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A molecular understanding of alphavirus entry and antibody protection.

ABSTRACT: Alphaviruses are arthropod-transmitted RNA viruses that cause epidemics of human infection and disease on a global scale. These viruses are classified as either arthritogenic or encephalitic based on their genetic relatedness and the clinical syndromes they cause. Although there are currently no approved therapeutics or vaccines against alphaviruses, passive transfer of monoclonal antibodies confers protection in animal models. This Review highlights recent advances in our understanding of the host factors required for alphavirus entry, the mechanisms of action by which protective antibodies inhibit different steps in the alphavirus infection cycle and candidate alphavirus vaccines currently under clinical evaluation that focus on humoral immunity. A comprehensive understanding of alphavirus entry and antibody-mediated protection may inform the development of new classes of countermeasures for these emerging viruses.

SUBMITTER: Kim AS

PROVIDER: S-EPMC9734810 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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A molecular understanding of alphavirus entry and antibody protection.

Kim Arthur S AS Diamond Michael S MS

Nature reviews. Microbiology 20221206 6

Alphaviruses are arthropod-transmitted RNA viruses that cause epidemics of human infection and disease on a global scale. These viruses are classified as either arthritogenic or encephalitic based on their genetic relatedness and the clinical syndromes they cause. Although there are currently no approved therapeutics or vaccines against alphaviruses, passive transfer of monoclonal antibodies confers protection in animal models. This Review highlights recent advances in our understanding of the h ...[more]

PMID: 36474012

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Project description:Antibody-dependent enhancement (ADE) of viral entry has been a major concern for epidemiology, vaccine development, and antibody-based drug therapy. However, the molecular mechanism behind ADE is still elusive. Coronavirus spike protein mediates viral entry into cells by first binding to a receptor on the host cell surface and then fusing viral and host membranes. In this study, we investigated how a neutralizing monoclonal antibody (MAb), which targets the receptor-binding domain (RBD) of Middle East respiratory syndrome (MERS) coronavirus spike, mediates viral entry using pseudovirus entry and biochemical assays. Our results showed that MAb binds to the virus surface spike, allowing it to undergo conformational changes and become prone to proteolytic activation. Meanwhile, MAb binds to cell surface IgG Fc receptor, guiding viral entry through canonical viral-receptor-dependent pathways. Our data suggest that the antibody/Fc-receptor complex functionally mimics viral receptor in mediating viral entry. Moreover, we characterized MAb dosages in viral-receptor-dependent, Fc-receptor-dependent, and both-receptors-dependent viral entry pathways, delineating guidelines on MAb usages in treating viral infections. Our study reveals a novel molecular mechanism for antibody-enhanced viral entry and can guide future vaccination and antiviral strategies.IMPORTANCE Antibody-dependent enhancement (ADE) of viral entry has been observed for many viruses. It was shown that antibodies target one serotype of viruses but only subneutralize another, leading to ADE of the latter viruses. Here we identify a novel mechanism for ADE: a neutralizing antibody binds to the surface spike protein of coronaviruses like a viral receptor, triggers a conformational change of the spike, and mediates viral entry into IgG Fc receptor-expressing cells through canonical viral-receptor-dependent pathways. We further evaluated how antibody dosages impacted viral entry into cells expressing viral receptor, Fc receptor, or both receptors. This study reveals complex roles of antibodies in viral entry and can guide future vaccine design and antibody-based drug therapy.

Dataset Information

A molecular understanding of alphavirus entry and antibody protection.

Publications

A molecular understanding of alphavirus entry and antibody protection.

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