Structural basis for breadth development in a HIV-1 neutralizing antibody

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

doi:10.1101/2022.09.14.507935

Cited by 3 publications

(3 citation statements)

References 37 publications

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“…In the case of our apex-stapled design, a differing folded state population was readily identified in our cryo-EM three-dimensional (3D) classification. No such state has been identified in any of our related SOSIP constructs (39,58,71,72), nor were substantial lotto-lot quality control variations observed that would indicate fold instability. Furthermore, a different fold would likely result in a distinct thermal denaturation profile, so a discernible bi-or multimodal denaturation profile would be expected.…”

Section: Discussionmentioning

confidence: 90%

Microsecond dynamics control the HIV-1 Envelope conformation

Bennett,

Edwards,

Kosheleva

et al. 2024

Sci. Adv.

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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.

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Section: Discussionmentioning

confidence: 90%

Microsecond dynamics control the HIV-1 Envelope conformation

Bennett,

Edwards,

Kosheleva

et al. 2024

Sci. Adv.

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show abstract

“…In the case of our apex stapled design, a differing folded state population was readily identified in our cryo-EM 3D classification. No such state has been identified in any of our related SOSIP constructs (42,49,90,133), nor were substantial lot-to-lot quality control variations observed that would indicate fold instability. Further, a different fold would likely result in a distinct thermal denaturation profile, so a discernable bi or multimodal denaturation profile would be expected.…”

Section: Discussionmentioning

confidence: 91%

Microsecond dynamics control the HIV-1 envelope conformation

Bennett,

Edwards,

Kosheleva

et al. 2023

Preprint

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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.

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“…Also key is the use of immunogens that can select for bnAb B cell maturation events that allow lineage members to bind and/or accommodate Env glycans. Accommodation of the V1 loop is a critical milestone in the generation of V3-glycan-targeted bnAbs ( 5 , 6 , 33 , 34 , 52 ). Here we used an Env with V1 glycans deleted as a prime ( 6 ) and an Env with the V1 glycans restored as a boost to select for V3-glycan bnAb lineage improbable mutations.…”

Section: Discussionmentioning

confidence: 99%

Mutation-Guided Vaccine Design: A Strategy for Developing Boosting Immunogens for HIV Broadly Neutralizing Antibody Induction

Wiehe

Saunders

Stalls

et al. 2022

Preprint

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A major goal of HIV-1 vaccine development is induction of broadly neutralizing antibodies (bnAbs). While success has been achieved in initiating bnAb B cell lineages, design of boosting immunogens that select for bnAb B cell receptors with improbable mutations required for bnAb affinity maturation remains difficult. Here we demonstrate a process for designing boosting immunogens for a V3-glycan bnAb B cell lineage. The immunogens induced affinity-matured antibodies by selecting for functional improbable mutations in bnAb precursor knock-in mice. Moreover, we show similar success in prime and boosting with nucleoside-modified mRNA-encoded HIV-1 envelope trimer immunogens, with improved selection by mRNA immunogens of improbable mutations required for bnAb binding to key envelope glycans. These results demonstrate the ability of both protein and mRNA prime-boost immunogens for selection of rare B cell lineage intermediates with neutralizing breadth after bnAb precursor expansion, a key proof-of concept and milestone towards development of an HIV vaccine.

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Structural basis for breadth development in a HIV-1 neutralizing antibody

Cited by 3 publications

References 37 publications

Microsecond dynamics control the HIV-1 Envelope conformation

Microsecond dynamics control the HIV-1 Envelope conformation

Microsecond dynamics control the HIV-1 envelope conformation

Mutation-Guided Vaccine Design: A Strategy for Developing Boosting Immunogens for HIV Broadly Neutralizing Antibody Induction

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