Focused Evolution of HIV-1 Neutralizing Antibodies Revealed by Structures and Deep Sequencing

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207

193

SummaryBeginning in 2009, studies of the humoral responses of HIV‐positive individuals have led to the identification of scores, if not hundreds, of antibodies that are both broadly reactive and potently neutralizing. This development has provided renewed impetus toward an HIV vaccine and led directly to the development of novel immunogens. Advances in identification of donors with the most potent and broad anti‐HIV serum neutralizing responses were crucial in this effort. Equally, development of methods for the rapid generation of human antibodies from these donors was pivotal. Primarily these methods comprise single B‐cell culture coupled to high‐throughput neutralization screening and flow cytometry‐based sorting of single B cells using HIV envelope protein baits. In this review, the advantages and disadvantages of these methodologies are discussed in the context of the specificities targeted by individual antibodies and the need for further improvements to evaluate HIV vaccine candidates.

Section: Specificity Of Hiv Bnabsmentioning

confidence: 99%

Identification and specificity of broadly neutralizing antibodies against HIV

McCoy

Burton

2017

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207

193

“…VRC01 binds to highly conserved amino acid residues which are almost invariant and maintained across viruses, critical for CD4 binding and viral entry (eg, the conserved CD4 binding loop contacts shown in Figure 2, that are important for all VRC01‐like antibodies) 65, 66. However, VRC01 also directly contacts amino acids in the hypervariable part of V5 (positions 460‐465) 65, 66. This short region of Env is extremely variable, and laden with insertions and deletions to the extent that it is extremely difficult to align in a meaningful way.…”

Section: Antibody Epitope Diversitymentioning

confidence: 99%

Polyvalent vaccine approaches to combat HIV‐1 diversity

Korber

Hraber

Wagh

et al. 2017

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.

“…This analysis yielded hundreds of new VRC01‐class antibody sequences, with lineage analysis allowing the tracing back to earlier developmental intermediates. This initial application was aided by the sequence of VRC‐PG04, a VRC01‐class antibody identified by probe sorting of donor 74 B cells 9. The results appeared promising enough that we undertook the de novo identification of VRC01‐class antibodies in a new donor, C38, from which no VRC01‐class antibodies were known.…”

Section: Antibodyomics1mentioning

confidence: 99%

“…The effects of antibody interface mutants for three VRC01‐class antibodies [VRC01, VRC03 40, and VRC‐PG04 9] on HIV‐1 gp120 binding were quantified by surface‐plasmon resonance (SPR) measurements. By using FEP simulations, we were able to reproduce the experimental changes in binding affinities for alanine mutants to gp120 (average error less than 1 kcal/mole)—the level of accuracy sufficient to provide meaningful prospective predictions of binding free energies for antibody improvement.…”

Section: Antibodyomics8mentioning

confidence: 99%

“…Our description is not intended to represent a comprehensive summary of the field; rather, we have been asked by the editors of this volume to synthesize key aspects and to focus on our specific contributions and ideas. The majority of the Antibodyomics technologies incorporate data generated by massively parallel next‐generation sequencing (NGS) of B‐cell transcripts to enhance the resolution of the genetic information underlying antibody development 5, 6, 7, 8, 9. We have also focused on technologies that allowed increased resolution of function relative to physical characteristics of antibodies and their targets.…”

Section: Introductionmentioning

confidence: 99%

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Antibodyomics: bioinformatics technologies for understanding B‐cell immunity to HIV‐1

Kwong

Chuang

DeKosky

et al. 2017

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SummaryNumerous antibodies have been identified from HIV‐1‐infected donors that neutralize diverse strains of HIV‐1. These antibodies may provide the basis for a B cell‐mediated HIV‐1 vaccine. However, it has been unclear how to elicit similar antibodies by vaccination. To address this issue, we have undertaken an informatics‐based approach to understand the genetic and immunologic processes controlling the development of HIV‐1‐neutralizing antibodies. As DNA sequencing comprises the fastest growing database of biological information, we focused on incorporating next‐generation sequencing of B‐cell transcripts to determine the origin, maturation pathway, and prevalence of broadly neutralizing antibody lineages (Antibodyomics1, 2, 4, and 6). We also incorporated large‐scale robotic analyses of serum neutralization to identify and quantify neutralizing antibodies in donor cohorts (Antibodyomics3). Statistical analyses furnish another layer of insight (Antibodyomics5), with physical characteristics of antibodies and their targets through molecular dynamics simulations (Antibodyomics7) and free energy perturbation analyses (Antibodyomics8) providing information‐rich output. Functional interrogation of individual antibodies (Antibodyomics9) and synthetic antibody libraries (Antibodyomics10) also yields multi‐dimensional data by which to understand and improve antibodies. Antibodyomics, described here, thus comprise resolution‐enhancing tools, which collectively embody an information‐driven discovery engine aimed toward the development of effective B cell‐based vaccines.