Abstract
SummaryThe Gn subcomponent of the Gn-Gc assembly that envelopes the human and animal pathogen, Rift Valley fever virus (RVFV), is a primary target of the neutralizing antibody response. To better understand the molecular basis for immune recognition, we raised a class of neutralizing monoclonal antibodies (nAbs) against RVFV Gn, which exhibited protective efficacy in a mouse infection model. Structural characterization revealed that these nAbs were directed to the membrane-distal domain of RVFV Gn and likely prevented virus entry into a host cell by blocking fusogenic rearrangements of the Gn-Gc lattice. Genome sequence analysis confirmed that this region of the RVFV Gn-Gc assembly was under selective pressure and constituted a site of vulnerability on the virion surface. These data provide a blueprint for the rational design of immunotherapeutics and vaccines capable of preventing RVFV infection and a model for understanding Ab-mediated neutralization of bunyaviruses more generally.
Highlights
First reported in 1931 (Daubney et al, 1931), Rift Valley fever virus (RVFV) is an arbovirus endemic to Africa and the Arabian peninsula that causes recurrent epidemics and epizootics
RVFV Gn Glycoprotein Elicits a Protective Neutralizing Ab Response As neutralizing Abs raised during infection and immunization have been shown to target the phleboviral Gn (Faburay et al, 2017), we hypothesized that recombinantly expressed RVFV Gn would constitute an effective immunogen and could be used to elicit neutralizing monoclonal antibodies (nAbs)
We isolated approximately 100 hybridomas and screened their supernatants for RVFV neutralization potency. This analysis revealed that approximately one-third of the hybridomas were able to neutralize RVFV in vitro, demonstrating that our RVFV Gn construct is an effective immunogen
Summary
First reported in 1931 (Daubney et al, 1931), Rift Valley fever virus (RVFV) is an arbovirus endemic to Africa and the Arabian peninsula that causes recurrent epidemics and epizootics. Human populations throughout East Africa are at high risk for RVFV infection, with seroprevalence reported to exceed 8% in communities located near water reservoirs that support mosquito populations (Pourrut et al, 2010). No licensed antivirals or vaccines for RVFV are currently available, a number of vaccine candidates are in development (Dungu et al, 2018; Faburay et al, 2017). The genetically diverse group of viruses within the genus Phlebovirus, family Phenuiviridae, currently contains ten species (Adams et al, 2017). RVFV is enveloped and contains a single-stranded, negative- or ambisense RNA genome that is divided into three segments: S, M, and L.
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