Acquisition of Avian-Origin PB1 Facilitates Viral RNA Synthesis by the 2009 Pandemic H1N1 Virus Polymerase

Abstract

The constant crosstalk between the large avian reservoir of influenza A viruses (IAV) and its mammalian hosts drives viral evolution and facilitates their host switching. Direct adaptation of an avian strain to human or reassortment between avian-origin gene segments with that of human strains are the two mechanisms for the emergence of pandemic viruses. While it was suggested that the 1918 pandemic virus is of avian origin, reassortment of 1918 human isolates and avian influenza viruses led to the generation of 1957 and 1968 pandemic viruses. Interestingly, the avian PB1 segment, which encodes the catalytic subunit of IAV polymerase, is present in the 1957 and 1968 pandemic viruses. The biological consequence and molecular basis of such gene exchange remain less well understood. Using the 2009 pandemic H1N1 virus as a model, whose polymerase contains a human-origin PB1 subunit, we demonstrate that the acquisition of an avian PB1 markedly enhances viral RNA synthesis. This enhancement is also effective in the absence of PB2 adaptive mutations, which are key determinants of host switching. Mechanistically, the avian-origin PB1 does not appear to affect polymerase assembly but imparts the reassorted pandemic polymerase-augmented viral primary transcription and replication. Moreover, compared to the parental pandemic polymerase, the reassorted polymerase displays comparable complementary RNA (cRNA)-stabilizing activity but is specifically enhanced in progeny viral RNA (vRNA) synthesis from cRNA in a trans-activating manner. Overall, our results provide the first insight into the mechanism via which avian-origin PB1 enhances viral RNA synthesis of the 2009 pandemic virus polymerase.

Homologous PB1 gene promotes the replication efficiency of avian influenza H7N4 candidate vaccine virus

“…The results of polymerase activity in both minigenome transfection and viral infection verified that homologous PB1 provided better polymerase activity than PR8 PB1. The better polymerase activity influenced high growth capacity of (5 + 3) virus, consistent with previous reports that avian PB1 improves polymerase activity better than human PB1 27,28 . In addition, some PB1 mutations are related to polymerase activity or replication ability 12,13,29–33 .…”

“…The better polymerase activity influenced high growth capacity of (5 + 3) virus, consistent with previous reports that avian PB1 improves polymerase activity better than human PB1. 27 , 28 In addition, some PB1 mutations are related to polymerase activity or replication ability. 12 , 13 , 29 , 30 , 31 , 32 , 33 Most PB1 mutations were the same in PR8 and JS‐Ck, except for three motifs: 180G, 473 L, and 654N (in PR8 PB1) and 180E, 473V, and 654S (in JS‐Ck PB1) (Table S1 ).…”