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Noncanonical antibody strategy for broad and potent neutralization of influenza virus

Cellular & Molecular Immunology volume 18, pages 1615–1617 (2021)Cite this article

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Pathogens with high levels of genetic variability, such as HIV-1 and influenza virus, evade the immune system by constantly changing their proteins vulnerable to neutralization by antibodies Consequently, these highly evolvable viruses are notoriously elusive targets for vaccines. In rare cases, infection of humans with HIV-1 or influenza virus results in production of antibodies that can neutralize a very broad spectrum of viral strains. Such antibodies are referred to as broadly neutralizing.1 The typical modus operandi of such neutralizing antibodies is recognition with high affinity and blocking by steric hinderance of conserved regions of viral proteins that are important for receptor binding or entry into host cells.1,2 This neutralization mechanism can be further supported by antibody functions dependent on constant regions, such as antibody-dependent cellular cytotoxicity.3,4 Since the rational induction of broadly neutralizing antibody responses may represent the key for the development of efficient vaccines against rapidly evolving viruses, these antibodies have been the subject of numerous thorough investigations. A recent publication in Immunity by Madsen et al described a nonconventional mechanism for potent and broad neutralization of influenza B virus.5

The principal targets of influenza virus recognized by neutralizing antibodies are the envelope glycoproteins hemagglutinin (HA) and neuraminidase (NA).4 These proteins are expressed on the viral membrane (supercapsid) and play critical roles in the life cycle of the virus. HA is a lectin that specifically recognizes terminal sialic acid. Many glycoproteins on the host cell membrane display sialic acid, thus serving as receptors for attachment of the virus. The second most abundant envelope protein, NA, is an enzyme with glycolytic activity; it specifically cleaves terminal sialic acid residues. By virtue of its enzymatic activity, NA mediates release of the virus from its initial retention in the mucosa, which is caused by the interaction of HA with secretory sialic acid-reach glycoproteins (mucins).4 The catalytic activity of NA also plays a critical role in the detachment of newly formed viral particles from the membrane of host cells. HA is the immunodominant envelope protein, i.e., most antibodies produced during infection recognize epitopes on it.2,4 HA is divided into two structural and functional regions – the head, which is responsible for recognition of sialic acid, and the stalk, which takes part in fusion of the viral membrane with the membrane of the host cell.2 The head region is the most frequent target of antibody responses; however, these antibodies usually exhibit only limited neutralization breadth. It is noteworthy that antibodies that recognize the stalk of HA, despite being less frequent, possess a better neutralization potential.2,4 This can be explained by the highly conserved nature of the stalk region of HA, contrary to the that of the head region. Notwithstanding that the focus of most research has been on antibodies specific for HA, it is known that NA can also be targeted by neutralizing and broadly neutralizing antibody responses.6

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Acknowledgements

JDD is supported by the Institut National de la Santé et de la Recherche Médicale (INSERM, France).

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  1. Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, F-75006, Paris, France

    Jordan D. Dimitrov

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Correspondence to Jordan D. Dimitrov.

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Dimitrov, J.D. Noncanonical antibody strategy for broad and potent neutralization of influenza virus. Cell Mol Immunol 18, 1615–1617 (2021). https://doi.org/10.1038/s41423-020-00617-0

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