Host cell state: an overlooked factor impacting the production of influenza A deletion-containing viral genomes and non-infectious particles

Influenza A virus remains a global public health threat, prompting the need for novel, broad-spectrum therapeutics. <u>Del</u>etion-containing <u>v</u>iral <u>g</u>enomes (DelVGs) produced during influenza replication have shown broad-spectrum therapeutic potential via defective interference, where DelVG accumulation depletes the relative abundance of standard viral genomes, diminishing the viral yield needed to sustain pathogenesis. Decades of research have focused on the viral factors affecting the production and maintenance of DelVGs in influenza infections. Surprisingly, the study of host factors that affect the emergence of DelVGs has been neglected. Uncovering host factors that affect DelVG production could help predict infection outcomes based on host state; facilitate the manipulation of host metabolism to increase DelVG production, potentially leading to milder clinical outcomes; and enhance biomanufacturing. The therapeutic potential of increasing <i>in situ</i> production of DelVGs is evident, but barriers to progress have persisted for decades, such as a lack of tailored methodologies to reliably quantify defective interference and early research findings that dismissed host cell involvement in the production of DelVGs and the defective interfering particles that carry them. Thus, the molecular mechanism of <i>de novo</i> DelVG production remains unknown in spite of evidence implicating host involvement. This review summarizes (i) newly discovered associations between host cell state and influenza DelVGs, (ii) the extensive host-virus metabolic signaling crosstalk that refocused the host as a potential contributor to DelVG/non-infectious particle production, and (iii) the methodological innovations that facilitated these recent discoveries. We conclude by providing an outlook on new avenues in DelVG basic and applied research.