The potential of maraviroc (MVC), a small-molecule CCR5 antagonist, as a candidate to prevent HIV-1 sexual transmission by oral or topical dosing has not yet been completely established. Using relevant cellular and mucosal tissue explant models, we show partial antiviral activity of MVC when tested in multiple preclinical dosing strategies.T he predominant transmission of R5 tropic HIV-1 isolates through sexual intercourse 1,2 makes CCR5 an appealing target to prevent viral entry in mucosal target cells. Maraviroc (MVC) is the first antiretroviral (ARV) smallmolecule CCR5 inhibitor 3 to have been included in highly active antiretroviral therapy (HAART) and is currently being considered in the field of prevention as a candidate for oral pre-exposure prophylaxis (PrEP) or for topical application as a microbicide. Formulated as a microbicide gel, MVC has shown promising pharmacological results in humans and nonhuman primates (NHPs) 4,5 and efficacy in NHPs when tested as a vaginal gel. 6,7 To model different potential prevention dosing conditions, we tested drug efficacy before viral challenge (3-h drug exposure), before and after challenge (24-h drug exposure), or continuous drug exposure mimicking sustained release. We first assessed the activity of MVC with these dosing conditions in activated peripheral blood mononuclear cells (PBMCs) and other cellular models for preclinical evaluation in a mucosal environment, including immature dendritic cells (iDCs) and monocyte-derived macrophages (MDMs). 8 We observed different susceptibility to infection in the three models with higher levels of p24 in culture supernatant after 14 days of culture in PBMCs (33.29 -1.43 ng/ml) compared with MDMs (12.77 -0.73 ng/ml) and iDCs (1.27 -0.60 ng/ml).With all three drug exposure times, a dose-response curve was obtained against HIV-1 BaL in activated PBMCs (Fig. 1a) and MVC was able to reach an IC 50 at low and decreasing nanomolar concentrations with increasing dosing times (9.93 -1.68 nM with a 3-h exposure, 5.00 -1.38 nM with a 24-h exposure, and 0.94 -0.12 nM after continuous exposure). The IC 50 of MVC in monocyte-derived iDCs against HIV-1 BaL was in the nanomolar range as shown in PBMCs. The antiviral potency of MVC increased with longer drug exposure times, resulting in a reduction of the IC 50 value from 23.96 -26.08 nM with a 3-h exposure to 3.37 -2.21 nM with a 24-h exposure and 0.47 -0.14 nM with continuous exposure.When iDCs were pre-exposed to MVC for 3 h, only partial inhibition was observed, failing to reach 95% inhibition even at the highest drug concentration tested (10 lM) (Fig. 1b). The plateau of maximum inhibition was increased with longer drug exposure, 24 h, and continuous exposure and was reached at lower concentrations with IC 95 values of 68.44 -48.85 nM and 20.91 -23.42 nM, respectively.The level of CCR5 expressed on the surface of MDMs has been described to increase when generated in the presence of granulocyte-macrophage colony-stimulating factor and to be higher than that measured in monocyte...