Broad-Spectrum Anti-HIV Microbicide Activity of the Non-Nucleoside Reverse Transcriptase Inhibitor UC781

Background: The tight-binding nonnucleoside reverse transcriptase inhibitor (NNRTI) UC781is under development as a topical microbicide to prevent sexual transmission of the human immunodeficiency virus type 1 (HIV-1). However, there are concerns whether UC781 will be broadly effective against different HIV subtypes as well as against the increasingly prevalent NNRTI-resistant HIV strains. Methods: A variety of in vitro tests were used to evaluate the microbicidal efficiency of UC781 against 25 different HIV-1 clades and subtypes, and drug-resistant HIV-1 variant. Anti-HIV microbicide activity of UC781 was assessed both in single cycle infectivity assays as well as in virus spreading assays using activated human peripheral blood mononuclear cells (PBMCs), CD4+ T cells and monocyte-derived macrophages (MDM). Results: For 20 of the 25 HIV-1 strains assessed, including several multi-drug-resistant HIV-1 strains, the mean EC50 for UC781 was 0.008 µM (range, 0.003 to 0.026 µM) in single cycle infectivity assays. UC781 was 60-fold less effective against one of the nine HIV-1 subtypes tested, subtype O (strain MVP5180). Not unexpectedly, UC781 was 465-fold, 1325-fold and 7-fold less effective against NNRTI-resistant HIV: UC781-resistant (UCR), efavirenz-resistant (EFVR), and nevirapine-resistant (NVPR), respectively. Nonetheless, pretreatment of PBMC, CD4+ T cells and MDM (induced by both M-CSF and GM-CSF) with UC781 concentrations of 25 µM or greater completely prevented subsequent infection of these cells by any of the virus strains in the absence of exogenous drug. Conclusion: Reduced potency of UC781 against NNRTI-resistant virus variants is well below those in current microbicide formulations due to the “memory effect” exerted by pretreatment. Thus, UC781 demonstrated potent and genetic-subtype independent anti-HIV activity swhich suggests that UC781-based microbicides will likely be efficacious in different geographical regions.