Home Search Abstracts Browse Sessions Program Committee E-mail Abstract Author View Session

Session 77 Poster Abstracts
New Antiretroviral Agents: RTI's and PI's
Wednesday, 1:30 - 3:30 pm
Poster Hall


528    
Diarylpyrimidines and Diaryltriazines Constitute a New Class of Highly Active Non-Nucleoside Reverse Transcriptase Inhibitors
Y Van Herrewege*1, J Michiels1, Z Kara1, K Andries2, M P de Béthune2, L Kestens1, P J Lewi3, P A J Janssen3, and G Vanham1
1Inst. of Tropical Med., Antwerp, Belgium; 2Tibotec, Mechelen, Belgium; and 3Janssen Pharmaceutica, Vosselaar, Belgium

Background: Co-cultures of monocyte-derived dendritic cells (MO-DC) and autologous CD4++ T cells represent the primary target cells during sexual HIV transmission. The antiviral and immune suppressive activity of a new class of non-nucleoside reverse transcriptase inhibitors (NN-RTI), Diarylpyrimidines (DAPYs) and diaryltriazines (DATAs) was compared with the RTIs UC-781 and PMPA, using this in vitro model.

Methods: A first set-up evaluated the standard antiviral activity of the compounds, determined after a 14-day treatment of HIV-infected MO-DC/T cell co-cultures with a dose range of compound. Supernatants were analysed in HIV-ELISA for calculation of 50% Effective Concentrations (EC50). In a second set-up, treatment was limited to 24-hours to evaluate the potency of the compounds as microbicides. After extensive washing, cells were co-cultured for 14 days, followed by secondary cultures with PHA/IL-2 blasts (always without compound). After 2 additional weeks, supernatants were analysed in ELISA and cells in PCR. Immune Suppressive Concentrations (ISC50) were determined in mixed leukocyte cultures of MO-DC and allogeneic CD4+ T cells, with compound either continuously present or only during the first 24 hours.

Results:  EC50 ranged from 0.4 to 3 nM, compared to 53 nM (UC-781) and 106 nM (PMPA). Part of the compounds were evaluated as 24-hours microbicides: the most potent ones, including the DAPY compound TMC120-R147681 (dapivirine), showed only a small increase in EC50 and completely protected HIV-infection at a concentration of 10 to 100 nM, whereas 100-fold higher concentrations of UC-781 or PMPA were needed. The 50% immune suppressive concentration (ISC50) ranged from 147 to over 10,000 nM, compared to 48,552 nM (UC-781) and 119,302 nM (PMPA), resulting in beneficial therapeutic indices (ISC50/EC50).

Conclusions: DAPY and DATA compounds are more potent than earlier RTI and show favourable pharmacological profiles in vitro. They could strengthen the armamentarium of antiretroviral drugs and might be useful as microbicides.

Keywords: non-nucleoside reverse transcriptase inhibitors; HIV in vitro model; sexual HIV transmission