Identification of a novel B-cell epitope of Hantaan virus glycoprotein recognized by neutralizing 3D8 monoclonal antibody

Yan, Guolin; Zhang, Yusi; Ma, Ying; Yi, Jun; Liu, Bei; Xu, Zhuwei; Zhang, Chunmei; Zhang, Fanglin; Zhang, Xu; Yang, An‐Gang; Zhuang, Ran; Jin, Boquan

doi:10.1099/vir.0.045302-0

Cited by 11 publications

(7 citation statements)

References 25 publications

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“…There are also data on Gc residues that affect binding of neutralizing antibodies for various other hantaviruses. Although often such epitopes are conformational and cannot be mimicked by peptides, the epitope of the neutralizing murine Mabs 3G1 and 3D8 [39] against Hantaan virus have been respectively mapped by peptide scanning to residues 96–105 [40] and 242–248 [41]. The 3G1 epitope thus maps to the bc loop and largely overlaps with that of scFv A5, whereas the 3D8 epitope maps to the i strand, at the opposite side (Fig 1C).…”

Section: Resultsmentioning

confidence: 99%

Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc

et al. 2016

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Hantaviruses are zoonotic viruses transmitted to humans by persistently infected rodents, giving rise to serious outbreaks of hemorrhagic fever with renal syndrome (HFRS) or of hantavirus pulmonary syndrome (HPS), depending on the virus, which are associated with high case fatality rates. There is only limited knowledge about the organization of the viral particles and in particular, about the hantavirus membrane fusion glycoprotein Gc, the function of which is essential for virus entry. We describe here the X-ray structures of Gc from Hantaan virus, the type species hantavirus and responsible for HFRS, both in its neutral pH, monomeric pre-fusion conformation, and in its acidic pH, trimeric post-fusion form. The structures confirm the prediction that Gc is a class II fusion protein, containing the characteristic β-sheet rich domains termed I, II and III as initially identified in the fusion proteins of arboviruses such as alpha- and flaviviruses. The structures also show a number of features of Gc that are distinct from arbovirus class II proteins. In particular, hantavirus Gc inserts residues from three different loops into the target membrane to drive fusion, as confirmed functionally by structure-guided mutagenesis on the HPS-inducing Andes virus, instead of having a single “fusion loop”. We further show that the membrane interacting region of Gc becomes structured only at acidic pH via a set of polar and electrostatic interactions. Furthermore, the structure reveals that hantavirus Gc has an additional N-terminal “tail” that is crucial in stabilizing the post-fusion trimer, accompanying the swapping of domain III in the quaternary arrangement of the trimer as compared to the standard class II fusion proteins. The mechanistic understandings derived from these data are likely to provide a unique handle for devising treatments against these human pathogens.

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Section: Resultsmentioning

confidence: 99%

Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc

et al. 2016

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“…We identified three positively selected sites for the Gn/Gc protein of HTNV at aa 289, aa 373, and aa 889. The aa 882–896 is reportedly a B-cell epitope that displays neutralizing activity to HTNV infection (Yan et al, 2012 ). The higher proportion of positively selected positions located in the variable Gn/Gc envelope glycoproteins was consistent with their functional roles in the viral escape from immunological responses (Holmes, 2003 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic Diversity and the Spatio-Temporal Analyses of Hantaviruses in Shandong Province, China

Zuo

Wang

et al. 2018

Front. Microbiol.

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Hemorrhagic fever with renal syndrome (HFRS) is a serious public health problem in Shandong Province, China. We conducted an epizootiologic investigation and phylogeographic and phylodynamic analyses to infer the phylogenetic relationships of hantaviruses in space and time, and gain further insights into their evolutionary dynamics in Shandong Province. Our data indicated that the Seoul virus (SEOV) is distributed throughout Shandong, whereas Hantaan virus (HTNV) co-circulates with SEOV in the eastern and southern areas of Shandong. Their distribution showed strong geographic clustering. In addition, our analyses indicated multiple evolutionary paths, long-distance transmission, and demographic expansion events for SEOV in some areas. Selection pressure analyses revealed that negative selection on hantaviruses acted as the principal evolutionary force, whereas a little evidence of positive selection exists. We found that several positively selected sites were located within major functional regions and indicated the importance of these residues for adaptive evolution of hantaviruses.

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“…HTNV-NP has been demonstrated to be highly immunogenic and conservative, inducing vigorous cellular and humoral immune responses in humans [ 11 ]. HTNV glycoprotein, heterodimers of mature glycoprotein Gn and Gc, is not only responsible for receptor binding and membrane fusion, but also considered as the main source of neutralizing antibody production [ 12 – 13 ]. T-cell immunity is a critical factor for protection from virus infections in humans.…”

Section: Introductionmentioning

confidence: 99%

Hantaan Virus Infection Induces Both Th1 and ThGranzyme B+ Cell Immune Responses That Associated with Viral Control and Clinical Outcome in Humans

Yuan

Zhuang

et al. 2015

PLoS Pathog

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Hantaviruses infection causing severe emerging diseases with high mortality rates in humans has become public health concern globally. The potential roles of CD4+T cells in viral control have been extensively studied. However, the contribution of CD4+T cells to the host response against Hantaan virus (HTNV) infection remains unclear. Here, based on the T-cell epitopes mapped on HTNV glycoprotein, we studied the effects and characteristics of CD4+T-cell responses in determining the outcome of hemorrhagic fever with renal syndrome. A total of 79 novel 15-mer T-cell epitopes on the HTNV glycoprotein were identified, among which 20 peptides were dominant target epitopes. Importantly, we showed the presence of both effective Th1 responses with polyfunctional cytokine secretion and ThGranzyme B+ cell responses with cytotoxic mediators production against HTNV infection. The HTNV glycoprotein-specific CD4+T-cell responses inversely correlated with the plasma HTNV RNA load in patients. Individuals with milder disease outcomes showed broader epitopes targeted and stronger CD4+T-cell responses against HTNV glycoproteins compared with more severe patients. The CD4+T cells characterized by broader antigenic repertoire, stronger polyfunctional responses, better expansion capacity and highly differentiated effector memory phenotype(CD27-CD28-CCR7-CD45RA-CD127hi) would elicit greater defense against HTNV infection and lead to much milder outcome of the disease. The host defense mediated by CD4+T cells may through the inducing antiviral condition of the host cells and cytotoxic effect of ThGranzyme B+ cells. Thus, these findings highlight the efforts of CD4+T-cell immunity to HTNV control and provide crucial information to better understand the immune defense against HTNV infection.

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Identification of a novel B-cell epitope of Hantaan virus glycoprotein recognized by neutralizing 3D8 monoclonal antibody

Cited by 11 publications

References 25 publications

Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc

Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc

Genetic Diversity and the Spatio-Temporal Analyses of Hantaviruses in Shandong Province, China

Hantaan Virus Infection Induces Both Th1 and ThGranzyme B+ Cell Immune Responses That Associated with Viral Control and Clinical Outcome in Humans

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