Highly Active Antiretroviral Therapies Are Effective against HIV-1 Cell-to-Cell Transmission

HIV-1 cell-to-cell transmission allows for 2-3 orders of magnitude more efficient viral spread than cell-free dissemination. The high local multiplicity of infection (MOI) observed at cell-cell contact sites may lower the efficacy of antiretroviral therapies (ART). Here we test the efficacy of commonly used antiretroviral inhibitors against cell-to-cell and cell-free HIV-1 transmission. We demonstrate that, while some nucleoside-analog reverse transcriptase inhibitors (NRTI) are less effective against HIV-1 cell-to-cell transmission, most non-nucleoside-analog reverse transcriptase inhibitors (NNRTI), entry inhibitors and protease inhibitors remain highly effective. Moreover, poor NRTIs become highly effective when applied in combinations explaining the effectiveness of ART in clinical settings. Investigating the underlying mechanism, we observe a strict correlation between the ability of individual drugs and combinations of drugs to interfere with HIV-1 cell-to-cell transmission, and their effectiveness against high viral MOIs. Our results suggest that the ability to suppress high viral MOI is a feature of effective ART regimens and this parameter should be considered when designing novel antiviral therapies. Author Summary HIV-1 cell-to-cell transmission has gained interest due to its potential role in AIDS pathogenesis. It has recently been suggested that antiretroviral therapies fail during cell-to-cell transmission because of the high number of particles transferred at sites of cell-cell contacts. However, these findings stand in contrast with the clinical observation that ART is successful in suppressing retroviral replication in HIV-positive patients. Consequently, many interpreted this observation to suggest that HIV-1 cell-to-cell transmission is not clinically relevant. Here we show that this interpretation is likely incorrect. By systematically testing the efficacy of commonly used antiretroviral inhibitors against cell-to-cell and cell-free HIV-1 transmission, we demonstrate that, while some NRTIs are less effective, most NNRTIs, entry inhibitors and protease inhibitors remain highly effective. Moreover, NRTIs become highly effective when combined, thus supporting the known effectiveness of HAART in clinical settings. Interestingly, the ability of individual drugs and combinations to interfere with HIV-1 cell-to-cell transmission correlates with their effectiveness against high viral MOIs. Our results suggest that the ability to suppress the high viral MOI during HIV-1 cell-to-cell transmission is a critical feature of existing ART regimens that should be tested when designing novel antiviral therapies.