Enhanced Immunogenicity of HIV-1 Envelope gp140 Proteins Fused to APRIL

Isik, Gözde; Sliepen, Kwinten; Montfort, Thijs van; Sanders, Rogier W.

doi:10.1371/journal.pone.0107683

Cited by 4 publications

(3 citation statements)

References 70 publications

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“…The approach described here could have several advantages when considering the use of minibinder agonists as "protein-based adjuvants." First, many vaccine antigens are proteins, which may enable the seamless integration of antigen and minibinder adjuvant into a single molecule by genetic fusion [59][60][61][62][63] . This strategy would be expected to simplify manufacturing and formulation compared to traditional nucleic acid, lipid, or small molecule adjuvants.…”

Section: Discussionmentioning

confidence: 99%

De novo design of protein minibinder agonists of TLR3

Adams,

Kim,

Burtner

et al. 2024

Preprint

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Toll-like Receptor 3 (TLR3) is a pattern recognition receptor that initiates antiviral immune responses upon binding double-stranded RNA (dsRNA). Several nucleic acid-based TLR3 agonists have been explored clinically as vaccine adjuvants in cancer and infectious disease, but present substantial manufacturing and formulation challenges. Here, we use computational protein design to create novel miniproteins that bind to human TLR3 with nanomolar affinities. Cryo-EM structures of two minibinders in complex with TLR3 reveal that they bind the target as designed, although one partially unfolds due to steric competition with a nearby N-linked glycan. Multimeric forms of both minibinders induce NF-κB signaling in TLR3-expressing cell lines, demonstrating that they may have therapeutically relevant biological activity. Our work provides a foundation for the development of specific, stable, and easy-to-formulate protein-based agonists of TLRs and other pattern recognition receptors.

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Section: Discussionmentioning

confidence: 99%

De novo design of protein minibinder agonists of TLR3

Adams,

Kim,

Burtner

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…With this study we have shown that BG505 SOSIP.664 is amenable to attaching medium-sized proteins to its C-terminus, while preserving its native-like conformation. This property can also be exploited for the fusion of native-like trimers to other similarly sized proteins, for example those with immunostimulatory properties [ 21 , 22 , 44 ], or those with an ability to form nanoparticles allowing for efficient B cell receptor cross-linking and enhancing immunogenicity [ 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

Engineering and Characterization of a Fluorescent Native-Like HIV-1 Envelope Glycoprotein Trimer

et al. 2015

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Generation of a stable, soluble mimic of the HIV-1 envelope glycoprotein (Env) trimer on the virion surface has been considered an important first step for developing a successful HIV-1 vaccine. Recently, a soluble native-like Env trimer (BG505 SOSIP.664) has been described. This protein has facilitated major advances in the HIV-1 vaccine field, since it was the first Env immunogen that induced consistent neutralizing antibodies against a neutralization-resistant (tier 2) virus. Moreover, BG505 SOSIP.664 enabled elucidation of the atomic resolution structure of the Env trimer and facilitated the isolation and characterization of new broadly neutralizing antibodies against HIV-1. Here, we designed and characterized the BG505 SOSIP.664 trimer fused to fluorescent superfolder GFP (sfGFP), a GFP variant that allows efficient folding (BG505 SOSIP.664-sfGFP). Despite the presence of the sfGFP, the Env protein largely retained its morphology, antigenicity, glycan composition, and thermostability. In addition, we show that BG505 SOSIP.664-sfGFP can be used for fluorescence-based assays, such as flow cytometry.

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“…While few high-affinity antibodies to gp140 were identified, they all lacked anti-viral activities. To improve immunogenicity at mucosal sites, fusion-constructs of HIV-1 gp140 with tumor necrosis factors (APRIL, BAFF, and CD40L) have been designed [ 211 , 212 ]. Mice primed with DNA via intramuscular immunization and then boosted with intraperitoneal injections of the corresponding protein constructs produced enhanced mucosal IgG and IgA responses in vaginal and fecal samples compared to controls.…”

Section: Early Prevention Of Hiv-1 Infection: Passive and Active Imentioning

confidence: 99%

HIV-1 Entry and Prospects for Protecting against Infection

et al. 2021

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Human Immunodeficiency Virus type-1 (HIV-1) establishes a latent viral reservoir soon after infection, which poses a major challenge for drug treatment and curative strategies. Many efforts are therefore focused on blocking infection. To this end, both viral and host factors relevant to the onset of infection need to be considered. Given that HIV-1 is most often transmitted mucosally, strategies designed to protect against infection need to be effective at mucosal portals of entry. These strategies need to contend also with cell-free and cell-associated transmitted/founder (T/F) virus forms; both can initiate and establish infection. This review will discuss how insight from the current model of HIV-1 mucosal transmission and cell entry has highlighted challenges in developing effective strategies to prevent infection. First, we examine key viral and host factors that play a role in transmission and infection. We then discuss preventive strategies based on antibody-mediated protection, with emphasis on targeting T/F viruses and mucosal immunity. Lastly, we review treatment strategies targeting viral entry, with focus on the most clinically advanced entry inhibitors.

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Enhanced Immunogenicity of HIV-1 Envelope gp140 Proteins Fused to APRIL

Cited by 4 publications

References 70 publications

De novo design of protein minibinder agonists of TLR3

De novo design of protein minibinder agonists of TLR3

Engineering and Characterization of a Fluorescent Native-Like HIV-1 Envelope Glycoprotein Trimer

HIV-1 Entry and Prospects for Protecting against Infection

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