Figure 3. Proposed mechanism of attenuation for codon deoptimized influenza A viruses.

(A) Schematic representation of wild-type influenza infection in a permissive cell. First, vRNP-mediated replication and transcription occurs in the cell nucleus, followed by viral protein synthesis (shown here as the HA and NA glycoproteins, and the IFN antagonist NS1), export of vRNPs from the nucleus (indicated by arrow) and production of infectious progeny (black virions). (B) During PR8^3F infection (light gray virions), less viral genome replication and gene transcription mediated by PB1 and NP deoptimization leads to a decrease in all viral proteins and their functions, including influenza NS1, nuclear export of vRNPs and virion production. (C) A paucity of influenza glycoproteins during (NA + HA)^Min infection (dark gray virions) results in ample viral protein production but minimal virion formation and release because of decreased levels of IAV HA and NA. (D) Infection with PR8 NScd (white virions) stimulates type I IFN responses because of suboptimal NS1 levels, and inefficient nuclear export of vRNPs due to low NEP levels. For simplicity, only certain stages of the life cycle are represented.

IAV: Influenza A viruses; vRNP: Viral ribonucleoprotein.