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The HA and NA proteins play complementary roles in the life cycle of the influenza virus. Both HA and NA bind to host cell receptors containing sialic acid residues: HA to initiate viral entry into the host cell, and NA to permit the release of viral progeny from infected cells. Experimental studies have suggested that a fine balance between HA and NA activity must be achieved for productive viral infection . Such a balance may, in fact, be more important for viral fitness than high levels of activity per se. For example, showed that when artificially generated reassortant viruses of the N1 NA subtype were cultured, several (e.g. H3N1) only gave low yields. However, when the low-yield H3N1 culture was passaged, a number of changes occurred in the HA which reduced its receptor binding affinity, apparently to match that of the NA in the reassortant rather than to return to the high levels of HA activity found in the H3N8 parent virus.

Both the HA and NA proteins are thought to determine sensitivity of naturally-occurring influenza viruses to neuraminidase-inhibiting drugs (NAIs) [10]. In vitro studies have investigated genetic interactions between HA and NA in terms of NAI resistance. Evidence suggests that mutations in the HA which decrease receptor binding activity may compensate for a decrease in NA activity resulting from treatment with NAIs, thus restoring the balance between HA and NA function . In addition, HA and NA mutations which individually confer low-level resistance to NAIs have been found to combine synergistically to confer resistance at a higher level . Interdependence between the length of the NA stalk section and the number of HA glycosylation sites has been identified in laboratory strains and may also have direct consequences for the transmission of influenza viruses to other host species. For example, influenza A viruses which have become established in terrestrial poultry may possess additional HA glycosylation sites, accompanied by deletions in the stalk section of their NA .

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