A Protective Monoclonal Antibody Targets a Site of Vulnerability on the Surface of Rift Valley Fever Virus

Allen, Elizabeth; Krumm, Stefanie A.; Raghwani, Jayna; Halldorsson, Steinar; Elliott, Angela; Graham, Victoria; Koudriakova, Elina; Harlos, K.; Wright, Daniel; Warimwe, George M.; Brennan, Benjamin; Huiskonen, Juha T.; Dowall, Stuart; Elliott, Richard M.; Pybus, Oliver G.; Burton, Dennis R.; Hewson, Roger; Doores, Katie J.; Bowden, Thomas A.

doi:10.1016/j.celrep.2018.12.001

Cited by 49 publications

(67 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The residue encoded by codon 66 falls within this predicted extramembrane domain, potentially exposing it to the host immune system. Unlike other bunyaviruses, such as phleboviruses (44,45) and hantaviruses (46,47), it is unlikely that the Gn is large enough to extend from the virion membrane and shield the fusion loops of the cognate Gc. Thus, while amino acid changes are unlikely to affect fusion loop shielding, it is possible that selective forces acting on Gn could just alter the stability of the Gn-Gc lattice during cell entry.…”

Section: Discussionmentioning

confidence: 99%

Evolutionary Dynamics of Oropouche Virus in South America

Gutierrez

Wise

Pullan

et al. 2020

J Virol

Self Cite

View full text Add to dashboard Cite

The Amazon basin is home to numerous arthropod-borne viral pathogens that cause febrile disease in humans. Among these, Oropouche orthobunyavirus (OROV) is a relatively understudied member of the genus Orthobunyavirus, family Peribunyaviridae, that causes periodic outbreaks in human populations in Brazil and other South American countries. Although several studies have described the genetic diversity of the virus, the evolutionary processes that shape the OROV genome remain poorly understood. Here, we present a comprehensive study of the genomic dynamics of OROV that encompasses phylogenetic analysis, evolutionary rate estimates, inference of natural selective pressures, recombination and reassortment, and structural analysis of OROV variants. Our study includes all available published sequences, as well as a set of new OROV genome sequences obtained from patients in Ecuador, representing the first set of genomes from this country. Our results show differing evolutionary processes on the three segments that comprise the viral genome. We infer differing times of the most recent common ancestors of the genome segments and propose that this can be explained by cryptic reassortment. We also present the discovery of previously unobserved putative N-linked glycosylation sites, as well as codons that evolve under positive selection on the viral surface proteins, and discuss the potential role of these features in the evolution of OROV through a combined phylogenetic and structural approach. IMPORTANCE The emergence and reemergence of pathogens such as Zika virus, chikungunya virus, and yellow fever virus have drawn attention toward other cocirculating arboviruses in South America. Oropouche virus (OROV) is a poorly studied pathogen responsible for over a dozen outbreaks since the early 1960s and represents a public health burden to countries such as Brazil, Panama, and Peru. OROV is likely underreported since its symptomatology can be easily confounded with other febrile illnesses (e.g., dengue fever and leptospirosis) and point-of-care testing for the virus is still uncommon. With limited data, there is a need to optimize the information currently available. Analysis of OROV genomes can help us understand how the virus circulates in nature and can reveal the evolutionary forces that shape the genetic diversity of the virus, which has implications for molecular diagnostics and the design of potential vaccines.

show abstract

Section: Discussionmentioning

confidence: 99%

Evolutionary Dynamics of Oropouche Virus in South America

Gutierrez

Wise

Pullan

et al. 2020

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, the β-sheet and α-helix structure could be abolished under reducing conditions, leading to the failure of 1332F11 to recognize Gn under these conditions. Coincidentally, the targeting region of an RVFV-neutralizing antibody (RV-Gn1) has also been structurally mapped and found to be near the polypeptides 409 GSKKCTGDAAFCSAY 423 in Gn [21]. In addition, this corresponding region of SFTSV Gn is also targeted by the neutralizing antibody Mab4-5 [16].…”

Section: Discussionmentioning

confidence: 99%

“…Given these observations, it is speculated that 1332F11 and 1331E4 likely preclude the sterical rearrangement RVFV glycoprotein, hindering the exposure of fusion loops in Gc to endosomal membranes after the virus invades a host cell. The neutralizing antibody RV-Gn1, targeting a similar region as 1332F11 and 1331E4, is speculated to exert neutralizing activities through the same mechanism [21].…”

Section: Discussionmentioning

confidence: 99%

“…A few decades ago, several studies have shown that there exist virus-neutralizing epitopes on the glycoproteins [18][19][20]. In 2018, Allen et al isolated some NAbs from rabbits, which were directed to the membrane-distal domain of RVFV Gn and can preclude virus entry into a host cell [21]. In 2019, Wang et al isolated eight Gn-specific NAbs from a convalescent RVF patient that can block the binding of virions to the host cells [22].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Characterization of Two Neutralizing Antibodies against Rift Valley Fever Virus Gn Protein

Meng

Zhang²,

Zhang

et al. 2020

Viruses

View full text Add to dashboard Cite

The Rift Valley fever virus (RVFV) is an arthropod-borne virus that can not only cause severe disease in domestic animals but also in humans. However, the licensed vaccines or available therapeutics for humans do not exist. Here, we report two Gn-specific neutralizing antibodies (NAbs), isolated from a rhesus monkey immunized with recombinant human adenoviruses type 4 expressing Rift Valley fever virus Gn and Gc protein (rHAdV4-GnGcopt). The two NAbs were both able to protect host cells from RVFV infection. The interactions between NAbs and Gn were then characterized to demonstrate that these two NAbs might preclude RVFV glycoprotein rearrangement, hindering the exposure of fusion loops in Gc to endosomal membranes after the virus invades the host cell. The target region for the two NAbs is located in the Gn domain III, implying that Gn is a desired target for developing vaccines and neutralizing antibodies against RVFV.

show abstract

“…Both glycoproteins are synthesized as a polyprotein precursor that becomes localized in Golgi membranes where they are glycosylated and cotranslationally processed by a yet unidentified cellular protease that releases one end of the membrane attachment sites, allowing both ectodomains to interact and the glycoproteins to acquire their final conformation on the surface of the virion [13,14]. The structure of GnGc architecture has been recently elucidated indicating that Gn shields Gc in the viral particles avoiding to expose the Gc fusion loop to antibodies [15] and offers an hypothesis for the neutralizing mechanisms of protective antibodies [16]. Our previous works using recombinant MVA (rMVA) as vector vaccines expressing both glycoprotein antigens (rMVAGnGc) showed an intriguingly low level of in vitro neutralizing antibody induction upon single dose administration, particularly when compared to other similar rMVA vaccines encoding RNA virus glycoprotein antigens [17].…”

Section: Introductionmentioning

confidence: 99%

MVA Vectored Vaccines Encoding Rift Valley Fever Virus Glycoproteins Protect Mice against Lethal Challenge in the Absence of Neutralizing Antibody Responses

et al. 2020

View full text Add to dashboard Cite

In vitro neutralizing antibodies have been often correlated with protection against Rift Valley fever virus (RVFV) infection. We have reported previously that a single inoculation of sucrose-purified modified vaccinia Ankara (MVA) encoding RVFV glycoproteins (rMVAGnGc) was sufficient to induce a protective immune response in mice after a lethal RVFV challenge. Protection was related to the presence of glycoprotein specific CD8+ cells, with a low-level detection of in vitro neutralizing antibodies. In this work we extended those observations aimed to explore the role of humoral responses after MVA vaccination and to study the contribution of each glycoprotein antigen to the protective efficacy. Thus, we tested the efficacy and immune responses in BALB/c mice of recombinant MVA viruses expressing either glycoprotein Gn (rMVAGn) or Gc (rMVAGc). In the absence of serum neutralizing antibodies, our data strongly suggest that protection of vaccinated mice upon the RVFV challenge can be achieved by the activation of cellular responses mainly directed against Gc epitopes. The involvement of cellular immunity was stressed by the fact that protection of mice was strain dependent. Furthermore, our data suggest that the rMVA based single dose vaccination elicits suboptimal humoral immune responses against Gn antigen since disease in mice was exacerbated upon virus challenge in the presence of rMVAGnGc or rMVAGn immune serum. Thus, Gc-specific cellular immunity could be an important component in the protection after the challenge observed in BALB/c mice, contributing to the elimination of infected cells reducing morbidity and mortality and counteracting the deleterious effect of a subneutralizing antibody immune response.

show abstract

A Protective Monoclonal Antibody Targets a Site of Vulnerability on the Surface of Rift Valley Fever Virus

Cited by 49 publications

References 68 publications

Evolutionary Dynamics of Oropouche Virus in South America

Evolutionary Dynamics of Oropouche Virus in South America

Characterization of Two Neutralizing Antibodies against Rift Valley Fever Virus Gn Protein

MVA Vectored Vaccines Encoding Rift Valley Fever Virus Glycoproteins Protect Mice against Lethal Challenge in the Absence of Neutralizing Antibody Responses

Contact Info

Product

Resources

About