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Structural Model for Factor X Inhibition of IgM and Complement-Mediated Neutralization of Adenovirus
Nicole Wagner1, Dmitry M Shayakhmetov2,3,4, Phoebe L Stewart1
1Cleveland Center for Membrane and Structural Biology, Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA.
Abstract:
Adenovirus has strong therapeutic potential as an oncolytic virus and gene therapy vector. However, injecting human species C serotype 5 adenovirus, HAdv-C5, into the bloodstream leads to numerous interactions with plasma proteins that affect viral tropism and biodistribution, and can lead to potent immune responses and viral neutralization. The HAdv/factor X (FX) interaction facilitates highly efficient liver transduction and protects virus particles from complement-mediated neutralization after intravenous delivery. Ablating the FX interaction site on the HAdv-C5 capsid leaves the virus susceptible to neutralization by natural IgM followed by activation of the complement cascade and covalent binding of complement components C4b and C3b to the viral capsid. Here we present structural models for IgM and complement components C1, C4b, and C3b in complex with HAdv-C5. Molecular dynamics simulations indicate that when C3b binds near the vertex, multiple stabilizing interactions can be formed between C3b, penton base, and fiber. These interactions may stabilize the vertex region of the capsid and prevent release of the virally encoded membrane lytic factor, protein VI, which is packaged inside of the viral capsid, thus effectively neutralizing the virus. In a situation where FX and IgM are competing for binding to the capsid, IgM may not be able to form a bent conformation in which most of its Fab arms interact with the capsid. Our structural modeling of the competitive interaction of FX and IgM with HAdv-C5 allows us to propose a mechanistic model for FX inhibition of IgM-mediated virus neutralization. According to this model, although IgM may bind to the capsid, in the presence of FX it will likely retain a planar conformation and thus be unable to promote activation of the complement cascade at the virus surface.
Insights
Factor X (FX) binding to human adenovirus serotype 5 (HAdv-C5) protects it from neutralization by natural IgM and complement. This interaction prevents IgM from activating the complement cascade, thus enhancing viral therapy potential.
Area of Science:
- Structural biology
- Immunology
- Virology
- Gene therapy
Background:
- Human adenovirus serotype 5 (HAdv-C5) shows therapeutic promise as an oncolytic virus and gene therapy vector.
- Intravenous administration of HAdv-C5 causes plasma protein interactions, affecting viral tropism, biodistribution, and immune responses, leading to neutralization.
- The interaction between HAdv and factor X (FX) enhances liver transduction and protects against complement-mediated neutralization.
Purpose of the Study:
- To present structural models of IgM and complement components (C1, C4b, C3b) complexed with HAdv-C5.
- To elucidate the mechanism by which FX binding inhibits IgM-mediated neutralization of HAdv-C5.
- To understand how complement component binding affects viral capsid stability and protein VI release.
Main Methods:
- Generation of structural models for IgM and complement components (C1, C4b, C3b) in complex with HAdv-C5.
- Molecular dynamics simulations to analyze the interactions between viral capsid proteins and bound molecules.
- Modeling of competitive binding between FX and IgM on the HAdv-C5 capsid.
Main Results:
- Structural models reveal interactions between C3b, penton base, and fiber when C3b binds to the HAdv-C5 vertex.
- These interactions stabilize the capsid vertex and may prevent the release of the viral lytic protein VI, neutralizing the virus.
- FX binding to HAdv-C5 inhibits IgM-mediated complement activation by preventing IgM from adopting a neutralizing bent conformation.
Conclusions:
- FX interaction with HAdv-C5 is crucial for protecting the virus from IgM and complement-mediated neutralization.
- Structural insights explain how FX binding prevents IgM from initiating the complement cascade, thus inhibiting viral neutralization.
- Understanding these interactions provides a mechanistic basis for engineering adenoviruses with improved in vivo performance for gene therapy.
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