Viral Membrane Channels: Role and Function in the Virus Life Cycle

Sze, Ching Wooen; Tan, Yee-Joo

In order for infection to occur, viruses first have to bind to and penetrate the host plasma membrane to deliver the genetic elements into the cytoplasm for replication to take place. Enveloped and non-enveloped viruses employ different strategies to achieve the same goal (see review [77] [78] [79] ). Upon binding of its hemagglutinin glycoprotein (HA) to the host surface sialic acid, IAV is internalized via the endosomal trafficking [80, 81] . Localization of M2 at the viral membrane enables it to function as a proton channel and acidify the interior environment of the virus within the endosome [7] . Under low pH conditions, fusion of the endosomal and viral membrane leads to the release of the nucleoprotein complex from the matrix protein M1 and subsequent uncoating of the viral RNA genome in the cytoplasm [8] [9] [10] . The M2 homotetramer has been well characterized throughout the years [7, 50, 56, 82, 83] . The protein has been dissected into smaller sections and each has a different role in contributing to the pathogenesis of this virus [15, 16, 56, 84] . Mutants with a defective M2 ion channel activity are still able to complete the viral life cycle in a cell culture system although they are severely compromised as compared to their wild-type counterparts. In addition, their growth was significantly suppressed when used to infect mice [85, 86] . This shows that M2 is essential for the overall fitness of IAV as well as its replication efficiency in host cells. Given its role in the virulence of IAV, an inhibitor has been developed against M2 to antagonize its ion channel function. For example, the anti-influenza drug, rimantadine, is believed to bind and stabilize M2 in the closed conformation and thus renders it inactive by preventing proton conductance [50] .