B-cell restriction – an alternative piece to the puzzle

Gershoni, Jonathan M.

• Concealing neutralizing epitopes. Antibody-mediated neutralization is based on the B-cell targeting of critical neutralizing epitopes of the virus. Viruses, for example, gain entry to their target host-cells by exploiting cell surface-proteins that serve as "receptors". Obviously, the "receptor binding site" (RBS) of the viral spike protein thus, presents a good neutralizing epitope. [23] [24] [25] [26] Antibodies that bind and thus occlude the RBS prevent the virus from being able to associate with the target cell surface. Hence, keeping the RBS concealed reduces its immunogenicity. The CD4 binding site of HIV-1 gp120 tends to be buried in a crypt and is certainly much less accessible than the surrounding surfaces of the spike protein. 27 Therefore, generally prime neutralizing epitopes are less available to B-cell scrutiny. • Shadowing neutralizing surfaces. Glycan-shields are another strategy employed by some viruses. [28] [29] [30] Viral spike proteins are typically highly glycosylated. The glycomoieties loom over the surface of the virus and shadow the access to the underlying spike amino-acid surfaces. Thus, access to the more immunogenic aspects of the spike is limited by steric hindrance imposed by the multiple glycan branches stemming from strategically positioned N or O glycosylation sites of the spike. 28, 30, 31 • Display of multiple non-neutralizing epitopes. The viral surface contains only a select, very few, truly critical neutralizing epitopes which may be hidden or shadowed. That being said, there is an extensive accessible surface of the spike that can and does interact with B-cells. The enormous diversity of B-cells that can complement literally any and every antigenic surface of the virus thus leads to a plethora of generally useless antibodies. Indeed, HIV and influenza stimulate a robust serological response upon infection; however, the vast majority of antibodies produced do little to counteract the invasion. 26, 32 Flooding the system with impotent antibodies can reduce viral load to some degree but does not really perturb the infectious process. A special case of distracting targets is realized by shedding "chaff" soluble spike components. • Dispensing chaff and false targets. Viral spikes often contain multiple subunits. In HIV-1, for example, gp160 is cleaved to produce membrane-anchored gp41 which is non-covalently associated with soluble gp120. The mature spike is then assembled to form a trimer consisting of three gp41/gp120 monomers. The buried inner-surfaces where the gp41/gp120 monomers meet to produce trimers do not contain neutralizing epitopes, as these surfaces are never exposed in the native functional spike. [33] [34] [35] However, shedding of monomeric gp120s into the serum reveals the previously buried surfaces of the spike. 36 B-cells, that target these "decoy" false targets of the virus, are dissuaded and immunity is evaded by the chaff-like shed gp120. 33 • Dynamic genetic variations. The success of polio and smallpox vaccines lies in that these viruses tend to be genetically stable. However, HIV and influenza exhibit extensive genetic instability. These viruses have evolved unique mechanisms to increase genetic variation. The RNA-DNA-RNA cycling of the HIV genome via reverse transcriptase is highly error-prone. 37 Influenza benefits from both genetic drift and shift. 20, 38 These dynamic instabilities produce vast amounts of variant viruses, many of which may be non-productive progeny. Howe