LCMV Glycosylation Modulates Viral Fitness and Cell Tropism

C, Bonhomme; Knopp, Kristeene A.; Bederka, Lydia H.; Angelini, Megan M.; Buchmeier, Michael J.

doi:10.1371/journal.pone.0053273

Cited by 22 publications

(28 citation statements)

References 62 publications

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“…Moreover, LCMV produces a systemic infection with broad cellular tropism. 28 In order to define the cell type(s) that was driving excessive T-cell activation in prf 2/2 mice, we tested various splenic cell populations for their ability to present endogenously derived viral antigen in an ex vivo assay with LCMV-specific transgenic T cells. When we assayed spleen populations from prf 2/2 mice 6 days after LCMV infection, we found that essentially all detectable antigen presentation was by CD11c 1 DCs, while other splenic cell populations were unable to stimulate antigen-specific effector T cells ( Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

Perforin deficiency impairs a critical immunoregulatory loop involving murine CD8+ T cells and dendritic cells

Terrell

Jordan

2013

Blood

108

106

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• Defects in perforin and related genes lead to abnormal T-cell activation and are associated with HLH. • The physiological mechanism by which perforin protects from HLH involves CD8 1 T-cell elimination of rare antigen-presenting dendritic cells.Humans and mice with impaired perforin-dependent cytotoxic function may develop excessive T-cell activation and the fatal disorder hemophagocytic lymphohistiocytosis (HLH) after infection. Though cytotoxic lymphocytes can kill antigen-presenting cells, the physiological mechanism of perforin-mediated immune regulation has never been demonstrated in a disease-relevant context. We used a murine model of HLH to examine how perforin controls immune activation, and we have defined a feedback loop that is critical for immune homeostasis. This endogenous feedback loop involves perforindependent elimination of rare, antigen-presenting dendritic cells (DCs) by CD8

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Section: Resultsmentioning

confidence: 99%

Perforin deficiency impairs a critical immunoregulatory loop involving murine CD8+ T cells and dendritic cells

Terrell

Jordan

2013

Blood

108

106

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“…The lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) is highly glycosylated (77), and mice either fail to develop nAbs to GP or they do so very slowly compared to less glycosylated proteins, like G proteins from VSV (78-82). Therefore, it seems possible that there is a strong selection pressure in mice against B cells that bind glycoprotein epitopes (83).…”

Section: Discussionmentioning

confidence: 99%

Murine Antibody Responses to Cleaved Soluble HIV-1 Envelope Trimers Are Highly Restricted in Specificity

Crampton

Cupo

et al. 2015

J Virol

150

167

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Generating neutralizing antibodies (nAbs) is a major goal of many current HIV-1 vaccine efforts. To be of practical value, these nAbs must be both potent and cross-reactive in order to be capable of preventing the transmission of the highly diverse and generally neutralization resistant (Tier-2) HIV-1 strains that are in circulation. The HIV-1 envelope glycoprotein (Env) spike is the only target for nAbs. To explore whether Tier-2 nAbs can be induced by Env proteins, we immunized conventional mice with soluble BG505 SOSIP.664 trimers that mimic the native Env spike. Here, we report that it is extremely difficult for murine B cells to recognize the Env epitopes necessary for inducing Tier-2 nAbs. Thus, while trimer-immunized mice raised Env-binding IgG Abs and had high-quality T follicular helper (Tfh) cell and germinal center (GC) responses, they did not make BG505.T332N nAbs. Epitope mapping studies showed that Ab responses in mice were specific to areas near the base of the soluble trimer. These areas are not well shielded by glycans and likely are occluded on virions, which is consistent with the lack of BG505.T332N nAbs. These data inform immunogen design and suggest that it is useful to obscure nonneutralizing epitopes presented on the base of soluble Env trimers and that the glycan shield of well-formed HIV Env trimers is virtually impenetrable for murine B cell receptors (BCRs). IMPORTANCEHuman HIV vaccine efficacy trials have not generated meaningful neutralizing antibodies to circulating HIV strains. One possible hindrance has been the lack of immunogens that properly mimic the native conformation of the HIV envelope trimer protein. Here, we tested the first generation of soluble, native-like envelope trimer immunogens in a conventional mouse model. We attempted to generate neutralizing antibodies to neutralization-resistant circulating HIV strains. Various vaccine strategies failed to induce neutralizing antibodies to a neutralization-resistant HIV strain. Further analysis revealed that mouse antibodies targeted areas near the bottom of the soluble envelope trimers. These areas are not easily accessible on the HIV virion due to occlusion by the viral membrane and may have resulted from an absence of glycan shielding. Our results suggest that obscuring the bottom of soluble envelope trimers is a useful strategy to reduce antibody responses to epitopes that are not useful for virus neutralization.

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“…Further, analysis of glycanprotein interactions in this structure reveals the molecular basis for the specific and strong influences of glycosylation on viral fitness (46). For example, Bonhomme and co-workers found that recombinant LCMV bearing a mutation to remove the N79 glycan site (Lassa numbering) was unable to be rescued (46). We find here that this glycan packs against the fusion peptide (fig.…”

Section: Architecture Of the Trimermentioning

confidence: 99%

Structural basis for antibody-mediated neutralization of Lassa virus

Hastie

Zandonatti

Kleinfelter

et al. 2017

Science

172

310

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The arenavirus Lassa causes severe hemorrhagic fever and a significant disease burden in West Africa every year. The glycoprotein, GPC, is the sole antigen expressed on the viral surface and the critical target for antibody-mediated neutralization. Here we present the crystal structure of the trimeric, prefusion ectodomain of Lassa GP bound to a neutralizing antibody from a human survivor at 3.2-angstrom resolution. The antibody extensively anchors two monomers together at the base of the trimer, and biochemical analysis suggests that it neutralizes by inhibiting conformational changes required for entry. This work illuminates pH-driven conformational changes in both receptor-binding and fusion subunits of Lassa virus, illustrates the unique assembly of the arenavirus glycoprotein spike, and provides a much-needed template for vaccine design against these threats to global health.

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LCMV Glycosylation Modulates Viral Fitness and Cell Tropism

Cited by 22 publications

References 62 publications

Perforin deficiency impairs a critical immunoregulatory loop involving murine CD8+ T cells and dendritic cells

Perforin deficiency impairs a critical immunoregulatory loop involving murine CD8+ T cells and dendritic cells

Murine Antibody Responses to Cleaved Soluble HIV-1 Envelope Trimers Are Highly Restricted in Specificity

Structural basis for antibody-mediated neutralization of Lassa virus

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