TY - JOUR
T1 - Defining influenza a virus hemagglutinin antigenic drift by sequential monoclonal antibody selection
AU - Das, Suman R.
AU - Hensley, Scott E.
AU - Ince, William L.
AU - Brooke, Christopher B.
AU - Subba, Anju
AU - Delboy, Mark G.
AU - Russ, Gustav
AU - Gibbs, James S.
AU - Bennink, Jack R.
AU - Yewdell, Jonathan W.
N1 - Funding Information:
We thank Glennys Reynoso for providing outstanding technical assistance. We thank Dr. Walter Gerhard for his generous gift of the large panel of mAbs and viruses. We thank Dr. Adolfo Garcia-Sastre and Dr. David Wentworth for kindly providing eight-plasmid reverse-genetics plasmid to rescue WT and mutant viruses. We thank Dr. Zhiping Ye for providing ferret anti-sera to PR8 virus. The sequencing of the whole genome of the SEQ- variants was done at JCVI, which is one of the Genomic Sequencing Center of Infectious Diseases (GSCID) and has been funded with federal funds from the NIAID, NIH, and Department of Health and Human Services under contract number HHSN272200900007C. S.R.D. is supported by JCVI internal start-up fund. J.W.Y. and J.R.B. are generously supported by the Division of Intramural Research, NIAID. S.R.D., S.E.H., W.L.I., G.R., J.R.B., and J.W.Y. conceived of and designed experiments. S.R.D., S.E.H., W.L.I., C.B.B., A.S., M.G.D., G.R., and J.S.G. performed experiments. S.R.D., S.E.H., W.L.I., C.B.B., A.S., M.G.D., G.R., J.R.B., and J.W.Y. analyzed data. S.R.D. and J.W.Y. wrote the manuscript.
PY - 2013/3/13
Y1 - 2013/3/13
N2 - Human influenza A virus (IAV) vaccination is limited by "antigenic drift," rapid antibody-driven escape reflecting amino acid substitutions in the globular domain of hemagglutinin (HA), the viral attachment protein. To better understand drift, we used anti-hemagglutinin monoclonal Abs (mAbs) to sequentially select IAV escape mutants. Twelve selection steps, each resulting in a single amino acid substitution in the hemagglutinin globular domain, were required to eliminate antigenicity defined by monoclonal or polyclonal Abs. Sequential mutants grow robustly, showing the structural plasticity of HA, although several hemagglutinin substitutions required an epistatic substitution in the neuraminidase glycoprotein to maximize growth. Selecting escape mutants from parental versus sequential variants with the same mAb revealed distinct escape repertoires, attributed to contextual changes in antigenicity and the mutation landscape. Since each hemagglutinin mutation potentially sculpts future mutation space, drift can follow many stochastic paths, undermining its unpredictability and underscoring the need for drift-insensitive vaccines.
AB - Human influenza A virus (IAV) vaccination is limited by "antigenic drift," rapid antibody-driven escape reflecting amino acid substitutions in the globular domain of hemagglutinin (HA), the viral attachment protein. To better understand drift, we used anti-hemagglutinin monoclonal Abs (mAbs) to sequentially select IAV escape mutants. Twelve selection steps, each resulting in a single amino acid substitution in the hemagglutinin globular domain, were required to eliminate antigenicity defined by monoclonal or polyclonal Abs. Sequential mutants grow robustly, showing the structural plasticity of HA, although several hemagglutinin substitutions required an epistatic substitution in the neuraminidase glycoprotein to maximize growth. Selecting escape mutants from parental versus sequential variants with the same mAb revealed distinct escape repertoires, attributed to contextual changes in antigenicity and the mutation landscape. Since each hemagglutinin mutation potentially sculpts future mutation space, drift can follow many stochastic paths, undermining its unpredictability and underscoring the need for drift-insensitive vaccines.
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U2 - 10.1016/j.chom.2013.02.008
DO - 10.1016/j.chom.2013.02.008
M3 - Article
C2 - 23498956
AN - SCOPUS:84875145733
SN - 1931-3128
VL - 13
SP - 314
EP - 323
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 3
ER -