Abstract
Influenza A virions possess two surface glycoproteins—the hemagglutinin (HA) and neuraminidase (NA)—which exert opposite functions. HA attaches virions to cells by binding to terminal sialic acid residues on glycoproteins/glycolipids to initiate the infectious cycle, while NA cleaves terminal sialic acids, releasing virions to complete the infectious cycle. Antibodies specific for HA or NA can protect experimental animals from IAV pathogenesis and drive antigenic variation in their target epitopes that impairs vaccine effectiveness in humans. Here, we review progress in understanding HA/NA co-evolution as each acquires epistatic mutations to restore viral fitness to mutants selected in the other protein by host innate or adaptive immune pressure. We also discuss recent exciting findings that antibodies to HA can function in vivo by blocking NA enzyme activity to prevent nascent virion release and enhance Fc receptor-based activation of innate immune cells.
Highlights
Year in and year out, influenza A virus (IAV) imposes an enormous economic and health burden, with the potential to cause periodic catastrophic pandemics
PB1, PB2, PA, NP, M1, NS1, and NEP are present inside the lipid envelope, while M2, hemagglutinin (HA), and neuraminidase (NA) are embedded in the envelope and available for antibody (Ab) binding
The high mutational tolerance [5] of these surface glycoproteins, both structurally and functionally compared to other IAV gene products [6], facilitates their “antigenic drift”—immune escape from Ab responses based on mutant selection [7]
Summary
Year in and year out, influenza A virus (IAV) imposes an enormous economic and health burden, with the potential to cause periodic catastrophic pandemics. Monoclonal Ab (mAb) selection of HA escape mutations in some instances co-selected NA mutants with single amino acid substitutions that reduce NA virion incorporation, likely due to interference with normal NA assembly or trafficking (Figure 1B) [77,78] Some of these NA mutations modified NA sensitivity to clinically used inhibitors and/or modified NA antigenicity. Adaptation of the mouse A/Puerto Rico/8/1934 (H1N1) strain to guinea pigs revealed another mechanism of controlling NA incorporation into virions, based on a single amino acid substitution in NP that reduced NA mRNA and vRNA expression, reducing NA synthesis and impairing NA gene segment packaging into progeny virions (Figure 1C) [8] Such semi-infectious (SI) virions lacking one or more gene segments outnumber intact virions in most virus preparations, with the NA segment being most frequently absent [79,80].
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