Abstract
The induction of antibodies specific for the influenza HA protein stalk domain is being pursued as a universal strategy against influenza virus infections. However, little work has been done looking at natural or induced antigenic variability in this domain and the effects on viral fitness. We analyzed human H1 HA head and stalk domain sequences and found substantial variability in both, although variability was highest in the head region. Furthermore, using human immune sera from pandemic A/California/04/2009 immune subjects and mAbs specific for the stalk domain, viruses were selected in vitro containing mutations in both domains that partially contributed to immune evasion. Recombinant viruses encoding amino acid changes in the HA stalk domain replicated well in vitro, and viruses incorporating two of the stalk mutations retained pathogenicity in vivo. These findings demonstrate that the HA protein stalk domain can undergo limited drift under immune pressure and the viruses can retain fitness and virulence in vivo, findings which are important to consider in the context of vaccination targeting this domain.
Highlights
The induction of antibodies specific for the influenza HA protein stalk domain is being pursued as a universal strategy against influenza virus infections
Because the antibodies against the dominant HA head domain are usually strain specific, and the HA head domain presents a high plasticity leading to antigenic drift, antibodies against the more conserved HA stalk domain are currently being discussed as promising therapeutic targets[8]
In order to address the ability of the stalk region to incorporate aa substitutions, publically available influenza H1N1 HA protein sequences were obtained from viruses that circulated since 1918
Summary
The induction of antibodies specific for the influenza HA protein stalk domain is being pursued as a universal strategy against influenza virus infections. Antibodies directed against the stalk domain, inhibiting HA-mediated fusion of viral and endosomal membranes necessary to release the virus genome in the cytoplasm[13] have been detected in humans[9,13,14,15], likely induced after natural infection[16,17]. The number of memory B cells specific for conserved epitopes in the HA stalk are not outcompeted[8,19,20] According to this hypothesis, it has been shown that HA stalk-reactive antibodies are boosted following sequential infection with seasonal and pH1N1 viruses in mice[22]. The HA protein incorporates mutations through a process called antigenic drift, decreasing the efficacy of the vaccine[24], requiring periodic updates to the seasonal vaccine to try to maintain a good match with circulating viruses[25,26,27]
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