Effect of nucleoside analog antivirals on influenza A mini viral RNA production and innate immune activation

Abstract

The influenza A virus (IAV) is a pathogen that affects approximately 20% of the human population in yearly epidemics. Certain IAV strains can cause pandemics, with the 1918 H1N1 flu pandemic remaining the most fatal IAV-related event in history. The process of viral replication copies the viral RNA genome in the nucleus of an infected cell. Occasionally, replication results in aberrant RNA products called mini viral RNAs (mvRNAs), important in their connection to innate immune activation and pandemic virulence. Yet, the mechanism for mvRNA synthesis is not well understood. To date, several viral polymerase processes, like stalling, backtracking, and template realignment, have been proposed to play a role in mvRNA formation. Interestingly, nucleoside analogs have mechanisms of action that can induce these processes. Thus, this study explores the effect of five antivirals—remdesivir, 5FU, ribavirin, favipiravir, and T-1105—on mvRNA production and innate immune activation. I find that all drug treatments increase IAV mvRNA production, but that only remdesivir and ribavirin treatments show trends of increasing innate immune activation, all in a concentration-independent manner. My findings contribute to the characterization of the mechanism of mvRNA synthesis as well as a continued exploration of the variable and oft-times inflammatory effects of antivirals. Overall, this investigation informs how viral infections affect the immune response, informing global health resilience.