Influenza A Virus Replication Induces Cell Cycle Arrest in G ₀ /G ₁ Phase

Abstract

Many viruses interact with the host cell division cycle to favor their own growth. In this study, we examined the ability of influenza A virus to manipulate cell cycle progression. Our results show that influenza A virus A/WSN/33 (H1N1) replication results in G0/G1-phase accumulation of infected cells and that this accumulation is caused by the prevention of cell cycle entry from G0/G1 phase into S phase. Consistent with the G0/G1-phase accumulation, the amount of hyperphosphorylated retinoblastoma protein, a necessary active form for cell cycle progression through late G1 into S phase, decreased after infection with A/WSN/33 (H1N1) virus. In addition, other key molecules in the regulation of the cell cycle, such as p21, cyclin E, and cyclin D1, were also changed and showed a pattern of G0/G1-phase cell cycle arrest. It is interesting that increased viral protein expression and progeny virus production in cells synchronized in the G0/G1 phase were observed compared to those in either unsynchronized cells or cells synchronized in the G2/M phase. G0/G1-phase cell cycle arrest is likely a common strategy, since the effect was also observed in other strains, such as H3N2, H9N2, PR8 H1N1, and pandemic swine H1N1 viruses. These findings, in all, suggest that influenza A virus may provide favorable conditions for viral protein accumulation and virus production by inducing a G0/G1-phase cell cycle arrest in infected cells.

Molecular Signatures Associated with Mx1-Mediated Resistance to Highly Pathogenic Influenza Virus Infection: Mechanisms of Survival

“…Our previous studies of nonhuman primates and mice infected with highly pathogenic viruses have also shown the differential regulation of cell cycle-related genes (3,4), suggesting that this is an important mechanism for host survival during lethal influenza virus infection. This is interesting, because it has been shown that influenza virus infection induces cell cycle arrest, which promotes a favorable environment for influenza virus protein expression (10). Consequently, the activation of cell cycle regulatory genes counters this mechanism by promoting host cell proliferation.…”

Temporal- and Strain-Specific Host MicroRNA Molecular Signatures Associated with Swine-Origin H1N1 and Avian-Origin H7N7 Influenza A Virus Infection

“…Targets of miR-449a/b include Cdk6 and Cdc25a, while the miR-34 family functions as tumor suppressors by targeting antiapoptotic mRNAs, including Ccne2, Bcl-2, and Cdk6 (21,39,63). Regulation of these mRNAs by the miR-449 and miR-34 families causes cell cycle arrest at G 0 /G 1 and the induction of apoptosis, both of which have been shown to be important to the infA life cycle (19,40,42). Furthermore, profiles of leukocytes from infected patients showed that profound changes in cell cycle regulation were associated with an increase in the severity of disease caused by infA infection (49).…”

Effects of quercetin on CDK4 mRNA and protein expression in A549 cells infected by H1N1

“…Several factors, such as the cyclin/cyclin-dependent kinase (cyclin/CDK) complex, closely regulate all the processes of each phase (15). If cell proliferation is disturbed by infection with the influenza A virus, the host cells are arrested in the G0̸G1 phase (16) and if the DNA damage is not repaired, the cells enter the apoptotic process (17).…”