Figure 5.

The relative activity of the HA and NA needs to be balanced to maintain the ability of the virion to efficiently infect and be released from cells. (A) Efficient cleavage of sialic acids from decoy receptors (such as cell-surface mucins) by NA enables HA access to sialic acids expressed by entry receptors and efficient endocytosis. After endosome escape of the viral genome and its migration to the nucleus, replication of the genome, synthesis of viral mRNAs, and translation of viral proteins take place. New virions assemble at the cell surface and are released from the cell by budding. As the viral components bud from the cell, NA cleaves sialic acids from receptors near the budding site to prevent virions binding back to the dying cell. NA cleavage of sialic acids from the carbohydrate side chains of nascent HA and NA also prevents newly budded virus from clumping together. Both these functions enable efficient release of the nascent virions from the cell. (B) If the HA and NA are mismatched and have mutations in important binding or catalytic sites that alter function, the relative activity of the two proteins may be imbalanced. If the sialidase function of NA is suboptimal, virus may remain bound by decoy receptors, which may shed and block virus entry into the cell. As the virus buds from the cell, an imbalance of HA and NA function may result in the lack of release of the virions due to the binding of HA to the sialic acids expressed at the cell surface that have not been removed by the NA. (C) Alternatively, if the sialidase activity of NA is too strong when compared to the HA-binding activity, sialic acids may be removed from receptors at the expense of the HA being able to bind and trigger endocytosis.