More than efficacy revealed by single-cell analysis of antiviral therapeutics

Wu Liu; Mehmet U. Caglar; Zhangming Mao; Andrew Woodman; Jamie J. Arnold; Claus O. Wilke; Craig E. Cameron

As a part of a study evaluating PV infection dynamics on the single-cell level, we 43 observed that a chain-terminating antiviral ribonucleotide selectively eliminates the most-fit 44 members of the viral population (Guo et al., 2017) . This class of antiviral agent has always been 45 touted as having a high barrier to resistance (Jordheim et al., 2013) . The typical explanation for 46 this high barrier is that amino acid substitutions in the active site of the viral RNA polymerase 47 conferring resistance to the antiviral ribonucleoside also impair the specificity and/or efficiency 48 of incorporation of natural ribonucleotides (Carroll et al., 2003) . Elimination of the most-fit 49 members of the viral population by an antiviral agent requires that resistance emerge from the 50 surviving, low-fitness member of the population, which would ultimately require restoration of 51 fitness for the population to survive the myriad mechanisms of host restriction (Andino and 52 All rights reserved. No reuse allowed without permission.