Mapping the immunogenic landscape of near-native HIV-1 envelope trimers in non-human primates

Cottrell, Christopher A.; Schooten, Jelle van; Bowman, Charles A.; Yuan, Meng; Oyen, David; Shin, Mia; Morpurgo, Robert; Woude, Patricia van der; Breemen, M van; Torres, Jonathan L.; Patel, Raj; Gross, Justin; Sewall, Leigh M.; Copps, Jeffrey; Ozorowski, Gabriel; Nogal, Bartek; Sok, Devin; Rakasz, Eva G.; LaBranche, Celia C.; Вигдорович, В. И.; Christley, Scott; Carnathan, Diane G.; Sather, D. Noah; Montefiori, David C.; Silvestri, Guido; Burton, Dennis R.; Moore, John P.; Wilson, Ian A.; Sanders, Rogier W.; Ward, Andrew B.; Gils, Marit J. van

doi:10.1371/journal.ppat.1008753

Cited by 68 publications

(95 citation statements)

References 82 publications

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“…S13). RM20C does not neutralize BG505 virus as an immunoglobulin G (IgG) but can weakly neutralize as a Fab, consistent with the hypothesis that the disposition of the second Fab arm and Fc can sterically inhibit access to the base epitope on intact virions ( 26 ). Therefore, although the base epitope shared by two known bnAbs and one autologous neutralizing Fab is a bona fide site of vulnerability, access is highly constrained.…”

Section: Resultssupporting

confidence: 61%

Disassembly of HIV envelope glycoprotein trimer immunogens is driven by antibodies elicited via immunization

et al. 2021

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Rationally designed protein subunit vaccines are being developed for a variety of viruses including influenza, RSV, SARS-CoV-2, and HIV. These vaccines are based on stabilized versions of the primary targets of neutralizing antibodies on the viral surface, namely, viral fusion glycoproteins. While these immunogens display the epitopes of potent neutralizing antibodies, they also present epitopes recognized by non-neutralizing or weakly neutralizing (“off-target”) antibodies. Using our recently developed electron microscopy polyclonal epitope mapping approach, we have uncovered a phenomenon wherein off-target antibodies elicited by HIV trimer subunit vaccines cause the otherwise highly stabilized trimeric proteins to degrade into cognate protomers. Further, we show that these protomers expose an expanded suite of off-target epitopes, normally occluded inside the prefusion conformation of trimer, that subsequently elicit further off-target antibody responses. Our study provides critical insights for further improvement of HIV subunit trimer vaccines for future rounds of the iterative vaccine design process.

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Section: Resultssupporting

confidence: 61%

Disassembly of HIV envelope glycoprotein trimer immunogens is driven by antibodies elicited via immunization

et al. 2021

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“…We also generated B cells expressing the base-specific non-NAb RM19R that was isolated from a BG505 SOSIP trimer-immunized macaque 36 . The exposed base of SOSIP trimers contains immunodominant non-NAb epitopes that may distract the immune response away from sites more favored to NAb induction 37 .…”

Section: Resultsmentioning

confidence: 99%

Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles

et al. 2021

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The HIV-1 envelope glycoprotein trimer is poorly immunogenic because it is covered by a dense glycan shield. As a result, recombinant Env glycoproteins generally elicit inadequate antibody levels that neutralize clinically relevant, neutralization-resistant (Tier-2) HIV-1 strains. Multivalent antigen presentation on nanoparticles is an established strategy to increase vaccine-driven immune responses. However, due to nanoparticle instability in vivo, the display of non-native Env structures, and the inaccessibility of many neutralizing antibody (NAb) epitopes, the effects of nanoparticle display are generally modest for Env trimers. Here, we generate two-component self-assembling protein nanoparticles presenting twenty SOSIP trimers of the clade C Tier-2 genotype 16055. We show in a rabbit immunization study that these nanoparticles induce 60-fold higher autologous Tier-2 NAb titers than the corresponding SOSIP trimers. Epitope mapping studies reveal that the presentation of 16055 SOSIP trimers on these nanoparticle focuses antibody responses to an immunodominant apical epitope. Thus, these nanoparticles are a promising platform to improve the immunogenicity of Env trimers with apex-proximate NAb epitopes.

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“…It has been suggested that glycans on gp41 are underoccupied compared with glycans on gp120 when expressed as recombinant protein on both native-like SOSIP trimers ( Guttman et al, 2014 ; Depetris et al, 2012 ; Cao et al, 2018 ; Behrens et al, 2016 ) and uncleaved recombinant gp140 ( Pabst et al, 2012 ; Go et al, 2011 ). The N611 glycosylation site, which falls within region 5, has been directly shown to be underglycosylated depending on the Env isolate ( Cottrell et al, 2020 ; Cao et al, 2018 ).…”

Section: Resultsmentioning

confidence: 99%

“…Hence, at least some of the Env-specific CD4 T cell responses are likely a result of suboptimal glycosylation on specific N-linked glycosylation sites. For example, N611 is thought to be underglycosylated in BG505 SOSIP Env trimers ( Cottrell et al, 2020 ), and N197 was directly shown to be underglycosylated in BG505 SOSIP ( Cao et al, 2018 ), although these results have yet to been shown in BG505 SOSIP trimer containing the MD39 trimer stabilizing mutations. The large CD4 T cell response to the underglycosylated gp41 region 5 trimer variants might not be recapitulated when immunizing with other Env constructs that have a much higher glycan occupancy at N611.…”

Section: Discussionmentioning

confidence: 99%

Modulating the quantity of HIV Env-specific CD4 T cell help promotes rare B cell responses in germinal centers

Lee

Georgeson

et al. 2020

Journal of Experimental Medicine

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Immunodominance to nonneutralizing epitopes is a roadblock in designing vaccines against several diseases of high interest. One hypothetical possibility is that limited CD4 T cell help to B cells in a normal germinal center (GC) response results in selective recruitment of abundant, immunodominant B cells. This is a central issue in HIV envelope glycoprotein (Env) vaccine designs, because precursors to broadly neutralizing epitopes are rare. Here, we sought to elucidate whether modulating the quantity of T cell help can influence recruitment and competition of broadly neutralizing antibody precursor B cells at a physiological precursor frequency in response to Env trimer immunization. To do so, two new Env-specific CD4 transgenic (Tg) T cell receptor (TCR) mouse lines were generated, carrying TCR pairs derived from Env-protein immunization. Our results suggest that CD4 T cell help quantitatively regulates early recruitment of rare B cells to GCs.

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Mapping the immunogenic landscape of near-native HIV-1 envelope trimers in non-human primates

Cited by 68 publications

References 82 publications

Disassembly of HIV envelope glycoprotein trimer immunogens is driven by antibodies elicited via immunization

Disassembly of HIV envelope glycoprotein trimer immunogens is driven by antibodies elicited via immunization

Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles

Modulating the quantity of HIV Env-specific CD4 T cell help promotes rare B cell responses in germinal centers

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