Key result
Single-cell analysis using a novel microfluidic device revealed that distinct classes of antiviral inhibitors interfere with the viral infection cycle in unique, distinguishable manners.
Why the study?
Long-term success of an antiviral therapeutic depends not only on efficacy but also on the time required for drug resistance to evolve, which standard population-level cell culture assays do not fully capture.
A novel microfluidic device for single-cell analysis can distinguish the mechanisms of action of different antiviral therapeutics based on viral infection dynamics.
Distinguishes antiviral mechanisms in animal models; leaves open translation to clinical antiviral strategies.
SUMMARY Development of antiviral therapeutics emphasizes minimization of the effective dose and maximization of the toxic dose, first in cell culture and later in animal models. Long-term success of an antiviral therapeutic is determined not only by its efficacy but also by the duration of time required for drug-resistance to evolve. We have developed a microfluidic device comprised of ~6000 wells, with each well containing a microstructure to capture single cells. We have used this device to characterize enterovirus inhibitors with distinct mechanisms of action. In contrast to population methods, single-cell analysis reveals that each class of inhibitor interferes with the viral infection cycle in a manner that can be distinguished by principal component analysis. Single-cell analysis of antiviral candidates reveals not only efficacy but also properties of the members of the viral population most sensitive to the drug, the stage of the lifecycle most affected by the drug, and perhaps even if the drug targets an interaction of the virus with its host.
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Liu et al. (2019) studied Poliovirus infection (in vitro). Antiviral therapeutics (2'-C-Me-A, rupintrivir, geldanamycin, ganetespib) vs. Untreated control was evaluated on Single-cell infection dynamics (maximum fluorescence, slope, infection time, start-point, midpoint) and percentage of infected cells. Single-cell analysis using a novel microfluidic device revealed that distinct classes of antiviral inhibitors interfere with the viral infection cycle in unique, distinguishable manners.
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