compensatory evolution of net-charge in influenza a virus hemagglutinin补偿进化甲型流感病毒血凝素的净电荷.pdfVIP

Compensatory Evolution of Net-Charge in Influenza A Virus Hemagglutinin 1,2 1 Yuki Kobayashi , Yoshiyuki Suzuki * 1 Graduate School of Natural Sciences, Nagoya City University, Nagoya City, Aichi, Japan, 2 Department of Zoology, University of Oxford, Oxford, United Kingdom Abstract The propagation of influenza A virus depends on the balance between the activities of hemagglutinin (HA) for binding to host cells and neuraminidase (NA) for releasing from infected cells (HA-NA balance). Since the host cell membrane and the sialic acid receptor are negatively charged, the amino acid substitutions increasing (charge+) and decreasing (charge 2) the positive charge of HA subunit 1 (HA1) enhance and reduce, respectively, the binding avidity and affinity. The positive charge of HA1 in human influenza A virus bearing subtype H3N2 (A/H3N2 virus) was observed to have increased during evolution, but the evolutionary mechanism for this observation was unclear because this may disrupt the HA-NA balance. Here we show, from the phylogenetic analysis of HA for human A/H3N2 and A/H1N1 viruses, that the relative frequencies of charge+ and charge 2 substitutions were elevated on the branches where the number of N-glycosylation sites (NGS) increased and decreased, respectively, compared to those where the number of NGS did not change. On the latter branches, the net- charge of HA1 appeared to have been largely maintained to preserve its structure and function. Since the charge+ and charge 2 substitutions in HA1 have opposite effects to the gain and loss of NGS on the binding and release of the virus, the net-charge of HA1 may have evolved to compensate for the effect of the gain and loss of NGS, probably through changing the avidity. Apparently, the relative frequency of charge 2 substitutions in HA1 of A/H3N2 virus w