Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors

Zhou, Tongqing; Lynch, Rebecca M.; Chen, Lei; Acharya, Priyamvada; Wu, Xueling; Doria‐Rose, Nicole A.; Joyce, Michael; Lingwood, Daniel; Soto, Cinque; Bailer, Robert T.; Ernandes, Michael J.; Kong, Rui; Longo, Nancy S.; Louder, Mark K.; McKee, Krisha; O’Dell, Sijy; Schmidt, Stephen D.; Tran, Lan Mai; Yang, Zhongjia; Druz, Aliaksandr; Luongo, Timothy S.; Moquin, S.; Srivatsan, Sanjay; Yang, Yongping; Zhang, Baoshan; Zheng, Anqi; Pancera, Marie; Kirys, Tatsiana; Georgiev, Ivelin S.; Gindin, Tatyana; Peng, Hung-Pin; Yang, An‐Suei; Mullikin, James C.; Gray, Matthew D.; Stamatatos, Leonidas; Burton, Dennis R.; Koff, Wayne C.; Cohen, Myron S.; Haynes, Barton F.; Casazza, Joseph P.; Connors, Mark; Corti, Davide; Lanzavecchia, Antonio; Sattentau, Quentin J.; Weiss, Robin A.; West, Anthony P.; Björkman, Pamela J.; Scheid, Johannes F.; Nussenzweig, Michel C.; Shapiro, Lawrence; Mascola, John R.; Kwong, Peter D.

doi:10.1016/j.cell.2015.05.007

Cited by 292 publications

(479 citation statements)

References 56 publications

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“…CD4bs bnAbs have been isolated from multiple HIV-1 infected individuals, suggesting that their induction is relatively common and therefore an achievable goal in the setting of vaccination. Moreover, CD4bs bnAbs isolated from infected individuals share similar V H and V L gene characteristics suggesting commonalities in their maturation pathways that could be recapitulated by a B-cell lineage design approach in multiple individuals (41, 42) (Stamatatos, this volume; Kelsoe and Haynes, this volume). Finally, CD4bs bnAbs are among the most broad and potent antibodies, surpassed in breadth only by distal MPER gp41 bnAbs such as 10E8 or DH511 (Williams L., Haynes B.F. et al, submitted).…”

Section: Characteristics Of Broadly Neutralizing Antibodiesmentioning

confidence: 99%

“…While such immunogens are designed for the UCA and intermediate antibodies of one particular bnAb lineage, they hold promise for inducing bnAb lineages in multiple individuals because of the remarkable conserved usage of V H and V L genes of bnAbs and the restricted nature of antibody motifs for many bnAb types, particularly for the gp41 membrane proximal region (89), the CD4 binding site (42) and the V1V2-glycan site (15, 41, 55, 56). To mimic the progression of maturation of bnAb lineages, each Env should engage a bnAb precursor with affinity sufficient to trigger the B cell but with low binding affinity to allow for affinity maturation to the next stage of bnAb development.…”

Section: B Cell Lineage Immunogen Designmentioning

confidence: 99%

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Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

Bonsignori

Liao

Gao

et al. 2017

Immunological Reviews

162

150

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Summary Induction of HIV-1 broadly neutralizing antibodies (bnAbs) to date has only been observed in the setting of HIV-1 infection, and then only years after HIV transmission. Thus, the concept has emerged that one path to induction of bnAbs is to define the viral and immunologic events that occur during HIV-1 infection, and then to mimic those events with a vaccine formulation. This concept has led to efforts to map both virus and antibody events that occur from the time of HIV-1 transmission to development of bnAbs. This work has revealed that a virus-antibody “arms race” occurs in which a HIV-1 transmitted/founder (TF) Env induces autologous neutralizing antibodies that can not only neutralize the TF virus but also can select virus escape mutants that in turn select affinity-matured neutralizing antibodies. From these studies has come a picture of bnAb development that has led to new insights in host-pathogen interactions and, as well, led to insight into immunologic mechanisms of control of bnAb development. Here we review the progress to date in elucidating bnAb B cell lineages in HIV-1 infection, discuss new research leading to understanding the immunologic mechanisms of bnAb induction, and address issues relevant to the use of this information for the design of new HIV-1 sequential envelope vaccine candidates.

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Section: Characteristics Of Broadly Neutralizing Antibodiesmentioning

confidence: 99%

Section: B Cell Lineage Immunogen Designmentioning

confidence: 99%

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

Bonsignori

Liao

Gao

et al. 2017

Immunological Reviews

162

150

View full text Add to dashboard Cite

show abstract

“…Supporting this idea is the observation that bNAbs can share V H ‐gene‐restriction. For example CD4bs bNAbs that are CD4 mimics typically arise from one of two highly similar V H 1‐2 and V H 1‐46 genes 73. In such a case, an initial triggering of a germ‐line B‐cell carrying an appropriate V H heavy gene is likely to be an important first step for vaccine‐induced CD4bs bNAb development,68 and it is possible that particular Envs have a propensity to bind to these germ‐line B‐cells.…”

Section: Antibody Epitope Diversitymentioning

confidence: 99%

“…Unlike CH103, CH235 is a CD4 mimic, similar to the VRC01‐class of CD4bs bNAbs 73. Development of the CH235 lineage breadth progressed over 6 years of longitudinal sampling.…”

Section: Immune Selection In Longitudinal Samples: Ontogeny Of Cd4bs mentioning

confidence: 99%

“…Of note, high levels of somatic hypermutation were required for breadth, despite an early, nearly optimal binding orientation of the CH235 lineage. Other CD4bs‐directed antibodies face similar developmental impediments, whether V H ‐gene restricted or CDR H3‐dominated 73. Studying coevolution of HIV‐1 with two bNAb lineages and their cooperative interactions13, 68 has led to unique insights into the complexities of bNAb development and suggested vaccination strategies for simultaneous induction of both lineages.…”

Section: Immune Selection In Longitudinal Samples: Ontogeny Of Cd4bs mentioning

confidence: 99%

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Polyvalent vaccine approaches to combat HIV‐1 diversity

Korber

Hraber

Wagh

et al. 2017

Immunological Reviews

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SummaryA key unresolved challenge for developing an effective HIV‐1 vaccine is the discovery of strategies to elicit immune responses that are able to cross‐protect against a significant fraction of the diverse viruses that are circulating worldwide. Here, we summarize some of the immunological implications of HIV‐1 diversity, and outline the rationale behind several polyvalent vaccine design strategies that are currently under evaluation. Vaccine‐elicited T‐cell responses, which contribute to the control of HIV‐1 in natural infections, are currently being considered in both prevention and treatment settings. Approaches now in preclinical and human trials include full proteins in novel vectors, concatenated conserved protein regions, and polyvalent strategies that improve coverage of epitope diversity and enhance the cross‐reactivity of responses. While many barriers to vaccine induction of broadly neutralizing antibody (bNAb) responses remain, epitope diversification has emerged as both a challenge and an opportunity. Recent longitudinal studies have traced the emergence of bNAbs in HIV‐1 infection, inspiring novel approaches to recapitulate and accelerate the events that give rise to potent bNAb in vivo. In this review, we have selected two such lineage‐based design strategies to illustrate how such in‐depth analysis can offer conceptual improvements that may bring us closer to an effective vaccine.

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Strategies for induction of HIV‐1 envelope‐reactive broadly neutralizing antibodies

et al. 2021

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IntroductionA 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.MethodsWe provide perspectives based on published research articles and reviews.DiscussionThe 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.ConclusionsA 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.

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Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors

Cited by 292 publications

References 56 publications

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

Polyvalent vaccine approaches to combat HIV‐1 diversity

Strategies for induction of HIV‐1 envelope‐reactive broadly neutralizing antibodies

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