Identification and specificity of broadly neutralizing antibodies against HIV

Abstract

Beginning 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.

Keywords: HIV; B cells; monoclonal antibody isolation; neutralization.

Figure 1

Methods for HIV bnAb isolation. (A) mAb isolation by phage library from plasma cells and subsequent phage display to enrich for antigen‐specific clones; (B) mAb isolation by immortalization of total B cells. Propagated cells are then serially diluted and Abs secreted in the supernatant tested for antigen specificity; (C) mAb isolation by single B‐cell culture without immortalization, Abs secreted in the supernatant tested for antigen specificity and Ab sequences obtained; (D) mAb isolation by antigen‐specific single B‐cell FACS. Ab sequences are amplified from each well and tested for antigen specificity

Figure 2

Epitope regions targeted by HIV bnAbs. Model based on the fully glycosylated BG505 SOSIP.664 trimer constructed using PDB: 4ZMJ.103 The gp120 and gp41 subunits are colored light gray and dark grey respectively. The five bnAb epitope regions are labeled as follows: the apex site is colored purple, the high‐mannose patch is colored magenta, the CD4bs is colored green, the gp120‐gp41 region is colored red, and MPER is colored yellow