Minimally Mutated HIV-1 Broadly Neutralizing Antibodies to Guide Reductionist Vaccine Design

Jardine, Joseph G.; Sok, Devin; Julien, Jean-Philippe; Briney, Bryan; Sarkar, Achyut; Liang, Chi; Scherer, Erin A.; Dunand, Carole J. Henry; Adachi, Yumiko; Diwanji, Devan; Hsueh, Jessica; Jones, Meaghan; Kalyuzhniy, Oleksandr; Kubitz, Michael; Spencer, Skye; Pauthner, Matthias; Saye-Francisco, Karen L.; Sesterhenn, Fabian; Wilson, Patrick C.; Galloway, Denise; Stanfield, Robyn L.; Wilson, Ian A.; Burton, Dennis R.; Schief, William R.

doi:10.1371/journal.ppat.1005815

Cited by 113 publications

(181 citation statements)

References 83 publications

(173 reference statements)

Supporting

Mentioning

170

Contrasting

Unclassified

Order By: Relevance

“…It is likely that VRC01-subclass (Vκ3-20 + ) naive B cells would require deletions in L-CDR1 to acquire bnAb attributes in a human HIV-1 vaccine regimen. In contrast, N6-subclass bnAb maturation can occur via Vκ1-33 CDR1 glycine mutations to enable flexibility to accommodate HIV Env N276 (21, 22, 24). Six N6-subclass naive B cells were identified during B cell repertoire screening (Figure 2A, Table S1, Figure S1F).…”

Section: Resultsmentioning

confidence: 99%

“…To investigate why this may be the case, we compared the Vκ gene usage from VRC01-class bnAbs and eOD-GT8 + VRC01-class naive B cells. We then cross-referenced the Vκ usage against the overall human BCR repertoire, restricted to B cells expressing 5-aa L-CDR3s (24). Finally, noting that nearly all VRC01-class naive B cells that used Vκ genes also contained a 5-aa L-CDR3 C QQYxx F motif, we tabulated the Vκ genes with a germline-encoded QQYxx motif (Figure 2C).…”

Section: Resultsmentioning

confidence: 99%

“…eOD-GT8 60-mer nanoparticles nanoparticles were separately labeled with Amine Reactive Alexa Fluor 488 and Alexa Fluor 647 kits (A10235 or A20173, respectively, Thermo Fisher Scientific). eOD-GT8 KO 60-mer nanoparticles (6, 24) were labeled with a Pacific Blue protein labeling kit (P30012, Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen

et al. 2018

Self Cite

View full text Add to dashboard Cite

One Sentence Summary: Inspection of the naive B cell repertoire specific for an HIV vaccine immunogen provides actionable information for human vaccine design and advancement. Traditional vaccine development to prevent some of the worst current pandemic diseases has been unsuccessful, so far. Germline-targeting immunogens have potential to prime protective antibodies (Abs) via more targeted immune responses. Success of germline-targeting vaccines in humans will depend on the composition of the human naive B cell repertoire, including the frequencies and affinities of epitope-specific B cells. However, the human naive B cell repertoire remains largely undefined. Assessment of antigen-specific human naive B cells among hundreds of millions of B cells from multiple donors may be used as pre-Phase I ex vivo human testing to potentially forecast B cell and Ab responses to new vaccine designs. VRC01 is an HIV broadly neutralizing Ab (bnAb) against the Env CD4 binding site (CD4bs). We characterized naive human B cells recognizing eOD-GT8, a germline-targeting HIV-1 vaccine candidate immunogen designed to prime VRC01-class Abs. Several distinct subclasses of VRC01-class naive B cells were identified, sharing sequence characteristics with inferred precursors of known bnAbs VRC01, VRC23, PCIN63, and N6. Multiple naive B cell clones exactly matched mature VRC01-class bnAb L-CDR3 sequences. Non-VRC01-class B cells were also characterized, revealing recurrent public light chain sequences. Unexpectedly, we also identified naive B cells related to the IOMA-class CD4bs bnAb. These different subclasses within the human repertoire had strong initial affinities (KD) to the immunogen, up to 13 nM, and represent encouraging indications that multiple independent pathways may exist for vaccine-elicited VRC01-class bnAb development in most individuals. The frequencies of these distinct eOD-GT8 B cell specificities give insights into antigen-specific compositional features of the human naive B cell repertoire and provide actionable information for vaccine design and advancement.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…These mutations are present both in the complementarity determining regions of the antibodies, but also in the usually conserved framework regions of the antibody structures [75]. Although some of these mutations may be redundant for breadth, as illustrated for the CD4bs bNAb VRC01 and for membrane proximal external region bNAb 10E8 [76, 77], the precursors of bNAbs are strain-specific [48, 70, 72] highlighting the importance of acquiring some degree of somatic hypermutation in developing breadth.…”

Section: Broadly Neutralizing Antibodiesmentioning

confidence: 99%

“…This, and the detailed understanding of the co-evolution between virus and host have led to the notion of sequential immunization or B cell lineage design, first proposed by Barton Haynes and colleagues [92], and now being widely pursued, with the first experimental confirmations of the validity of this approach emerging in the literature [93]. This approach has the potential to drive higher levels of somatic hypermutation, but is also based on the premise that clever use of immunogens may lower the threshold required for breadth by enriching for the “right” mutations [76]. Studies of lineages that exhibit breadth with more moderate levels of somatic hypermutation, such as pediatric bNAbs [32] and the recently described CD4bs PC63 lineage (Landais et al , HIV Vaccines Keystone 2017), will prove useful in the selection of tailored immunogens…”

Section: What Vaccine Lessons Have We Learned From Studies Of Infection?mentioning

confidence: 99%

The Neutralizing Antibody Response to the HIV-1 Env Protein

Moore

2018

CHR

View full text Add to dashboard Cite

Objective: Background:A vaccine able to elicit broadly neutralizing antibodies capable of blocking infection by global viruses has not been achieved, and remains a key public health challenge. Objective: Objective:During infection, a robust strain-specific neutralizing response develops in most people, but only a subset of infected people develop broadly neutralizing antibodies. Understanding how and why these broadly neutralizing antibodies develop has been a focus of the HIV-1 vaccine field for many years, and has generated extraordinary insights into the neutralizing response to HIV-1 infection. Results: This review describes the features, targets and developmental pathways of early strain-specific antibodies and later broadly neutralizing antibodies, and explores the reasons such broad antibodies are not more commonly elicited during infection. Conclusion: The insights from these studies have been harnessed for the development of pioneering new vaccine approaches that seek to drive B cell maturation towards breadth. Overall, this review describes how findings from infected donors have impacted on active and passive immunization approaches that seek to prevent HIV-1 infection.

show abstract

Protein design: from computer models to artificial intelligence

Paladino

Marchetti

Rinaldi

et al. 2017

WIREs Comput Mol Sci

View full text Add to dashboard Cite

The rational design of novel biomolecules with desired functional properties is one of the most fascinating challenges in science, with implications at the fundamental and practical levels. From the fundamental point of view, the design of proteins able to support nonnatural reactivities represents the decisive test on our understanding of the molecular mechanisms through which biomolecules operate. From the practical point of view, new designs may open the way to applications in a wide variety of fields, ranging from health to life science, and from catalysis to material sciences. During the past decades, we have witnessed an amazing transition in the application of computational methods to protein and enzyme design, from simple fold prediction to ab initio structural design. Herein, we review key areas and fundamental aspects of research in the design of protein structures, interactions, and reactivities. We also provide our perspective on the exciting range of developments that are made possible by the integration of innovations in hardware, software, and theory, while keeping an eye on the applications, challenges, and opportunities that can open up in many different domains of science. WIREs Comput Mol Sci 2017, 7:e1318. doi: 10.1002/wcms.1318 This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Molecular Dynamics and Monte-Carlo Methods

show abstract

Minimally Mutated HIV-1 Broadly Neutralizing Antibodies to Guide Reductionist Vaccine Design

Cited by 113 publications

References 83 publications

The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen

The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen

The Neutralizing Antibody Response to the HIV-1 Env Protein

Protein design: from computer models to artificial intelligence

Contact Info

Product

Resources

About