Abstract
Hepatitis C virus (HCV) entry inhibitors (EIs) act synergistically with drugs targeting other stages of the HCV lifecycle. The origin of this synergy remains unknown. Here, we argue that the synergy may arise from the complementary activities of the drugs across cell subpopulations expressing different levels of HCV entry receptors. We employ mathematical modeling of viral kinetics in vitro, where cells with a distribution of entry receptor expression levels are exposed to HCV with or without drugs. The drugs act independently in each cell, as expected in the absence of underlying interactions. Yet, at the cell population level our model predicts that the drugs exhibit synergy. EIs effectively block infection of cells with low receptor levels. With high receptor levels, where EIs are compromised, other drugs are potent. This novel mechanism of synergy, arising at the cell population level may facilitate interpretation of drug activity and treatment optimization.