Читать книгу Principles of Virology - Jane Flint, S. Jane Flint - Страница 243

The genomes of many enveloped RNA viruses are present as ribonucleoproteins (vRNP) in the virus particle. In the case of influenza virus, each vRNP is composed of a segment of the RNA genome bound by nucleoprotein (NP) molecules and the viral RNA polymerase, which must be released into the cytoplasm and enter the nucleus, where mRNA synthesis takes place. The vRNP structures interact with viral M1 protein, an abundant protein in virus particles that underlies the envelope and provides rigidity (Fig. 5.13). The M1 protein also contacts the internal tails of the HA and neuraminidase transmembrane proteins. This arrangement presents problems. Unless M1-vRNP interactions are disrupted, vRNPs might not be released into the cytoplasm. Furthermore, the vRNPs cannot enter the nucleus, because M1 masks a nuclear localization signal (see “Import of Influenza Virus Ribonucleoprotein” below).

The influenza virus M2 protein, the first viral protein identified as an ion channel, provides the solution to both problems. The envelope of the virus particle contains a small number of molecules of M2 protein, which form a homotetramer. When purified M2 was reconstituted into synthetic lipid bilayers, ion channel activity was observed, indicating that this property requires only the M2 protein. The M2 protein channel is structurally much simpler than other ion channels and is the smallest channel discovered to date.

The M2 ion channel is activated by the low pH of the endosome before HA-catalyzed membrane fusion occurs. As a result, protons enter the interior of the virus particle. It has been suggested that the reduced pH of the particle interior leads to conformational changes in the M1 protein, thereby disrupting M1-vRNP interactions. When fusion between the viral envelope and the endosomal membrane takes place, vRNPs are released into the cytoplasm free of M1 and can then be imported into the nucleus (Fig. 5.13). Support for this model comes from studies with the anti-influenza virus drug amantadine, which specifically inhibits M2 ion channel activity (Volume II, Fig. 8.12). In the presence of this drug, influenza virus particles can bind to cells, enter endosomes, and undergo HA-mediated membrane fusion, but vRNPs are not released from endosomes.