361:279C285 [PubMed] [Google Scholar] 4. removal of glycosylation sites from SI/06 HA imposed constraints on the theoretical structure surrounding the glycan receptor binding sites, which in turn led to distinct glycan receptor binding properties. The modification of glycosylation sites for the 1918 and SI/06 viruses also caused changes in viral antigenicity based on cross-reactive hemagglutinin inhibition antibody titers with antisera from mice infected with wild-type or glycan mutant viruses. These results demonstrate that glycosylation patterns of the 1918 and seasonal H1N1 viruses directly contribute to differences in virulence and are partially responsible for their distinct antigenicity. INTRODUCTION Among the 17 known hemagglutinin (HA) subtypes and 9 known neuraminidase (NA) subtypes of influenza A viruses, only three subtypes (H1N1, H2N2, and H3N2) have adapted successfully to infect and transmit efficiently among humans (1). The influenza A virus subtype H1N1 was PPP2R1B responsible for the most devastating pandemic in recorded history, resulting in an estimated 20 to 50 million worldwide deaths in 1918 (2). Following the 1918 pandemic, the H1N1 influenza virus continued to circulate in humans, causing IX 207-887 annual epidemics with the exception of years 1957 to 1977, in which the H2N2 and H3N2 viruses emerged in humans to become the dominant subtypes (3). Unlike seasonal influenza, in which infection usually IX 207-887 causes only mild respiratory symptoms in most healthy adults, the 1918 virus caused severe respiratory illness with high mortality rates (4, 5). In particular, mortality rates were high among healthy adults 15 to 34 years old, an age group not usually associated with severe illness or death from influenza (5). In 2009 2009, a novel influenza A H1N1 virus [A(H1N1)pdm09] emerged in humans and spread throughout the world, resulting in the declaration of a pandemic by the World Health Organization IX 207-887 (WHO) (6). During the subsequent winter seasons, the A(H1N1)pdm09 virus continued to circulate throughout the world and appears to IX 207-887 have replaced the seasonal H1N1 virus (7). It has been demonstrated previously that the HA gene is a major determinant for the high virulence of the 1918 virus (8, 9). In particular, among the eight 1918 gene segments studied, only the HA gene was able to confer a virulent phenotype in mice when rescued on the genetic background of avirulent human influenza viruses. The HA protein is a homotrimer of approximately 200 kDa and is synthesized as a polypeptide HA0 that is posttranslationally cleaved into two subunits, HA1 and HA2. HA0 cleavage is essential for viral infectivity, pathogenicity, and spread of the virus in the infected host (10). The presence of polybasic amino acids at the cleavage site of HA is a major virulence determinant of highly pathogenic avian influenza viruses (subtype H5 and H7) facilitating systemic spread and lethal disease in poultry and mammals (11). The 1918 virus does not IX 207-887 possess the typical polybasic cleavage motif; thus, the mechanism of HA-mediated virulence remains unclear. Structurally, the HA comprises two distinct regions: the globular head region bearing the receptor binding domain and major antigenic sites and the long, extended membrane-proximal stem bearing the fusion peptide (12). The HA can undergo cotranslational or posttranslational glycosylation modification by attaching oligosaccharides to the asparagine (Asn) side chain in N-X-(S/T) sequons (X represents any residue except proline). The structure and composition of glycans on the HA molecule surface are dependent largely on the accessibility of glycosylation sequons to saccharide-modifying enzymes provided by.
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