154 Samji: Influenza A: understanding the viral life cycle which makes up around 17 percent of the viral envelope proteins. M2 is a very minor component of the envelope, with only 16 to 20 molecules per virion. HA and are ex- clusively associated with the lipid rafts in the viral lipid membrane, whereas M2 is not [4,5]. Sitting just underneath the viral lipid membrane is M1, which forms a matrix holding the viral ribonucleoproteins (vRNPs). These vRNPs are the core of the virus and are made up of the viral negative stranded RNAs, which are wrapped up around NP and very small amounts of NEP. At one end of the vRNPs are the three poly- merase (3P) proteins (PB1, PB2 and PA) that make up the viral RNA polymerase complex [1,4,6]. The influenza virus life cycle can be di- vided into the following stages: entry into the host cell; entry of vRNPs into the nu- cleus; transcription and replication of the viral genome; export of the vRNPs from the nucleus; and assembly and budding at the host cell plasma membrane. In this review, each stage of the viral life cycle will briefly be described. ENTRY INTO THE HOST CELL HA is a homotrimer that forms spikes on the viral lipid membrane. These spikes of HA bind to sialic acid found on the sur- face of the host cell’s membrane [7]. The HA precursor, HA0, is made up of two subunits: HA1, which contains the recep- tor binding domain, and HA2, which con- tains the fusion peptide. These subunits are linked by disulphide bonds [8]. Two major linkages are found between sialic acids and the carbohydrates they are bound to in glycoproteins: α(2,3) and α(2,6). These are extremely important for the specificity of the HA molecules in binding to cell surface sialic acid receptors found in different species. Viruses from humans recognize the α(2,6) linkage, whereas those from avians and equines recognize the α(2,3) linkages. Those from swine recognize both [7]. This explains the importance of swine being a good mix- ing vessel for avian and human influenza viruses, hence producing dangerous path- ogenic viruses. Upon binding to the host cell’s sialic acid residues, receptor-mediated endocyto- sis occurs and the virus enters the host cell in an endosome. The endosome has a low pH of around 5 to 6, which triggers the fusion of the viral and endosomal membranes. The low pH induces a conformational change in HA0, leading to maintenance of the HA1 re- ceptor-binding domain but exposing the HA2 fusion peptide. This fusion peptide in- serts itself into the endosomal membrane, bringing both the viral and endosomal mem- branes into contact with each other. Several crystal structures of HA in its various con- formations, i.e., at neutral and acid pH, have been solved and are reviewed in [7] and [8]. The acidic environment of the endo- some is not only important for inducing the conformation in HA0 and, thus, fusion of the viral and endosomal membranes but also opens up the M2 ion channel. M2 is a type III transmembrane protein that forms tetramers, whose transmembrane domains form a channel that acts as a proton-selec- tive ion channel [9,10]. Opening the M2 ion channels acidifies the viral core. This acidic environment in the virion releases the vRNP from M1 such that vRNP is free to enter the host cell’s cytoplasm [11]. ENTRY OF vRNPs INTO THE NUCLEUS Influenza viral transcription and repli- cation occurs in the nucleus; therefore, after being released into the cytoplasm, the vRNP must enter the nucleus. The viral proteins that make up the vRNP are NP, PA, PB1, and PB2. All of these proteins have known nu- clear localization signals (NLSs) that can bind to the cellular nuclear import machin- ery and, thus, enter the nucleus. To date, it is unclear which NLS is the most important for vRNP nuclear entry. The different NLSs present in each of these viral proteins are re- viewed in [12]. It is known that import oc- curs via the Crm1 dependent pathway by binding to the various karyopherins in- volved in nuclear import, for example, im- portin α and β.