HIV-1 Vaccines Based on Antibody Identification, B Cell Ontogeny, and Epitope Structure

Abstract

HIV-1 vaccine development has been stymied by an inability to induce broadly reactive neutralizing antibodies to the envelope (Env) trimer, the sole viral antigen on the virion surface. Antibodies isolated from HIV-1-infected donors, however, have been shown to recognize all major exposed regions of the prefusion-closed Env trimer, and an emerging understanding of the immunological and structural characteristics of these antibodies and the epitopes they recognize is enabling new approaches to vaccine design. Antibody lineage-based design creates immunogens that activate the naive ancestor-B cell of a target antibody lineage and that mature intermediate-B cells toward effective neutralization, with proof of principle achieved with select HIV-1-neutralizing antibody lineages in human-gene knock-in mouse models. Epitope-based vaccine design involves the engineering of sites of Env vulnerability as defined by the recognition of broadly neutralizing antibodies, with cross-reactive neutralizing antibodies elicited in animal models. Both epitope-based and antibody lineage-based HIV-1 vaccine approaches are being readied for human clinical trials.

Techniques to Study Antigen-Specific B Cell Responses

“…For HIV-1, the discovery of broadly neutralizing antibodies (bnAbs) that protect against infection across diverse viral isolates has intensified efforts to understand the developmental pathway of the rare B cells that produce these antibodies (6)(7)(8)(9). Insights into the ontogeny of these rare B cells could allow the design of a step-wise vaccine regimen that stimulates the germ-line precursor to expand and mature to produce circulating bnAbs which could protect against HIV acquisition (10,11). For RSV, stabilized versions of the fusion (F) protein in the pre-fusion conformation have led to insights in the B cell's response to infection and has generated potentially safer and more efficacious vaccine candidates (12,13).…”

Broadly resistant HIV-1 against CD4-binding site neutralizing antibodies

“…Among the bnAbs isolated to date, those targeting the CD4bs are the most abundant and thoroughly studied as they disrupt the first and crucial step of viral interaction with the cellular receptor CD4 [3,4,17,18]. In this step, the trimeric envelope glycoprotein, composed of gp120 and gp41, binds with the target cell through the receptor CD4, with either CCR5 or CXCR4 as co-receptor [19][20][21].…”

“…Resistance is largely attributed to mutated residues within the epitopes or steric hindrance imposed by the bulky side-chain or glycan shield of the mutated residues, and is largely correlated with reduced binding avidity of the antibody to the quaternary trimeric envelope protein expressed on the PLOS Pathogens | https://doi.surface of the transfected cells. Treatment strategies based on the CD4bs bnAbs therefore must overcome such resistance to achieve optimal clinical outcomes.Recent scientific advances have identified a growing number of broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus type I (HIV-1), providing promising candidates for HIV-1 prevention and treatment [1][2][3][4][5]. Compared with bnAbs isolated in earlier studies, these bnAbs demonstrated broader and more potent activity against global HIV-1 panels and displayed impressive safety and efficacy profiles for therapeutic applications in a number of animal models and human clinical trials [1,[6][7][8][9][10][11].…”

“…Broadly speaking, these bnAbs recognize six major "vulnerable sites" on the HIV-1 envelope glycoprotein gp160 (gp120 and gp41), which are (1) the CD4-binding site (CD4bs), (2) the V1V2 apex, (3) the V3 glycan, (4) the fusion peptide (FP), (5) subunit interface and (6) membrane proximal external region (MPER) of gp41[1-5]. These bnAbs neutralize HIV-1 by blocking viral entry into the target cells, although additional effector functions are likely at play, particularly in the context of in vivo infection and clinical application[1, 12-16].Among the bnAbs isolated to date, those targeting the CD4bs are the most abundant and thoroughly studied as they disrupt the first and crucial step of viral interaction with the cellular receptor CD4 [3,4,17,18]. In this step, the trimeric envelope glycoprotein, composed of gp120 and gp41, binds with the target cell through the receptor CD4, with either CCR5 or CXCR4 as co-receptor [19][20][21].…”

Functional characterization and lineage analysis of broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics

“…Antigenic mismatch between vaccine and circulating strains impacted vaccine efficacy (Juraska et al, 2018), highlighting the importance of rational selection of vaccine components. An alternative strategy, largely exemplified by vaccine development efforts for HIV (Kwong & Mascola, 2018) and respiratory syncytial virus (RSV) (Crank et al, 2019), relies on identifying antibodies with desirable properties and precisely defining their epitopes to guide epitope-based vaccine design (Graham, Gilman, & McLellan, 2019). For antigenically diverse viruses such as DENV, a conserved epitope-based vaccine strategy to elicit a broad and potent monoclonal neutralizing antibody response could mitigate the challenge of selecting representative vaccine strains.…”