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J Virol. 2015 Mar 4. pii: JVI.03636-14. [Epub ahead of print]
Diversifying selection analysis predicts antigenic evolution of 2009 pandemic H1N1 influenza A virus in humans.
Lee AJ1, Das SR2, Wang W2, Fitzgerald T3, Pickett BE1, Aevermann BD1, Topham DJ3, Falsey AR3, Scheuermann RH4.
Author information
Abstract
Although a large number of immune epitopes have been identified in the influenza A virus (IAV) hemagglutinin (HA) protein using various experimental systems, it is unclear which are involved in protective immunity to natural infection in humans. We developed a data mining approach analyzing natural H1N1 human isolates to identify HA protein regions that may be targeted by the human immune system and can predict the evolution of IAV. We identified sixteen amino acid sites experiencing diversifying selection during the evolution of pre-pandemic seasonal H1N1 strains and found that eleven sites were located in experimentally-determined B-cell/Antibody(Ab) epitopes, including three distinct neutralizing Caton epitopes: Sa, Sb and Ca2 (Caton AJ, et al., Cell 31: 417-427, 1982). We predicted that these diversified epitope regions would be the targets of mutation as the 2009 H1N1 pandemic (pH1N1) lineage evolves in response to the development of population-level protective immunity in humans. Using a chi-squared goodness-of-fit test we identified ten amino acid sites that significantly differed between the pH1N1 isolates and isolates from the recent 2012-2013 and 2013-2014 influenza seasons. Three of these sites were located in the same diversified B-cell/Ab epitope regions identified in the analysis of pre-pandemic sequences, including Sa and Sb. As predicted, hemagglutination inhibition (HI) assays using human sera from subjects vaccinated with the initial pH1N1 isolate demonstrated reduced reactivity against 2013-2014 isolates. Taken together, these results suggest that diversifying selection analysis can identify key immune epitopes responsible for protective immunity to influenza virus in humans and thereby predict virus evolution.
IMPORTANCE:
The WHO estimates that approximately 5-10% of adults and 20-30% of children in the world are infected by the influenza virus each year. While an adaptive immune response helps eliminate the virus following acute infection, the virus rapidly evolves to evade the established protective memory immune response, thus allowing for the regular seasonal cycles of influenza infection. The analytical approach described here, which combines an analysis of diversifying selection with an integration of immune epitope data, has allowed us to identify antigenic regions that contribute to protective immunity and are therefore the key targets of immune evasion by the virus. This information can be used to determine when sequence variations in seasonal influenza strains have affected regions responsible for protective immunity in order to decide when new vaccine formulations are warranted.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 25741011 [PubMed - as supplied by publisher]
Diversifying selection analysis predicts antigenic evolution of 2009 pandemic H1N1 influenza A virus in humans.
Lee AJ1, Das SR2, Wang W2, Fitzgerald T3, Pickett BE1, Aevermann BD1, Topham DJ3, Falsey AR3, Scheuermann RH4.
Author information
Abstract
Although a large number of immune epitopes have been identified in the influenza A virus (IAV) hemagglutinin (HA) protein using various experimental systems, it is unclear which are involved in protective immunity to natural infection in humans. We developed a data mining approach analyzing natural H1N1 human isolates to identify HA protein regions that may be targeted by the human immune system and can predict the evolution of IAV. We identified sixteen amino acid sites experiencing diversifying selection during the evolution of pre-pandemic seasonal H1N1 strains and found that eleven sites were located in experimentally-determined B-cell/Antibody(Ab) epitopes, including three distinct neutralizing Caton epitopes: Sa, Sb and Ca2 (Caton AJ, et al., Cell 31: 417-427, 1982). We predicted that these diversified epitope regions would be the targets of mutation as the 2009 H1N1 pandemic (pH1N1) lineage evolves in response to the development of population-level protective immunity in humans. Using a chi-squared goodness-of-fit test we identified ten amino acid sites that significantly differed between the pH1N1 isolates and isolates from the recent 2012-2013 and 2013-2014 influenza seasons. Three of these sites were located in the same diversified B-cell/Ab epitope regions identified in the analysis of pre-pandemic sequences, including Sa and Sb. As predicted, hemagglutination inhibition (HI) assays using human sera from subjects vaccinated with the initial pH1N1 isolate demonstrated reduced reactivity against 2013-2014 isolates. Taken together, these results suggest that diversifying selection analysis can identify key immune epitopes responsible for protective immunity to influenza virus in humans and thereby predict virus evolution.
IMPORTANCE:
The WHO estimates that approximately 5-10% of adults and 20-30% of children in the world are infected by the influenza virus each year. While an adaptive immune response helps eliminate the virus following acute infection, the virus rapidly evolves to evade the established protective memory immune response, thus allowing for the regular seasonal cycles of influenza infection. The analytical approach described here, which combines an analysis of diversifying selection with an integration of immune epitope data, has allowed us to identify antigenic regions that contribute to protective immunity and are therefore the key targets of immune evasion by the virus. This information can be used to determine when sequence variations in seasonal influenza strains have affected regions responsible for protective immunity in order to decide when new vaccine formulations are warranted.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 25741011 [PubMed - as supplied by publisher]