Role of paramyxovirus glycoproteins in the interactions between viral and cell membranes.

Interactions of paramyxoviruses with cell membranes are mediated by two virus-coded glycoproteins of the virus membrane: HN and F. The HN protein is responsible for the attachment of virions to the membrane of the target cell. The F protein mediates fusion between the virus membrane and the cell membrane, and this step is essential for the infection process as well as for the expression of other biological activities of paramyxoviruses, i.e., cell fusion and hemolysis. The activity of F is dependent on the proteolytic processing of a precursor (F0) to yield two disulfide-linked subunits (F1 and F2), and unless this cleavage occurs, the virions are inactive and not infectious. Viruses differ in their susceptibility to specific proteases, as demonstrated with Sendai virus and its protease activation (pa) mutants. Findings with these viruses indicate that the host range, tissue tropism, and the ability of paramyxoviruses to spread within a host and to cause disease are dependent on the availability of an appropriate protease capable of cleaving the viral glycoprotein. Experiments with reconstituted particles that contain purified F protein and phosphatidylcholine indicate that to be active the F protein must be inserted in a lipid bilayer, and that no other viral function is needed for the membrane fusion process. Attachment of the F-protein-containing particles to the target membrane is a prerequisite for fusion; however, this function can be supplied by wheat germ agglutinin as well as by the virus protein responsible for attachment of intact virus, i.e., HN. Studies on the structure of the paramyxovirus glycoproteins indicate that they are inserted with a hydrophobic region of the molecule in the lipid bilayer of the virus membrane. Analysis of the primary structure of the F protein at the cleavage site revealed striking sequence homology among three paramyxoviruses, indicating a requirement for cleavage at a sharply defined site and the importance of a specific primary sequence for biological activity. This region is highly hydrophobic, suggesting that it may interact with the lipid biylayer of the target cell membrane during virus penetration, cell fusion, or hemolysis. Further studies of this system should provide knowledge regarding the mechanisms involved in viral penetration and in membrane fusion in general.