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SUMMARY:Influenza Adrift: Rethinking Influenza A Virus Evolution - Dr Jon 
 Yewdell\, National Institutes of Health\, USA
DTSTART:20131016T113000Z
DTEND:20131016T123000Z
UID:TALK46817@talks.cam.ac.uk
CONTACT:Sue Griffin
DESCRIPTION:Influenza A virus (IAV) hemagglutinin (HA) initiates infection
  by attaching virus to host cell surface sialic acids and catalysing the f
 usion of viral and cellular membranes.  The neuraminidase (NA) ends the in
 fectious cycle by releasing nascent virions from the infected cell surface
 .  Antibodies (Abs) to HA block viral entry and play a critical role in im
 munity following infection or vaccination.  Due to the rapid appearance of
  HA-escape mutants in human populations\, vaccines must be constantly refo
 rmulated. \n \nTo better understand antigenic drift\, we modelled IAV infe
 ctions in mice and guinea pigs.   Our findings indicate that antigenic dri
 ft is likely to be more than direct escape from neutralizing antibodies.  
 Instead\, they point to a key role for HA binding avidity for host cell si
 alic acid receptors\, and an oft-neglected feature of antibody mediated ne
 utralization: it represents a ternary competition between receptor and ant
 ibody for virus.  \n\nFacing a partially neutralizing antibody response\, 
 virus can escape by increasing receptor avidity.  Partial neutralization m
 ust be a common occurrence in nature due to variability in human immune re
 sponses and infection with drifted variants that demonstrate fractional es
 cape from the Ab response to (un-drifted) parent.  Predictably\, increased
  viral receptor avidity incurrs fitness costs in vivo.  Re-passage of adso
 rptive mutants in naïve mice selected HA-single substitution mutants with
  diminished receptor avidity.  Despite the lack of Ab pressure\, some of t
 he substitutions occurred in antigenic regions.  That single substitutions
  in the HA globular domain simultaneously modulate antigenicity and recept
 or binding\, confounds retrospective analysis of genetic variation in HA. 
  \n\nThe situation is complicated further by the occurrence of epistatic c
 hanges within HA and between HA and NA to maximize viral fitness following
  selection. Moreover\, substitutions selected to modulate receptor avidity
  will inevitably modify receptor specificity for various sialic acid termi
 nated-glycans and vice versa. \n \nFrom leaves to forest: even in the simp
 lest species (viruses)\, evolution is complicated\, and oversimplified ana
 lysis leads to all sorts of errors\, including those with practical ramifi
 cations in interpreting sequences for choosing vaccine strains.\n
LOCATION:Lecture Theatre\, Department of Pathology\, Tennis Court Road
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