Compounds with anti-influenza activity: present and future of strategies for the optimal treatment and management of influenza. Part I: influenza life-cycle and currently available drugs

GASPARINI, R.; AMICIZIA, D.; LAI, PL.; BRAGAZZI, NL.; PANATTO, D.

The exportation of RNPs is favoured as the infection progresses, which results in activation of the mechanism of spontaneous cell death (apoptosis) through the activation of caspase 3 [184] . By altering the nuclear membrane, the activation of caspase 3 increases perviousness through the nuclear pore [185, 186] . Indeed, caspase signalling pathways play an important role in the activation, replication, propagation and pathogenicity of the influenza virus, and are therefore related to the severity of influenza symptoms and its clinical burden [187] . The virus finely tunes and modulates the host cellular pro- teins involved in the processes of regulation and control of the induction of apoptosis [188] . The units of RNP released from the nucleus are concentrated in the perinuclear cytoplasm [189] , particularly in the region of the centre for organizing microtubules (MTOC) [190] and, subsequently, in the area of recycling endosomes (REs) [191] . Interaction with the REs allows the RNPs to interact better with the network of microtubules, and thus to orient themselves and to travel towards the cell membrane [192] . The exportation of RNPs is a complicated mechanism that requires wellsynchronized timing, and results in an accumulation of RNPs on the apical surface of the cell in the late stages of viral multiplication. In the late stages of viral replication, the accumulation of HA molecules on the cell membrane, probably by activating the mitogen-activated protein kinase (MAPK) [193] , increases the exportation of RNPs, which, through a still unknown mechanism, is oriented towards the apical surface of the cell. Subsequently, as each unit of RNP contains only one of the eight segments of the viral genome, it is particularly important that the different segments be assembled properly. The viral RNAs themselves mediate this process through a "hierarchical assembly" signalling mechanism [194] .