Antigenic Subversion: A Novel Mechanism of Host Immune Evasion by Ebola Virus

Abstract

In addition to its surface glycoprotein (GP1,2), Ebola virus (EBOV) directs the production of large quantities of a truncated glycoprotein isoform (sGP) that is secreted into the extracellular space. The generation of secreted antigens has been studied in several viruses and suggested as a mechanism of host immune evasion through absorption of antibodies and interference with antibody-mediated clearance. However such a role has not been conclusively determined for the Ebola virus sGP. In this study, we immunized mice with DNA constructs expressing GP1,2 and/or sGP, and demonstrate that sGP can efficiently compete for anti-GP12 antibodies, but only from mice that have been immunized by sGP. We term this phenomenon “antigenic subversion”, and propose a model whereby sGP redirects the host antibody response to focus on epitopes which it shares with membrane-bound GP1,2, thereby allowing it to absorb anti-GP1,2 antibodies. Unexpectedly, we found that sGP can also subvert a previously immunized host's anti-GP1,2 response resulting in strong cross-reactivity with sGP. This finding is particularly relevant to EBOV vaccinology since it underscores the importance of eliciting robust immunity that is sufficient to rapidly clear an infection before antigenic subversion can occur. Antigenic subversion represents a novel virus escape strategy that likely helps EBOV evade host immunity, and may represent an important obstacle to EBOV vaccine design.

Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol

“…Virulence has been attributed not only to the membraneanchored GP but also to the soluble form of this protein, sGP, which results from RNA editing 18 . sGP increases endothelial permeability by acting as an activator of neutrophils and macrophages, which regulates the host immune response [19][20][21][22] .…”

Ebolavirus evolves in human to minimize the detection by immune cells by accumulating adaptive mutations

“…Notably, sGP protein is secreted by infected cells and is not present in virions. Previous study showed that to promote immune evasion, sGP serves as an antibody decoy or presents alternative non-neutralizing antibody epitopes for the humoral immune response [17,20,32]. Another study revealed that the 71 and 81 % of humoral immune response of symptomatic and asymptomatic individuals, respectively from Gabonese EBOV outbreaks mainly targets GP peptides [3].…”

Codon-optimized filovirus DNA vaccines delivered by intramuscular electroporation protect cynomolgus macaques from lethal Ebola and Marburg virus challenges

“…In an earlier study, Mohan et al gave mice a priming vaccination with a construct similar to ours, which only generated GP1,2, and subsequently boosted the mice with a construct that only produced sGP. 40 Using competition ELISA, they demonstrated that sGP could compete for GP1,2 antibodies very effectively, and that pseudovirion neutralization titers dropped after boosting with the sGP construct. They theorized that their findings might suggest that the sGP produced during an EBOV infection might subvert the antibody response to GP1,2 in individuals receiving a vaccine that produces only GP1,2 unless the virus is rapidly cleared.…”