Abstract
The evolutionary adaptation of the influenza A virus (IAV) to human antibodies is well characterised. Much less is known about the long-term evolution of cytotoxic T lymphocyte (CTL) epitopes, which are important antigens for clearance of infection. We construct an antigenic map of IAVs of all human subtypes using a compendium of 142 confirmed CTL epitopes, and show that IAV evolved gradually in the period 1932–2015, with infrequent antigenic jumps in the H3N2 subtype. Intriguingly, the number of CTL epitopes per virus decreases with more than one epitope per three years in the H3N2 subtype (from 84 epitopes per virus in 1968 to 64 in 2015), mostly attributed to the loss of HLA-B epitopes. We confirm these observations with epitope predictions. Our findings indicate that selection pressures imposed by CTL immunity shape the long-term evolution of IAV.
Highlights
The evolutionary adaptation of the influenza A virus (IAV) to human antibodies is well characterised
Many cytotoxic T lymphocyte (CTL) epitopes have been identified in IAV24,25, but a framework capturing the dynamics of CTL epitopes in all proteins over long evolutionary time is lacking
Antigenic cartography based on CTL epitopes
Summary
The evolutionary adaptation of the influenza A virus (IAV) to human antibodies is well characterised. The number of CTL epitopes per virus decreases with more than one epitope per three years in the H3N2 subtype (from 84 epitopes per virus in 1968 to 64 in 2015), mostly attributed to the loss of HLA-B epitopes We confirm these observations with epitope predictions. Viruses escape CTL recognition by mutating amino acid residues within CTL epitopes Such immune escape mutations play an important role in the within-host dynamics of chronic pathogens (e.g. HIV) and are observed during acute IAV infection[16,17]. While immune escape mutations in IAV cripple the virus[18,19], these mutations can persist in a prolonged infection[20], and at the population level despite the high polymorphism of human leukocyte antigen (HLA)[21,22]. We analyse historical and contemporary IAV sequence data spanning the period 1932–2015, using 142 empirically confirmed CTL epitopes known to date[26,27] (Supplementary Tables S1, S2 and S3; Methods)
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