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Review
. 2019 May 20;11(5):458.
doi: 10.3390/v11050458.

Competitive Cooperation of Hemagglutinin and Neuraminidase during Influenza A Virus Entry

Ruikun Du  1   2   3 , Qinghua Cui  4   5   6 , Lijun Rong  7
Affiliations
Review

Competitive Cooperation of Hemagglutinin and Neuraminidase during Influenza A Virus Entry

Ruikun Du et al. Viruses. .

Abstract

The hemagglutinin (HA) and neuraminidase (NA) of influenza A virus possess antagonistic activities on interaction with sialic acid (SA), which is the receptor for virus attachment. HA binds SA through its receptor-binding sites, while NA is a receptor-destroying enzyme by removing SAs. The function of HA during virus entry has been extensively investigated, however, examination of NA has long been focused to its role in the exit of progeny virus from infected cells, and the role of NA in the entry process is still under-appreciated. This review summarizes the current understanding of the roles of HA and NA in relation to each other during virus entry.

Keywords: hemagglutinin; influenza A virus; neuraminidase; virus entry.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cartoon structures of the spikes of hemagglutinin (HA) and neuraminidase (NA). (a) The HA spike is formed by an HA trimer. Each HA monomer contains two functional domains, the receptor binding globular domain and the helix-rich stalk domain. (b) NA exists as a tetramer of four identical monomers. Each NA monomer consists of four distinct structure domains, including the catalytic head, the stalk, the transmembrane region and the cytoplasmic tail.
Figure 2
Figure 2
Representative model for influenza A virus moving on sialic acid (SA) decorated surface. In order to infect a target host cell, the virus might need to move either across airway mucus to reach the target cell or on the cell surface to access an entry receptor. After viral attachment, the NA could degrade SAs near the attachment site, resulting in reduced SA density; the SA density gradient promotes virus moving until successful infection occur.
Figure 3
Figure 3
The relative HA binding affinity and NA activity need to be balanced for efficient entry. (a) If the HA and NA are mismatched and the NA activity is suboptimal, the virus may remain bound to decoy receptors, blocking virus movement and entry. (b) Efficient cleavage of SA from decoy receptors by NA enables HA access to the right entry receptors, followed by efficient endocytosis. (c) In the case that NA activity is too strong when compared to HA binding affinity, every binding attempt of the virus via HA will be disrupted by NA cleavage, resulting in failed binding.
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