Structure-Based Modeling of Complement C4 Mediated Neutralization of Adenovirus.

Corey C Emerson,Phoebe L Stewart

doi:10.3390/v13010111

Abstract

Adenovirus (AdV) infection elicits a strong immune response with the production of neutralizing antibodies and opsonization by complement and coagulation factors. One anti-hexon neutralizing antibody, called 9C12, is known to activate the complement cascade, resulting in the deposition of complement component C4b on the capsid, and the neutralization of the virus. The mechanism of AdV neutralization by C4b is independent of downstream complement proteins and involves the blockage of the release of protein VI, which is required for viral escape from the endosome. To investigate the structural basis underlying how C4b blocks the uncoating of AdV, we built a model for the complex of human adenovirus type-5 (HAdV5) with 9C12, together with complement components C1 and C4b. This model positions C4b near the Arg-Gly-Asp (RGD) loops of the penton base. There are multiple amino acids in the RGD loop that might serve as covalent binding sites for the reactive thioester of C4b. Molecular dynamics simulations with a multimeric penton base and C4b indicated that stabilizing interactions may form between C4b and multiple RGD loops. We propose that C4b deposition on one RGD loop leads to the entanglement of C4b with additional RGD loops on the same penton base multimer and that this entanglement blocks AdV uncoating.

Highlights

There are multiple parallel pathways for neutralizing pathogens such as adenovirus (AdV)
Previous work has shown that a particular anti-hexon neutralizing immunoglobulin G (IgG), called 9C12, stimulates binding of complement component C4b to the capsid and mediates potent neutralization of HAdV-C5 [24]. There is both cryo-electron microscopy (cryo-EM) and crystallographic structural information on the binding of 9C12 to HAdV-C5 [32,33], there are still open questions about how this particular IgG interacts with the full virion
It has been shown that the minimum ratio of 9C12 to HAdV-C5 for neutralization is 240 antibody molecules per virus particle, which is equivalent to an average of two Fab fragments per hexon trimer [33]

Summary

Introduction

There are multiple parallel pathways for neutralizing pathogens such as adenovirus (AdV). While neutralization pathways are beneficial in the case of natural infections, they represent roadblocks in the development of virus-based therapeutics, such as oncolytic viruses [1], and gene therapy vectors [2,3]. Both pre-clinical and clinical data showed that anti-AdV-specific neutralizing immunity reduce efficacy of AdV-based vaccines, including against HIV-1 [4], and SARS-CoV-2 [5]. A better understanding of the molecular mechanisms underlying host neutralization pathways, involving neutralizing antibodies and complement, would be beneficial for engineering AdV-based therapeutics with improved safety and efficacy. When human species C HAdV-C5 is injected into the bloodstream, the innate immune system responds with natural immunoglobulin M (IgM)

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