Membrane Accumulation of Influenza A Virus Hemagglutinin Triggers Nuclear Export of the Viral Genome via Protein Kinase Cα-mediated Activation of ERK Signaling

Verapamil has Antiviral Activities that Target Different Steps of the Influenza Virus Replication Cycle

“…Inhibition of the signalling cascade was shown to reduce IAV replication both, in vitro and in vivo, further supporting its key role in IV replication [10,11]. Interestingly, the cascade is activated at least in part by viral HA protein accumulation and the signal is transmitted via the calciumdependent PKC-alpha to Raf [12]. In line with this observation, the calcium channel blocker Verapamil was found to reduce ERK activation.…”

“…For treatment, Verapamil-containing medium was added 2 h post infection (p.i.) to avoid any effects on virus entry [12,19,20]. The MEK inhibitor U0126 (Taros GmbH, Germany) was dissolved at a stock concentration of 10 mM in DMSO (Roth, Germany).…”

Role of Sulfatide in Influenza A Virus Replication

“…The binding between sulfatide and nascent HA is thought to be an initiation switch for the progeny virus formation process. Activation of the Raf/MEK/ERK pathway, which probably begins with binding between sulfatide and nascent HA on the cellular surface, 42) is likely to be associated with these processes. Activation of caspase-8 and -9 by sulfatide expression is not directly associated with enhancement of virus replication through AIF-mediated virus-inducing apoptosis, because of no activation of caspase-3 at the final stage of caspase cascades and no effect of a pan-caspase inhibitor in virus replication.…”

Role of Membrane Rafts in Viral Infection

“…The role of membrane rafts in the assembly and budding of enveloped viruses has been investigated for influenza virus [59,63,[150][151][152][153][154][155][156][157][158][159][160], HIV-1 [63,[161][162][163][164][165][166][167][168][169][170][171][172][173], HTLV-1 [174], measles virus (Paramyxoviridae) [63,175,176], Sendai virus [Paramyxoviridae] [177,178], Newcastle disease virus (NDV; Paramyxoviridae) [179,180], RSV [147,148,[181][182][183][184], HSV [185,186], murine cytomegalovirus (MCMV; Herpesviridae) [187], Ebola virus [70,188], Marburg virus [70], and vesicular stomatitis virus (VSV; Rhabdoviridae) …”

“…MAPK activation induces viral RNP export from the nucleus to the cytoplasm, leading to an enhancement of infectious progeny virus production [158]. Our recent study showed that sulfatide, a sulfated glycosphingolipid, was required for efficient virus replication and that association of newly synthesized HA transferred to the infected cell surface with sulfatide induced viral RNP export from the nucleus to the cytoplasm, leading to enhancement of infectious progeny virus formation [197].…”