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Review
. 2018 Sep 5;15(1):61.
doi: 10.1186/s12977-018-0443-0.

Development of broadly neutralizing antibodies in HIV-1 infected elite neutralizers

Elise Landais  1   2   3 , Penny L Moore  4   5   6
Affiliations
Review

Development of broadly neutralizing antibodies in HIV-1 infected elite neutralizers

Elise Landais et al. Retrovirology. .

Abstract

Broadly neutralizing antibodies (bNAbs), able to prevent viral entry by diverse global viruses, are a major focus of HIV vaccine design, with data from animal studies confirming their ability to prevent HIV infection. However, traditional vaccine approaches have failed to elicit these types of antibodies. During chronic HIV infection, a subset of individuals develops bNAbs, some of which are extremely broad and potent. This review describes the immunological and virological factors leading to the development of bNAbs in such "elite neutralizers". The features, targets and developmental pathways of bNAbs from their precursors have been defined through extraordinarily detailed within-donor studies. These have enabled the identification of epitope-specific commonalities in bNAb precursors, their intermediates and Env escape patterns, providing a template for vaccine discovery. The unusual features of bNAbs, such as high levels of somatic hypermutation, and precursors with unusually short or long antigen-binding loops, present significant challenges in vaccine design. However, the use of new technologies has led to the isolation of more than 200 bNAbs, including some with genetic profiles more representative of the normal immunoglobulin repertoire, suggesting alternate and shorter pathways to breadth. The insights from these studies have been harnessed for the development of optimized immunogens, novel vaccine regimens and improved delivery schedules, which are providing encouraging data that an HIV vaccine may soon be a realistic possibility.

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Figures

Fig. 1
Fig. 1
Identification of HIV-1 elite neutralizers and epitope mapping. Typically, plasma samples collected from HIV-1 infected individuals are tested for neutralization against panels of global env-pseudotyped viruses. Volunteers are ranked based on a their neutralization breadth and potency. The broad neutralizing activity in the top neutralizers is then mapped for epitope specificity using mutant viruses, and peptide and protein adsorptions. Reproduced with permission from [21]
Fig. 2
Fig. 2
HIV and bNAb co-evolution studies. Longitudinal PBMCs samples are used for bNAb isolation (by functional screening of single B-cell micro-culture and/or antigen-specific cell sorting) and NGS sequencing of the memory B-cell repertoire. In parallel, corresponding longitudinal plasma samples are used to sequence and clone viral env variants. NGS data are used to re-construct the Ab and Env phylogenies over the course of infection. Cloned bNAbs and Env variants are functionally and structurally evaluated, both individually and in complex, to retrace the evolution of the virus-antibody interaction from elicitation to acquisition of neutralization breadth and inform vaccine design
Fig. 3
Fig. 3
Factors associated with bNAb development, and how to leverage these factors in vaccination strategies. During infection, both the virus and the antibodies evolve rapidly through relatively random genetic variation. BNAb development is associated with factors likely increasing the chances of a productive encounter between rare low-affinity B-cells with unusual features, and rare Env variants with unusual characteristics. High antigen concentration (1), larger B cell repertoire (2a), antigen diversity (3), and increased germinal center activity (2b) are all factors that may be enhanced in vaccine design
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