Several classes of
microbicides are being evaluated for the prevention of sexual HIV transmission. In vivo, the infectious dose and viral source involved in transmission remain uncertain and it is likely that women will use
microbicides both before and after high-risk HIV exposure. Therefore, we evaluated
HIV entry inhibitors (EIs) and
reverse transcriptase inhibitors (RTIs) for their ability to block cell-free and cell-associated HIV-1
infection in co-cultures of monocyte-derived dendritic cells (MO-DC) and CD4+ T-cells using settings of pre- and post-exposure prophylaxis. In the pre-exposure assay, where compound was present before, during and 24 h after
infection, all tested EIs (
BMS806, TAK779 and T20) and RTIs (PMPA, TMC120 and
UC781) blocked
infection with 10(-4) multiplicity of
infection (MOI) of cell-free virus at a dose between 100 and 10,000 nM, dependent on the compound used.
At 10(-3) MOI, however, only T20 and the RTIs completely blocked
infection. Furthermore, in experiments with cell-associated virus, EIs were ineffective, whereas RTIs actively blocked
infection with similar potency as in the experiments with cell-free virus. In the post-exposure assay, where compound was added 2 h after
infection and remained present for 24 h, EIs were inactive whereas RTIs blocked cell-free and cell-associated
viral infections equally efficiently. Moreover, post-exposure prophylaxis initiated 24 h after
infection with cell-free or cell-associated HIV-1 was still effective with 1,000 nM of TMC120. Both EIs and RTIs were non-cytotoxic at any tested concentration for MO-DC and CD4+ T-cells in co-culture. Our study shows that RTIs are potent inhibitors of cell-free and cell-associated virus used either in pre- or post-exposure settings. It highlights that parameters such as viral input, viral source, the time of compound addition and the target cells should be considered in
microbicides evaluation.