Figure 8. Proposed mechanism for antigenic subversion.

Regions of GP_1,2 that are shared with sGP are in red, while unshared epitopes are in green. B-cells are colored according to the regions of GP_1,2 and sGP against which they react. (A) A naïve animal begins with B-cells that can potentially recognize epitopes distributed throughout GP_1,2 and sGP. When sGP is expressed at much higher levels than GP_1,2, as occurs during infection, those B-cells that recognize sGP epitopes, many of which are shared with GP_1,2 (red regions of sGP and GP_1,2) are preferentially activated and expanded compared to B-cells that recognize unshared epitopes of GP_1,2 (green regions of GP_1,2). Thus, sGP-reactive antibodies dominate the immune response. (B) Prior immunization by sGP. Because sGP shares over 90% of its linear sequence with GP_1,2, animals primed with sGP generate anti-sGP antibodies, many of which are directed against epitopes shared with GP_1,2. When these animals (or individuals who have previously been infected and recovered from EBOV infection) are boosted with GP_1,2, sGP cross-reactive memory cells outnumber and express higher affinity receptors than naïve GP_1,2 specific B-cells, resulting in preferential expansion of these sGP-cross-reactive B-cells and a predominantly sGP-reactive immune response. (C) Prior immunization by GP_1,2. Priming naïve animals with GP_1,2 results in antibodies largely against GP_1,2 epitopes not shared with sGP, presumably due to the immunodominance and high accessibility of the GP_1,2 mucin domain and shielding of shared epitopes. When these animals are boosted with sGP, or if they are infected with EBOV and do not have sufficiently high titers of anti-GP_1,2 antibodies to clear the infection rapidly, memory B-cells that recognize shared epitopes encounter their cognate antigen and expand, while non-cross-reactive GP_1,2-specific B-cells are not boosted, resulting in subversion of the host immune response towards sGP cross-reactivity. (D) Successful clearance of EBOV infection. In order to avoid sGP-mediated antigenic subversion, high enough titers of non-crossreactive anti-GP_1,2 antibodies must be maintained to rapidly clear EBOV infection before subversion can occur.