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Article ; Online: Guiding HIV-1 vaccine development with preclinical nonhuman primate research.

Counts, James A / Saunders, Kevin O

2023 Volume 18, Issue 6, Page(s) 315–322

Abstract: Purpose of the review: Nonhuman primates (NHPs) are seen as the closest animal model to humans in terms of anatomy and immune system makeup. Here, we review how preclinical studies in this model system are teaching the field of HIV vaccinology the basic ...

Abstract	Purpose of the review: Nonhuman primates (NHPs) are seen as the closest animal model to humans in terms of anatomy and immune system makeup. Here, we review how preclinical studies in this model system are teaching the field of HIV vaccinology the basic immunology that is needed to induce broadly neutralizing antibodies (bnAbs) with vaccination and elicit protective T cell responses. These lessons are being translated into clinical trials to advance towards protective active vaccination against HIV-1 infection. Recent findings: Preclinical vaccination studies in NHPs have shown that highly engineered HIV-1 immunogens can initiate bnAb precursors providing proof of concept for Phase I clinical trials. Additionally, NHP models of HIV-1 infection are elucidating the pathways for bnAb development while serving as systems to evaluate vaccine protection. Innovative immunization strategies have increased affinity maturation of HIV-1 antibodies in long-lived germinal centers. Preclinical studies in macaques have defined the protective level of neutralizing antibodies and have shown that T cell responses can synergize with antibody-mediated immunity to provide protection in the presence of lower neutralizing antibody titers. Summary: The NHP model provides vaccine regimens and desired antibody and T cell responses that serve as benchmarks for clinical trials, accelerating HIV vaccine design.
MeSH term(s)	Animals ; Humans ; HIV Infections/prevention & control ; HIV-1 ; Broadly Neutralizing Antibodies ; HIV Antibodies ; Antibodies, Neutralizing ; Primates ; Vaccines ; AIDS Vaccines
Chemical Substances	Broadly Neutralizing Antibodies ; HIV Antibodies ; Antibodies, Neutralizing ; Vaccines ; AIDS Vaccines
Language	English
Publishing date	2023-09-11
Publishing country	United States
Document type	Review ; Journal Article
ZDB-ID	2502511-9
ISSN	1746-6318 ; 1746-630X
ISSN (online)	1746-6318
ISSN	1746-630X
DOI	10.1097/COH.0000000000000819
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Article ; Online: Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life.

Saunders, Kevin O

Frontiers in immunology

2019 Volume 10, Page(s) 1296

Abstract: Antibodies and Fc-fusion antibody-like proteins have become successful biologics developed for cancer treatment, passive immunity against infection, addiction, and autoimmune diseases. In general these biopharmaceuticals can be used for blocking protein: ... ...

Abstract	Antibodies and Fc-fusion antibody-like proteins have become successful biologics developed for cancer treatment, passive immunity against infection, addiction, and autoimmune diseases. In general these biopharmaceuticals can be used for blocking protein:protein interactions, crosslinking host receptors to induce signaling, recruiting effector cells to targets, and fixing complement. With the vast capability of antibodies to affect infectious and genetic diseases much effort has been placed on improving and tailoring antibodies for specific functions. While antibody:antigen engagement is critical for an efficacious antibody biologic, equally as important are the hinge and constant domains of the heavy chain. It is the hinge and constant domains of the antibody that engage host receptors or complement protein to mediate a myriad of effector functions and regulate antibody circulation. Molecular and structural studies have provided insight into how the hinge and constant domains from antibodies across different species, isotypes, subclasses, and alleles are recognized by host cell receptors and complement protein C1q. The molecular details of these interactions have led to manipulation of the sequences and glycosylation of hinge and constant domains to enhance or reduce antibody effector functions and circulating half-life. This review will describe the concepts being applied to optimize the hinge and crystallizable fragment of antibodies, and it will detail how these interactions can be tuned up or down to mediate a biological function that confers a desired disease outcome.
MeSH term(s)	Animals ; Antibodies, Monoclonal/chemistry ; Half-Life ; Humans ; Immunoglobulin Heavy Chains/blood ; Immunoglobulin Heavy Chains/chemistry ; Immunotherapy/methods ; Protein Engineering/methods ; Protein Stability
Chemical Substances	Antibodies, Monoclonal ; Immunoglobulin Heavy Chains
Language	English
Publishing date	2019-06-07
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.01296
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Article ; Online: Progress with induction of HIV broadly neutralizing antibodies in the Duke Consortia for HIV/AIDS Vaccine Development.

Haynes, Barton F / Wiehe, Kevin / Alam, S Munir / Weissman, Drew / Saunders, Kevin O

Current opinion in HIV and AIDS

2023 Volume 18, Issue 6, Page(s) 300–308

Abstract: Purpose of review: Design of an HIV vaccine that can induce broadly neutralizing antibodies (bnAbs) is a major goal. However, HIV bnAbs are not readily made by the immune system. Rather HIV bnAbs are disfavored by a number of virus and host factors. The ...

Abstract	Purpose of review: Design of an HIV vaccine that can induce broadly neutralizing antibodies (bnAbs) is a major goal. However, HIV bnAbs are not readily made by the immune system. Rather HIV bnAbs are disfavored by a number of virus and host factors. The purpose of the review is to discuss recent progress made in the design and use of immunogens capable of inducing HIV bnAbs in the Duke Consortia for HIV/AIDS Vaccine Development. Recent findings: New immunogens capable of binding with high affinity to unmutated common ancestors (UCAs) of bnAb B cell lineages have been designed and strategies for stabilization of HIV Env in its prefusion state are being developed. Success is starting to be translated from preclinical studies of UCA-targeting immunogens in animals, to success of initiating bnAb lineages in humans. Summary: Recent progress has been made in both immunogen design and in achieving bnAb B cell lineage induction in animal models and now in human clinical trials. With continued progress, a practical HIV/AIDS vaccine may be possible. However, host constraints on full bnAb maturation remain as potential roadblocks for full maturation of some types of bnAbs.
Language	English
Publishing date	2023-09-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2502511-9
ISSN	1746-6318 ; 1746-630X
ISSN (online)	1746-6318
ISSN	1746-630X
DOI	10.1097/COH.0000000000000820
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Article ; Online: Microsecond dynamics control the HIV-1 Envelope conformation.

Bennett, Ashley L / Edwards, Robert / Kosheleva, Irina / Saunders, Carrie / Bililign, Yishak / Williams, Ashliegh / Bubphamala, Pimthada / Manosouri, Katayoun / Anasti, Kara / Saunders, Kevin O / Alam, S Munir / Haynes, Barton F / Acharya, Priyamvada / Henderson, Rory

Science advances

2024 Volume 10, Issue 5, Page(s) eadj0396

Abstract: The HIV-1 Envelope (Env) glycoprotein facilitates host cell fusion through a complex series of receptor-induced structural changes. Although remarkable progress has been made in understanding the structures of various Env conformations, microsecond ... ...

Abstract	The HIV-1 Envelope (Env) glycoprotein facilitates host cell fusion through a complex series of receptor-induced structural changes. Although remarkable progress has been made in understanding the structures of various Env conformations, microsecond timescale dynamics have not been studied experimentally. Here, we used time-resolved, temperature-jump small-angle x-ray scattering to monitor structural rearrangements in an HIV-1 Env SOSIP ectodomain construct with microsecond precision. In two distinct Env variants, we detected a transition that correlated with known Env structure rearrangements with a time constant in the hundreds of microseconds range. A previously unknown structural transition was also observed, which occurred with a time constant below 10 μs, and involved an order-to-disorder transition in the trimer apex. Using this information, we engineered an Env SOSIP construct that locks the trimer in the prefusion closed state by connecting adjacent protomers via disulfides. Our findings show that the microsecond timescale structural dynamics play an essential role in controlling the Env conformation with impacts on vaccine design.
MeSH term(s)	env Gene Products, Human Immunodeficiency Virus/chemistry ; HIV-1 ; HIV Antibodies ; Molecular Conformation ; Protein Multimerization ; Protein Conformation
Chemical Substances	env Gene Products, Human Immunodeficiency Virus ; HIV Antibodies
Language	English
Publishing date	2024-02-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adj0396
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Article ; Online: Strategies for induction of HIV-1 envelope-reactive broadly neutralizing antibodies.

Williams, Wilton B / Wiehe, Kevin / Saunders, Kevin O / Haynes, Barton F

Journal of the International AIDS Society

2021 Volume 24 Suppl 7, Page(s) e25831

Abstract: Introduction: A primary focus of HIV-1 vaccine development is the activation of B cell receptors for naïve or precursor broadly neutralizing antibodies (bnAbs), followed by expansion and maturation of bnAb B cell lineage intermediates leading to highly ... ...

Abstract	Introduction: A primary focus of HIV-1 vaccine development is the activation of B cell receptors for naïve or precursor broadly neutralizing antibodies (bnAbs), followed by expansion and maturation of bnAb B cell lineage intermediates leading to highly affinity-matured bnAbs. HIV-1 envelope (Env) encodes epitopes for bnAbs of different specificities. Design of immunogens to induce bnAb precursors of different specificities and mature them into bnAb status is a goal for HIV-1 vaccine development. We review vaccine strategies for bnAb lineages development and highlight the immunological barriers that these strategies must overcome to generate bnAbs. Methods: We provide perspectives based on published research articles and reviews. Discussion: The recent Antibody Mediated Protection (AMP) trial that tested the protective efficacy of one HIV-1 Env bnAb specificity demonstrated that relatively high levels of long-lasting serum titers of multiple specificities of bnAbs will be required for protection from HIV-1 transmission. Current vaccine efforts for induction of bnAb lineages are focused on immunogens designed to expand naïve HIV-1 bnAb precursor B cells following the recent success of vaccine-induction of bnAb precursor B cells in macaques and humans. BnAb precursor B cells serve as templates for priming-immunogen design. However, design of boosting immunogens for bnAb maturation requires knowledge of the optimal immunogen design and immunological environment for bnAb B cell lineage affinity maturation. BnAb lineages acquire rare genetic changes as mutations during B cell maturation. Moreover, the immunological environment that supports bnAb development during HIV-1 infection is perturbed with an altered B cell repertoire and dysfunctional immunoregulatory controls, suggesting that in normal settings, bnAb development will be disfavoured. Thus, strategies for vaccine induction of bnAbs must circumvent immunological barriers for bnAb development that normally constrain bnAb B cell affinity maturation. Conclusions: A fully protective HIV-1 vaccine needs to induce durable high titers of bnAbs that can be generated by a sequential set of Env immunogens for expansion and maturation of bnAb B cell lineages in a permitted immunological environment. Moreover, multiple specificities of bnAbs will be required to be sufficiently broad to prevent the escape of HIV-1 strains during transmission.
MeSH term(s)	AIDS Vaccines ; Antibodies, Neutralizing ; Broadly Neutralizing Antibodies ; HIV Antibodies ; HIV Infections/prevention & control ; HIV-1 ; Humans ; env Gene Products, Human Immunodeficiency Virus/immunology
Chemical Substances	AIDS Vaccines ; Antibodies, Neutralizing ; Broadly Neutralizing Antibodies ; HIV Antibodies ; env Gene Products, Human Immunodeficiency Virus
Language	English
Publishing date	2021-11-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2467110-1
ISSN	1758-2652 ; 1758-2652
ISSN (online)	1758-2652
ISSN	1758-2652
DOI	10.1002/jia2.25831
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Article ; Online: Author Correction: Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies.

Haynes, Barton F / Wiehe, Kevin / Borrow, Persephone / Saunders, Kevin O / Korber, Bette / Wagh, Kshitij / McMichael, Andrew J / Kelsoe, Garnett / Hahn, Beatrice H / Alt, Frederick / Shaw, George M

Nature reviews. Immunology

2023 Volume 23, Issue 4, Page(s) 265

Language	English
Publishing date	2023-03-15
Publishing country	England
Document type	Published Erratum
ZDB-ID	2062776-2
ISSN	1474-1741 ; 1474-1733
ISSN (online)	1474-1741
ISSN	1474-1733
DOI	10.1038/s41577-023-00854-0
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Zs.A 5565: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Antibody responses to the HIV-1 envelope high mannose patch.

Daniels, Christine N / Saunders, Kevin O

Advances in immunology

2019 Volume 143, Page(s) 11–73

Abstract: Neutralizing antibodies against human immunodeficiency virus subtype 1 (HIV-1) bind to its envelope glycoprotein (Env). Half of the molecular mass of Env is carbohydrate making it one of the most heavily glycosylated proteins known in nature. HIV-1 Env ... ...

Abstract	Neutralizing antibodies against human immunodeficiency virus subtype 1 (HIV-1) bind to its envelope glycoprotein (Env). Half of the molecular mass of Env is carbohydrate making it one of the most heavily glycosylated proteins known in nature. HIV-1 Env glycans are derived from the host and present a formidable challenge for host anti-glycan antibody induction. Anti-glycan antibody induction is challenging because anti-HIV-1 glycan antibodies should recognize Env antigen while not acquiring autoreactivity. Thus, the glycan network on HIV-1 Env is referred to as the glycan shield. Despite the challenges presented by immune recognition of host-derived glycans, neutralizing antibodies capable of binding the glycans on HIV-1 Env can be generated by the host immune system in the setting of HIV-1 infection. In particular, a cluster of high mannose glycans, including an N-linked glycan at position 332, form the high mannose patch and are targeted by a variety of broadly neutralizing antibodies. These high mannose patch-directed HIV-1 antibodies can be categorized into distinct categories based on their antibody paratope structure, neutralization activity, and glycan and peptide reactivity. Below we will compare and contrast each of these classes of HIV-1 glycan-dependent antibodies and describe vaccine design efforts to elicit each of these antibody types.
MeSH term(s)	Animals ; Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal/metabolism ; Antibodies, Monoclonal/therapeutic use ; Antibodies, Neutralizing/chemistry ; Antibodies, Neutralizing/genetics ; Antibodies, Neutralizing/metabolism ; Antibodies, Neutralizing/therapeutic use ; Antibody Formation ; Broadly Neutralizing Antibodies/chemistry ; Broadly Neutralizing Antibodies/metabolism ; Broadly Neutralizing Antibodies/therapeutic use ; Epitopes/metabolism ; Glycosylation ; HIV Antibodies/chemistry ; HIV Antibodies/metabolism ; HIV Antibodies/therapeutic use ; HIV Envelope Protein gp120/immunology ; HIV Infections/immunology ; HIV Infections/metabolism ; HIV-1/immunology ; Humans ; Immunogenicity, Vaccine ; Mannose/immunology ; Peptide Fragments/immunology ; Polysaccharides/chemistry ; Polysaccharides/immunology
Chemical Substances	2G12 monoclonal antibody ; Antibodies, Monoclonal ; Antibodies, Neutralizing ; Broadly Neutralizing Antibodies ; Epitopes ; HIV Antibodies ; HIV Envelope Protein gp120 ; HIV envelope protein gp120 (305-321) ; Peptide Fragments ; Polysaccharides ; Mannose (PHA4727WTP)
Language	English
Publishing date	2019-09-11
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	80226-8
ISSN	1557-8445 ; 0065-2776
ISSN (online)	1557-8445
ISSN	0065-2776
DOI	10.1016/bs.ai.2019.08.002
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Article ; Online: Identification of CDRH3 loops in the B cell receptor repertoire that can be engaged by candidate immunogens.

Swanson, Olivia / Martin Beem, Joshua S / Rhodes, Brianna / Wang, Avivah / Barr, Maggie / Chen, Haiyan / Parks, Robert / Saunders, Kevin O / Haynes, Barton F / Wiehe, Kevin / Azoitei, Mihai L

PLoS pathogens

2023 Volume 19, Issue 5, Page(s) e1011401

Abstract: A major goal for the development of vaccines against rapidly mutating viruses, such as influenza or HIV, is to elicit antibodies with broad neutralization capacity. However, B cell precursors capable of maturing into broadly neutralizing antibodies ( ... ...

Abstract	A major goal for the development of vaccines against rapidly mutating viruses, such as influenza or HIV, is to elicit antibodies with broad neutralization capacity. However, B cell precursors capable of maturing into broadly neutralizing antibodies (bnAbs) can be rare in the immune repertoire. Due to the stochastic nature of B cell receptor (BCR) rearrangement, a limited number of third heavy chain complementary determining region (CDRH3) sequences are identical between different individuals. Thus, in order to successfully engage broadly neutralizing antibody precursors that rely on their CDRH3 loop for antigen recognition, immunogens must be able to tolerate sequence diversity in the B cell receptor repertoire across an entire vaccinated population. Here, we present a combined experimental and computational approach to identify BCRs in the human repertoire with CDRH3 loops predicted to be engaged by a target immunogen. For a given antibody/antigen pair, deep mutational scanning was first used to measure the effect of CDRH3 loop substitution on binding. BCR sequences, isolated experimentally or generated in silico, were subsequently evaluated to identify CDRH3 loops expected to be bound by the candidate immunogen. We applied this method to characterize two HIV-1 germline-targeting immunogens and found differences in the frequencies with which they are expected to engage target B cells, thus illustrating how this approach can be used to evaluate candidate immunogens towards B cell precursors engagement and to inform immunogen optimization strategies for more effective vaccine design.
MeSH term(s)	Humans ; HIV Antibodies ; Antibodies, Neutralizing ; HIV-1 ; B-Lymphocytes ; Broadly Neutralizing Antibodies ; Receptors, Antigen, B-Cell/genetics ; AIDS Vaccines ; HIV Infections
Chemical Substances	HIV Antibodies ; Antibodies, Neutralizing ; Broadly Neutralizing Antibodies ; Receptors, Antigen, B-Cell ; AIDS Vaccines
Language	English
Publishing date	2023-05-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011401
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Article ; Online: Structural basis for breadth development in the HIV-1 V3-glycan targeting DH270 antibody clonal lineage.

Henderson, Rory / Zhou, Ye / Stalls, Victoria / Wiehe, Kevin / Saunders, Kevin O / Wagh, Kshitij / Anasti, Kara / Barr, Maggie / Parks, Robert / Alam, S Munir / Korber, Bette / Haynes, Barton F / Bartesaghi, Alberto / Acharya, Priyamvada

Nature communications

2023 Volume 14, Issue 1, Page(s) 2782

Abstract: Antibody affinity maturation enables adaptive immune responses to a wide range of pathogens. In some individuals broadly neutralizing antibodies develop to recognize rapidly mutating pathogens with extensive sequence diversity. Vaccine design for ... ...

Abstract	Antibody affinity maturation enables adaptive immune responses to a wide range of pathogens. In some individuals broadly neutralizing antibodies develop to recognize rapidly mutating pathogens with extensive sequence diversity. Vaccine design for pathogens such as HIV-1 and influenza has therefore focused on recapitulating the natural affinity maturation process. Here, we determine structures of antibodies in complex with HIV-1 Envelope for all observed members and ancestral states of the broadly neutralizing HIV-1 V3-glycan targeting DH270 antibody clonal B cell lineage. These structures track the development of neutralization breadth from the unmutated common ancestor and define affinity maturation at high spatial resolution. By elucidating contacts mediated by key mutations at different stages of antibody development we identified sites on the epitope-paratope interface that are the focus of affinity optimization. Thus, our results identify bottlenecks on the path to natural affinity maturation and reveal solutions for these that will inform immunogen design aimed at eliciting a broadly neutralizing immune response by vaccination.
MeSH term(s)	Humans ; HIV Infections/prevention & control ; HIV-1/genetics ; Antibodies, Neutralizing ; HIV Antibodies ; Polysaccharides
Chemical Substances	Antibodies, Neutralizing ; HIV Antibodies ; Polysaccharides
Language	English
Publishing date	2023-05-15
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-38108-1
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Article: Microsecond dynamics control the HIV-1 envelope conformation.

Bennett, Ashley L / Edwards, R J / Kosheleva, Irina / Saunders, Carrie / Bililign, Yishak / Williams, Ashliegh / Manosouri, Katayoun / Saunders, Kevin O / Haynes, Barton F / Acharya, Priyamvada / Henderson, Rory

bioRxiv : the preprint server for biology

2023

Abstract: The HIV-1 Envelope (Env) glycoprotein facilitates host cell fusion through a complex series of receptor-induced structural changes. Although significant progress has been made in understanding the structures of various Env conformations and transition ... ...

Abstract	The HIV-1 Envelope (Env) glycoprotein facilitates host cell fusion through a complex series of receptor-induced structural changes. Although significant progress has been made in understanding the structures of various Env conformations and transition intermediates that occur within the millisecond timescale, faster transitions in the microsecond timescale have not yet been observed. In this study, we employed time-resolved, temperature-jump small angle X-ray scattering to monitor structural rearrangements in an HIV-1 Env ectodomain construct with microsecond precision. We detected a transition correlated with Env opening that occurs in the hundreds of microseconds range and another more rapid transition that preceded this opening. Model fitting indicated that the early rapid transition involved an order-to-disorder transition in the trimer apex loop contacts, suggesting that conventional conformation-locking design strategies that target the allosteric machinery may be ineffective in preventing this movement. Utilizing this information, we engineered an envelope that locks the apex loop contacts to the adjacent protomer. This modification resulted in significant angle-of-approach shifts in the interaction of a neutralizing antibody. Our findings imply that blocking the intermediate state could be crucial for inducing antibodies with the appropriate bound state orientation through vaccination.
Language	English
Publishing date	2023-05-18
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.17.541130
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