Structural Model for Factor X Inhibition of IgM and Complement-Mediated Neutralization of Adenovirus

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.