title: Dynamics of glycoprotein charge in the evolutionary history of human influenza.
abstract: BACKGROUND
  Influenza viruses show a significant capacity to evade host immunity; this is manifest both as large occasional jumps in the antigenic phenotype of viral surface molecules and in gradual antigenic changes leading to annual influenza epidemics in humans. Recent mouse studies show that avidity for host cells can play an important role in polyclonal antibody escape, and further that electrostatic charge of the hemagglutinin glycoprotein can contribute to such avidity.
  
  
  RESULTS
  We test the role of glycoprotein charge on sequence data from the three major subtypes of influenza A in humans, using a simple method of calculating net glycoprotein charge. Of all subtypes, H3N2 in humans shows a striking pattern of increasing positive charge since its introduction in 1968. Notably, this trend applies to both hemagglutinin and neuraminidase glycoproteins. In the late 1980s hemagglutinin charge reached a plateau, while neuraminidase charge started to decline. We identify key groups of amino acid sites involved in this charge trend.
  
  
  CONCLUSIONS
  To our knowledge these are the first indications that, for human H3N2, net glycoprotein charge covaries strongly with antigenic drift on a global scale. Further work is needed to elucidate how such charge interacts with other immune escape mechanisms, such as glycosylation, and we discuss important questions arising for future study.
authors.affiliation: Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America. nimpathy@princeton.edu
authors.forename: Nimalan
authors.initials: N
authors.lastname: Arinaminpathy
authors.forename: Bryan
authors.initials: B
authors.lastname: Grenfell
mesh_terms: D019295:Computational Biology / Q000379:methods; D030562:Databases, Protein; D058872:Epidemics; D019143:Evolution, Molecular; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D006031:Glycosylation; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007107:Immune System; D053122:Influenza A Virus, H3N2 Subtype / Q000378:metabolism; D007251:Influenza, Human / Q000453:epidemiology*; D009439:Neuraminidase / Q000737:chemistry; D010641:Phenotype; D014780:Viruses / Q000235:genetics*
chemical_list: D006023:Glycoproteins; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D009439:Neuraminidase