Naturally Acquired Rift Valley Fever Virus Neutralizing Antibodies Predominantly Target the Gn Glycoprotein

Abstract

Summary Rift Valley fever (RVF) is a viral hemorrhagic disease first discovered in Kenya in 1930. Numerous animal studies have demonstrated that protective immunity is acquired following RVF virus (RVFV) infection and that this correlates with acquisition of virus-neutralizing antibodies (nAbs) that target the viral envelope glycoproteins. However, naturally acquired immunity to RVF in humans is poorly described. Here, we characterized the immune response to the viral envelope glycoproteins, Gn and Gc, in RVFV-exposed Kenyan adults. Long-lived IgG (dominated by IgG1 subclass) and T cell responses were detected against both Gn and Gc. However, antigen-specific antibody depletion experiments showed that Gn-specific antibodies dominate the RVFV nAb response. IgG avidity against Gn, but not Gc, correlated with nAb titers. These data are consistent with the greater level of immune accessibility of Gn on the viral envelope surface and confirm the importance of Gn as an integral component for RVF vaccine development.

Recent Advances in Bunyavirus Glycoprotein Research: Precursor Processing, Receptor Binding and Structure

“…It has been postulated that placement of the Gn shields the hydrophobic fusion loop of the Gc, preventing premature fusion. Shielding of the Gc is consistent with sera binding data from RVFV infected individuals [ 181 ], which demonstrated that antibodies preferentially target the Gn. Further cryoET imaging and reconstructions of acidified RVFV have given clues to the repositioning of the Gn and are consistent with the requirement for Gc to extend towards the target membrane [ 151 ].…”

Entry of Phenuiviruses into Mammalian Host Cells

“…This model is very similar to the one proposed for the fusion of flaviviruses, which are unrelated enveloped viruses with a class II viral fusion glycoprotein [ 82 ]. Interestingly, antibodies exhibit much higher neutralizing activities in vitro and in vivo when they target G N rather than G C [ 88 , 89 , 90 ]. It has been proposed that anti-G N neutralizing antibodies block the fusogenic rearrangement of the G N -G C array by targeting the G N distal domain [ 91 , 92 ].…”

Isotype-Specific Fc Effector Functions Enhance Antibody-Mediated Rift Valley Fever Virus Protection In Vivo

“…Therefore, it will be important to determine if MAb therapy can prevent progression to late-onset encephalitis and the role of Fc effector functions therein, as this is where MAbs have the most human promise. Recent work in humans found that the antibody response to naturally acquired infection preferentially targets Gn, with neutralizing anti-Gn IgG responses lasting decades ( 42 ). Future investigation into the contribution of Fc effector functions in the human humoral response could further increase understanding of how antibody-mediated immunity protects against RVFV disease.…”