Evolution of the PB1 gene of human influenza A (H3N2) viruses circulating between 1968 and 2019

Abstract

One avian H3N2 influenza virus, providing its PB1 and HA segments, reassorted with one human H2N2 virus and caused a pandemic outbreak in 1968, killing over 1 million people. After its introduction to humanity, the pandemic H3N2 virus continued adapting to humans and has resulted in epidemic outbreaks every influenza season. To understand the functional roles of the originally avian PB1 gene in the circulating strains of human H3N2 influenza viruses, we analyzed the evolution of the PB1 gene in all human H3N2 isolates from 1968 to 2019. We found several specific residues dramatically changed around 2002–2009 and remained stable through to 2019. Then, we verified the functions of these PB1 mutations in the genetic background of the early pandemic virus, A/Hong Kong/1/1968(HK/68), as well as a recent seasonal strain, A/Jiangsu/34/2016 (JS/16). The PB1 V709I or PB1 V113A/K586R/D619N/V709I induced higher polymerase activity of HK/68 in human cells. And the four mutations acted cooperatively that had an increased replication capacity in vitro and in vivo at an early stage of infection. In contrast, the backward mutant, A113V/R586K/N619D/I709V, reduced polymerase activity in human cells. The PB1 I709V decreased viral replication in vitro, but this mutant only showed less effect on mice infection experiment, which suggested influenza A virus evolved in human host was not always consisted with highly replication efficiency and pathogenicity in other mammalian host. Overall, our results demonstrated that the identified PB1 mutations contributed to the viral evolution of human influenza A (H3N2) viruses.

Mutual information networks reveal evolutionary relationships within the influenza A virus polymerase

“…The thumb domain forms the right-side wall of the viral RNA–dependent polymerase (RdRp) active site chamber, while the C-terminal domain interacts closely with the PB2 N-terminus and PA endonuclease domains. In addition, the mutations V709I and D619N in PB1 each lead to increased polymerase activity (by minigenome assay in human cells) in the early pandemic H3N2 strain A/Hong Kong/1/1968(HK/68) ( Sun et al. 2022 : 1).…”

Mutual information networks reveal evolutionary relationships within the influenza A virus polymerase

“…The thumb domain forms the right-side wall of the viral RNA- dependent polymerase (RdRp) active site chamber, while the C-terminal domain interacts closely with the PB2 N-terminus and PA endonuclease domains. In addition, the mutations V709I and D619N in PB1 each lead to increased polymerase activity (by minigenome assay in human cells) in the early pandemic H3N2 strain A/Hong Kong/1/1968(HK/68) (Sun et al 2022: 1). PB1-52 and PB1-576 of Subgraph 8 are in the finger and thumb domains of PB1 (Figure 7C).…”