Dead-end complexes contribute to the synergistic inhibition of HIV-1 RT by the combination of rilpivirine, emtricitabine, and tenofovir.

In this study, two-drug combinations of TFV+FTC, RPV+TFV, and RPV+FTC inhibited HIV replication in cell culture with strong synergy and no evidence of antagonism. The triple drug combination of RPV+FTC+TFV displayed moderate synergy comparable to efavirenz (EFV)+FTC+TFV. The formation of dead-end complexes (DEC) of HIV-1 reverse transcriptase (RT), NRTI chain-terminated primer/template, and the next complementary nucleotide or NNRTIs was studied using gel mobility shift assays. DEC formation was seen with TFV-terminated DNA primer/template, HIV-1 RT, and FTC-triphosphate (TP) in addition to the natural nucleotide dCTP, thus stabilizing chain-termination. The NNRTI RPV also formed DEC-like complexes with TFV- and FTC-monophosphate (MP)-terminated DNA primer/templates and HIV-1 RT, and stabilized chain-termination by both NRTIs. Overall, the combinations of RPV, FTC, and TFV inhibit HIV-1 replication with moderate to strong synergy. This may be partially explained by enhanced DEC formation of NRTI chain-terminated DNA primer/template and HIV-1 RT in the presence of the other drugs in the combination, leading to more stable chain-termination and replication inhibition by NRTIs.
PMID: 24291780 [PubMed - as supplied by publisher]

Source: Antiviral Research - November 28, 2013 Category: Virology Authors: Kulkarni R, Feng JY, Miller MD, White KL Tags: Antiviral Res Source Type: research