Resistance of influenza viruses to neuraminidase inhibitors--a review.

Influenza virus is a negative stranded RNA virus. It contains two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). HA exists as a trimer and is responsible for binding to the terminal sialic acid bound to receptors on the surface of the target cell, leading to attachment and subsequent penetration by the virus into the cell. Influenza virus isolates from different animals appear to have a preference for specific receptor linkages. Equine and avian isolates bind preferentially to the a2,3 galactose structure, while human isolates bind preferentially to the a2,6 galactose structure (Leigh et al., 1995). A single amino acid mutation is sufficient to change receptor specificity (Rogers and Paulson, 1983; Nobusawa and Nakajima, 1988; Martin et al., 1998). Sequence analysis and alignment has identified key residues conserved across all HA subtypes, which are involved in receptor binding (Nobusawa et al., 1991). The sialic acid binding site forms a groove across the top of the HA surrounded by antibody binding sites (Weis et al., 1988). Residues 134–138 form the right side of the ligand binding site, and residues 224–228 form the left side. Other conserved residues appear to play a role in orienting several of the surface atoms for binding to the sialic acid, these include Tyr 98, Trp 153, His 183, Glu 190, Leu 194 and Tyr at 195 (Weis et al., 1988; Nobusawa et al., 1991). After replication of the virus, progeny virions bud from the cell surface. NA is thought to be responsible for cleavage of terminal sialic acid moieties from receptors, to facilitate elution of progeny virions from the infected cell. Since they are also glycosylated, newly synthesized HA and NA on virions may also contain sialic acid residues on their oligosaccharide chains. Removal of these terminal sugars is therefore also necessary to prevent self-aggregation, due to the HA of one virion binding to the sialic acids on an adjacent * Fax: +61-3-96627101. E-mail address: [email protected] (J.L. McKimmBreschkin).