The Influenza Life Cyclea
The Orthomyxoviridae are a family of single-stranded RNA viruses that includes five genera: Influenza virus A, Influenza virus B, Influenza virus C, Isavirus, and Thogotovirus. A sixth has recently been described (Presti et al., 2009). The first genus contains viruses that cause influenza in vertebrates, including birds, humans, and other mammals. Influenza B and C viruses circulate in humans. Isaviruses infect salmon; thogotoviruses infect both vertebrates and invertebrates such as ticks (Ely, 1999; Jones and Nuttall, 1989; Raynard et al., 2001).
Viruses can only replicate in living cells. Influenza infection and replication is a multistep process: the virus must first bind to and enter the cell, then deliver its genome to a site where it can produce new copies of viral proteins and RNA, assemble these components into new viral particles, and finally exit the host cell.
Influenza viruses infect epithelial cells of the respiratory tract by attaching to sialic acid receptors. The virus particle contains a genome consisting of eight single stranded, negative sense RNA genes surrounded by viral proteins and a host-derived lipid membrane. The surface of the virus particle contains spikes of hemagglutinin (HA) that are responsible for attachment of virions to the cell surface. The HA binds to sialic acid receptors located at the tip of glycan chains conjugated to host cell membrane proteins and lipids (stage 1 in Figure WO-1)—typically in the nose, throat, and lungs of mammals and in the intestines of birds. Multivalent binding of the virus particle to the cell triggers uptake by endocytosis and subsequent fusion of the viral envelope to the endosome membrane, delivering the genome into the host cell cytoplasm.
Once inside the cell, the acidic conditions in the endosome cause two events to happen: first part of the HA protein fuses the viral envelope with the vacuole’s membrane, then the M2 ion channel allows protons to move through the viral envelope and acidify the core of the virus, which causes the core to disassemble and release the viral RNA and core proteins. The viral RNA (vRNA) molecules, accessory proteins, and RNA-dependent RNA polymerase are then released into the cytoplasm (stage 2). The M2 ion channel is blocked by amantadine drugs, preventing infection.
These core proteins and vRNA form a complex that is transported into the cell nucleus, where the RNA-dependent RNA polymerase begins transcribing complementary positive-sense vRNA (stages 3a and 3b). The vRNA is either exported into the cytoplasm and translated (stage 4) or remains in the nucleus. Newly synthesised viral proteins are either secreted through the Golgi apparatus onto the cell surface (in the case of neuraminidase and hemagglutinin, stage 5b) or transported back into the nucleus to bind vRNA and form new viral genome particles (stage 5a). Other viral proteins have multiple actions in the host cell,