sch, London, UK
Background: In the absence of an effective vaccine, microbicides provide a female controlled method of preventing HIV-1 infection that could significantly reduce worldwide transmission rates. UC-781, and related UC-22, are highly potent and selective thiocarboxanilide non-nucleoside reverse transcriptase inhibitors (NNRTI) of HIV-1. Their high affinity facilitates irreversible inactivation of both intracellular and intravirion RT. Thus when applied topically they have potential to inactivate free virions within the vaginal or rectal lumen. We have developed multiple candidate formulations of both compounds including aqueous suspension gels, anionic creams, and solution gels. The objective of this study was to determine the physical and chemical stability of these formulations under multiple conditions and to measure their activity in vitro. Furthermore, we have tested the hypothesis that these formulations can both blockade localized infection of human cervical tissue and inhibit dendritic cell dissemination pathways.
Methods: Drug stability, release, and viscosity of formulations were assessed by standardized protocols and in accordance with SUPAC guidelines. In vitro activity and toxicity was determined by pre-treatment of immobilized virus or target cells. An established ex-vivo cervical explant model was used to assess efficacy on localized mucosal infection and potential uptake of infectious virus by migratory dendritic cell.
Results: Although all UC-781 formulations were active, suspension gels were most stable, active, and least toxic, while drug release was not inhibited by formulation. Both native and formulated UC781 potently inhibited HIV replication in cervical tissue explants and transfer of infectious virus from migratory dendritic cells. Similar, though less potent, results were seen with UC-22. For UC781, protection against viral challenge was still detectable 7 days post-drug treatment, suggesting a potent memory effect, which was also active against virion dissemination by migratory cells.
Conclusions: The NNRTI UC-781 can be formulated as a microbicide gel that is chemically and physically stable, providing potent and prolonged activity against HIV-1 without being toxic to target cells. Suspension gel formulations of UC-781 represent promising candidates for continued pre-clinical and clinical development.
