Presenting native-like HIV-1 envelope trimers on ferritin nanoparticles improves their immunogenicity

Sliepen, Kwinten; Ozorowski, Gabriel; Burger, Judith A.; Montfort, Thijs van; Stunnenberg, Melissa; LaBranche, Celia C.; Montefiori, David C.; Moore, John P.; Ward, Andrew B.; Sanders, Rogier W.

doi:10.1186/s12977-015-0210-4

Cited by 170 publications

(198 citation statements)

References 24 publications

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“…Nanoparticle-based antigen display has been shown to result in an enhanced humoral immune response [6-8]. However, it is poorly understood how protein density influences the magnitude and quality of immune responses to NP displayed antigens [9].…”

Section: Discussionmentioning

confidence: 99%

Nanoparticles decorated with viral antigens are more immunogenic at low surface density

Brewer

DiPiazza

Acklin

et al. 2017

Vaccine

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There is an urgent need to develop protective vaccines for high priority viral pathogens. One approach known to enhance immune responses to viral proteins is to display them on a nanoparticle (NP) scaffold. However, little is known about the effect of protein density on the B cell response to antigens displayed on NPs. To address this question HIV-1 Envelope (Env) and influenza hemagglutinin (HA) were displayed on a polystyrene-based NP scaffold at various densities - corresponding to mean antigen distances that span the range encountered on naturally occurring virions. Our studies revealed that NPs displaying lower densities of Env or HA more efficiently stimulated antigen-specific B cells in vitro, as measured by calcium flux, than did NPs displaying higher antigen densities. Similarly, NPs displaying a low density of Env or HA also elicited higher titers of antigen-specific serum IgG in immunized BALB/c mice (including elevated titers of hemagglutination-inhibiting antibodies), as well as an increased frequency of antigen-specific antibody secreting cells in the lymph node, spleen and bone marrow. Importantly, our studies showed that the enhanced B cell response elicited by the lower density NPs is likely secondary to more efficient development of follicular helper CD4 T cells and germinal center B cells. These findings demonstrate that the density of antigen on a NP scaffold is a critical determinant of the humoral immune response elicited, and that high density display does not always result in an optimal response

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Section: Discussionmentioning

confidence: 99%

Nanoparticles decorated with viral antigens are more immunogenic at low surface density

Brewer

DiPiazza

Acklin

et al. 2017

Vaccine

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“…However, HIV-1 Env shows greater genetic and antigenic diversity than most other viruses and is more densely shielded by glycan, and the fact remains that no reported vaccine, multivalent or otherwise, has elicited bnAbs against HIV-1 (25, 64, 67). Encouragingly, arrays of well-ordered gp140 trimers with an SOS disulfide (68) or a native flexible linker (NFL) (69) and mutation I559P on liposomes and self-assembling nanoparticles have shown some capacity to increase humoral responses to Env (23)(24)(25). Specific immunization strategies with hVLPs or other Env arrays combined with rational design might benefit humoral responses as well.…”

Section: Discussionmentioning

confidence: 99%

“…Efforts to enhance immune responses to Env have involved multimerization of soluble native-like trimers (gp140s) on nanoparticles by fusion with self-assembling proteins or by conjugation to liposomes (23)(24)(25). These soluble trimers mimic the structure and antigenicity of native spikes (26); however, in many cases truncations to the CTT, TM domain, and the membrane-proximal external region (MPER) perturb Env structure, albeit to various degrees (8,12,14,17,27), expose nonneutralizing epitopes at the base of the spike (28), and/or eliminate epitopes of MPER bnAbs.…”

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confidence: 99%

Dense Array of Spikes on HIV-1 Virion Particles

Stano

Leaman

Kim

et al. 2017

J Virol

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HIV-1 is rare among viruses for having a low number of envelope glycoprotein (Env) spikes per virion, i.e., ϳ7 to 14. This exceptional feature has been associated with avoidance of humoral immunity, i.e., B cell activation and antibody neutralization. Virus-like particles (VLPs) with increased density of Env are being pursued for vaccine development; however, these typically require protein engineering that alters Env structure. Here, we used instead a strategy that targets the producer cell. We employed fluorescence-activated cell sorting (FACS) to sort for cells that are recognized by trimer cross-reactive broadly neutralizing antibody (bnAb) and not by nonneutralizing antibodies. Following multiple iterations of FACS, cells and progeny virions were shown to display higher levels of antigenically correct Env in a manner that correlated between cells and cognate virions (P ϭ 0.027). High-Env VLPs, or hVLPs, were shown to be monodisperse and to display more than a 10-fold increase in spikes per particle by electron microscopy (average, 127 spikes; range, 90 to 214 spikes). Sequencing revealed a partial truncation in the C-terminal tail of Env that had emerged in the sort; however, iterative rounds of "cell factory" selection were required for the high-Env phenotype. hVLPs showed greater infectivity than standard pseudovirions but largely similar neutralization sensitivity. Importantly, hVLPs also showed superior activation of Env-specific B cells. Hence, high-Env HIV-1 virions, obtained through selection of producer cells, represent an adaptable platform for vaccine design and should aid in the study of native Env.IMPORTANCE The paucity of spikes on HIV is a unique feature that has been associated with evasion of the immune system, while increasing spike density has been a goal of vaccine design. Increasing the density of Env by modifying it in various ways has met with limited success. Here, we focused instead on the producer cell. Cells that stably express HIV spikes were screened on the basis of high binding by bnAbs and low binding by nonneutralizing antibodies. Levels of spikes on cells correlated well with those on progeny virions. Importantly, high-Env virus-like particles (hVLPs) were produced with a manifest array of well-defined spikes, and these were shown to be superior in activating desirable B cells. Our study describes HIV particles that are densely coated with functional spikes, which should facilitate the study of HIV spikes and their development as immunogens.KEYWORDS antigenicity, broadly neutralizing antibodies, envelope glycoprotein, fluorescence-activated cell sorting, HIV-1, vaccine design, virus-like particles, cellPACK, electron microscopy, viral infectivity H uman immunodeficiency virus type 1 (HIV-1) displays around 7 to 14 envelope (Env) spikes per virion (1-3). This low number of spikes is unusual for enveloped viruses in comparison to numbers for influenza virus (ϳ400 to 500 spikes), vesicular

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“…Although Furin co-transfection is inexpensive and technically simple, particularly via a single plasmid that expresses both env and furin (106), it was argued that there might be a reduction in trimer yield. An additional rationale was that eliminating the need for Furin cleavage could simplify Env immunization strategies based around DNA, mRNA, viral vectors or self-assembling nanoparticles (128,130,132,140,141). Four groups each followed the same strategy of adding a flexible Gly-Ser linker sequence of between 8 and 20 residues between the gp120 and gp41 ECTO components of the gp140 construct, to replace the Furin cleavage motif (69,128,130,132).…”

Section: Alternative Designs Of Native-like Trimersmentioning

confidence: 99%

Native‐like Env trimers as a platform for HIV‐1 vaccine design

Sanders

Moore

2017

Immunological Reviews

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Summary We describe the development and potential use of various designs of recombinant HIV-1 envelope glycoprotein trimers that mimic the structure of the virion-associated spike, which is the target for neutralizing antibodies. The goal of trimer development programs is to induce broadly neutralizing antibodies with the potential to intervene against multiple circulating HIV-1 strains. Among topics we address are the designs of various constructs; how native-like trimers can be produced and purified; the properties of such trimers in vitro and their immunogenicity in various animals; and the immunization strategies that may lead to the eventual elicitation of broadly neutralizing antibodies. In summary, native-like trimers are a now a platform for structure- and immunology-based design improvements that could eventually yield immunogens of practical value for solving the long-standing HIV-1 vaccine problem.

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Presenting native-like HIV-1 envelope trimers on ferritin nanoparticles improves their immunogenicity

Cited by 170 publications

References 24 publications

Nanoparticles decorated with viral antigens are more immunogenic at low surface density

Nanoparticles decorated with viral antigens are more immunogenic at low surface density

Dense Array of Spikes on HIV-1 Virion Particles

Native‐like Env trimers as a platform for HIV‐1 vaccine design

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