Colorectal microbicide design: triple combinations of reverse transcriptase inhibitors are optimal against HIV-1 in tissue explants

Objective: Receptive anal intercourse in both men and women is associated with the highest probability for sexual acquisition of HIV infection. As part of a strategy to develop an effective rectal microbicide, we performed an ex-vivo preclinical evaluation to determine the efficacy and limitation of multiple combinations of reverse transcriptase inhibitors (RTIs). Design: A nucleotide, PMPA (tenofovir), a nucleoside, FTC (emtricitabine), RTIs and two nonnucleoside RTIs, UC781 and TMC120 (dapivirine), were used in double, triple and quadruple combinations against a panel of CCR5-uing and CXCR4-using clade B HIV-1 isolates and against RTI-escape variants. Methods: Indicator cells and colorectal tissue explants were used to assess antiviral activity of drug combinations. Results: All combinations inhibited the isolates tested in a cellular model and in colorectal explants and produced, for at least one of the compounds, a change in the dose-response curve. Double and triple combinations incrementally augmented activity, even against RTI-escape mutants, whereas quadruple combinations conferred little further advantage. Conclusion: The colorectal explant model may be used to identify the best candidate molecules and their combinations at the preclinical stage. Furthermore, this study demonstrates that combinations based on RTIs with different HIV-1 inhibitory mechanisms have potential as colorectal microbicides. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins