Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1

Xu, Kai; Acharya, Priyamvada; Kong, Rui; Ченг, Чиа-Чи; Chuang, Gwo-Yu; Liu, K.; Louder, Mark K.; O’Dell, Sijy; Rawi, Reda; Sastry, Mallika; Shen, Chen‐Hsiang; Zhang, B.; Zhou, Tongqing; Asokan, Mangaiarkarasi; Bailer, Robert T.; Chambers, Michael; Chen, X.; Choi, Chang Won; Dandey, Venkata P.; Doria‐Rose, Nicole A.; Druz, Aliaksandr; Eng, Edward T.; Farney, S. Katie; Foulds, Kathryn E.; Geng, Hui; Georgiev, Ivelin S.; Gorman, Jason; Hill, Kurt R.; Jafari, Alexander J.; Kwon, Young Do; Lai, Yen‐Ting; Lemmin, Thomas; McKee, Krisha; Ohr, Tiffany Y.; Ou, Li; Peng, Dongjun; Rowshan, Ariana P.; Sheng, Zizhang; Todd, John-Paul; Tsybovsky, Yaroslav; Viox, Elise G.; Wang, Yonghu; Wei, Hui; Yang, Yongping; Zhou, Amy F.; Chen, R.; Yang, Lifei; Scorpio, Diana G.; McDermott, Adrian B.; Shapiro, Lawrence; Carragher, Bridget; Potter, Clinton S.; Mascola, John R.; Kwong, Peter D.

doi:10.1038/s41591-018-0042-6

Cited by 259 publications

(285 citation statements)

References 80 publications

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“…One approach to focus the response on the FP is through repeated immunization with 10-100s of copies of the FP displayed on carrier proteins, such as keyhole limpet hemacyanin (KLH), followed by a booster immunization with the Env trimer spike to present the FP in a more native context. This approach has produced encouraging responses in animals with up to 31% and 59% neutralization breadth in mice and macaques, respectively, against panel of diverse HIV isolates [27,28]**. This concept is now being developed for human clinical trials [29].…”

Section: Introductionmentioning

confidence: 99%

Innovations in structure-based antigen design and immune monitoring for next generation vaccines

Ward

Wilson

2020

Current Opinion in Immunology

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Please cite this article as: Ward AB, Wilson IA, Innovations in structure-based antigen design and immune monitoring for next generation vaccines, J o u r n a l P r e -p r o o f Highligthts Immunofocusing as a strategy for structure-based vaccine design. Structure-based vaccine design for RSV F, influenza HA, HIV-1 Env. Structure-based vaccine design translated into the clinic. AbstractThe recent explosion of atomic-level structures of glycoproteins that comprise the surface antigens of human enveloped viruses, such as RSV, influenza, hepatitis C and HIV, provide tremendous opportunities for rational, structure-based vaccine design. Several concepts in structure-based vaccine design have been put into practice and are are well along preclinical and clinical implementation. Testing of these designed immunogens will provide key insights into the ability to induce the desired immune responses, namely neutralizing antibodies. Many of these immunogens in human clinical trials represent only the first wave of designs and will likely require continued tweaking and elaboration to achieve the ultimate result of ever increasingly breadth and potency. Considerable effort is now being invested in germline targeting, epitope focusing, and improved immune presentation such as multivalent nanoparticle incorporation. This review highlights some of the recent advances in these areas as we prepare for the next generation of immunogens for subsequent rounds of iterative vaccine development.

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Section: Introductionmentioning

confidence: 99%

Innovations in structure-based antigen design and immune monitoring for next generation vaccines

Ward

Wilson

2020

Current Opinion in Immunology

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“…Clustering of the PCA results indicated that the F14 and F14/Vt8 structures indeed differed from the majority of the available SOSIP structures, residing in distinct clusters closer to a cluster of fusion peptide-directed antibody-bound SOSIP structures including those induced in mice and Rhesus macaques (Figure 5E, Supplementary Table 5). 38 This finding indicated that the changes observed in the layer1/2 contact region with gp41 indeed altered the overall orientation of gp120 relative to gp41, and showed that these changes were structurally similar to those induced by fusion peptide-directed antibodies. We next examined the structure of the vFP antibodies in the region of the F14 conformational changes.…”

Section: Resultsmentioning

confidence: 74%

Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements

Henderson

Zhou

et al. 2019

Preprint

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30The trimeric HIV-1 Envelope protein (Env) mediates viral-host cell fusion via a network of 31 conformational transitions, with allosteric elements in each protomer orchestrating host 32 receptor-induced exposure of the co-receptor binding site and fusion elements. To 33 understand the molecular details of this allostery, we introduced Env mutations aimed to 34 prevent CD4-induced rearrangements in the HIV-1 BG505 Env trimer. Binding analysis 35 performed on the soluble ectodomain BG505 SOSIP Env trimers, cell-surface expressed 36 BG505 full-length trimers and single-molecule Förster Resonance Energy Transfer 37 (smFRET) performed on the full-length virion-bound Env confirmed that these mutations 38 prevented CD4-induced transitions of the HIV-1 Env. Structural analysis by single-39 particle cryo-electron microscopy performed on the BG505 SOSIP mutant Env proteins 40 revealed rearrangements in the gp120 topological layer contacts with gp41. Specifically, 41 a conserved tryptophan at position 571 (W571) was displaced from its typical pocket at 42 the interface of gp120 topological layers 1 and 2 by lysine 567, disrupting key gp120-43 gp41 contacts and rendering the Env insensitive to CD4 binding. Vector based analysis 44 of closed Env SOSIP structures revealed the newly designed trimers exhibited a 45 quaternary structure distinct from that typical of SOSIPs and residing near a cluster of 46 Env trimers bound to vaccine-induced fusion peptide-directed antibodies (vFP Mabs). 47These results reveal the critical function of W571 as a conformational switch in Env 48 allostery and receptor-mediated viral entry and provide insights on Env conformation that 49 are relevant for vaccine design.50 51 52 53 54Host cell entry of HIV-1 is accomplished by the envelope glycoprotein (Env) spike. HIV-1 55Env is a trimer of heterodimers comprised of gp120 and gp41 protomers, and exists in a 56 metastable conformation capable of transitioning from a prefusion closed configuration to a 57 fusion-competent open state upon triggering by CD4. 1,2 The C-terminal gp41 domain contains a 58 single transmembrane helix and the membrane fusion elements of the trimer. 3-5 The gp12059 segment binds the primary receptor CD4, triggering conformational changes leading to the 60 binding of co-receptor CCR5/CXCR4 that causes global rearrangements in the trimer structure 61 leading to viral and cell membrane fusion and gp120 shedding. 6-8 While many studies have 62 sought to understand the nature of the communication between the CD4 binding site, the 63 coreceptor binding site and the fusogenic elements of the HIV-1 Env, a complete understanding 64 of the allosteric mechanism and metastability in HIV-1 Env remains lacking. 65The design of a soluble, stabilized ectodomain Env (SOSIP), containing an engineered 66 gp120 to gp41 disulfide (SOS) and an HR1 helix breaking I to P mutation, has revealed 67 structural details regarding broadly neutralizing antibody (bnAb) epitopes and as an immunogen 68 has induced autologous neutralizing antibodies. 2,9 The...

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“…They immunized guinea pigs and macaques with a fusion peptide coupled to the carrier protein KLH, and boosted the responses with stabilized BG505 SOSIP trimers. This immunization strategy induced autologous NAb responses in all the animals and substantial NAb responses against heterologous Tier-2 viruses in some animals [88]. When they isolated the antibodies that were responsible for the broad neutralization they could confirm that these antibodies targeted the fusion peptide on both autologous and heterologous viruses [88].…”

Section: Evaluating Env Trimers In Vivo: Learning From Different Immumentioning

confidence: 98%

Stabilizing HIV-1 envelope glycoprotein trimers to induce neutralizing antibodies

Peña

Sanders

2018

Retrovirology

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An effective HIV-1 vaccine probably will need to be able to induce broadly neutralizing HIV-1 antibodies (bNAbs) in order to be efficacious. The many bNAbs that have been isolated from HIV-1 infected patients illustrate that the human immune system is able to elicit this type of antibodies. The elucidation of the structure of the HIV-1 envelope glycoprotein (Env) trimer has further fueled the search for Env immunogens that induce bNAbs, but while native Env trimer mimetics are often capable of inducing strain-specific neutralizing antibodies (NAbs) against the parental virus, they have not yet induced potent bNAb responses. To improve the performance of Env trimer immunogens, researchers have studied the immune responses that Env trimers have induced in animals; they have evaluated how to best use Env trimers in various immunization regimens; and they have engineered increasingly stabilized Env trimer variants. Here, we review the different approaches that have been used to increase the stability of HIV-1 Env trimer immunogens with the aim of improving the induction of NAbs. In particular, we draw parallels between the various approaches to stabilize Env trimers and ones that have been used by nature in extremophile microorganisms in order to survive in extreme environmental conditions.

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Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1

Cited by 259 publications

References 80 publications

Innovations in structure-based antigen design and immune monitoring for next generation vaccines

Innovations in structure-based antigen design and immune monitoring for next generation vaccines

Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements

Stabilizing HIV-1 envelope glycoprotein trimers to induce neutralizing antibodies

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