Elicitation of HIV-1-neutralizing antibodies against the CD4-binding site

Abstract

Purpose of review: The HIV-1 site of binding for the CD4 receptor has long attracted attention as a potential supersite of vulnerability to antibody-mediated neutralization. We review recent findings related to effective CD4-binding site antibodies isolated from HIV-1-infected individuals and discuss implications for immunogen design.

Recent findings: Highly effective CD4-binding site antibodies such as antibody VRC01 have the ability to neutralize over 90% of circulating HIV-1 strains. Sequence and structural analysis of these antibodies from over half a dozen HIV-1-infected donors reveals remarkable similarity in their ontogenies and their modes of recognition, all of which involve mimicry of CD4 receptor by antibody-heavy chain. Meanwhile, other effective CD4-binding site neutralizers such as antibody CH103 have been shown to utilize a different mode of recognition, with next-generation sequencing of both virus and antibody suggesting co-evolution to drive the development of antibody-neutralization breadth.

Summary: The nexus of information concerning the CD4-binding site and its recognition by human antibodies capable of effective neutralization has expanded remarkably in the last few years. Although barriers are substantial, new insights from donor-serum responses, atomic-level structures of antibody-Env complexes, and next-generation sequencing of B-cell transcripts are invigorating vaccine-design efforts to elicit effective CD4-binding site antibodies.

Figure 1. Structural details of the HIV-1 viral spike and its interaction with the CD4 receptor

Although substantial effort has been expended to determine the structure of the HIV-1 spike, unliganded or in complex with CD4, surprisingly few atomic-level details are known. The overall architecture of the unliganded and CD4-bound forms of the HIV-1 spike were determined by cryo-electron tomography at ~20 A resolution by Subramanian and colleagues [5] and are shown here, fitted with known atomic-level structures. On the unliganded spike (left image), only the outer domain and the V1/V2 regions are known [6-9], as the inner domain and bridging sheet regions likely assume conformations differ from those determined in currently available crystal structures [10-12]. On the CD4-bound spike (right), the entire gp120 has been determined in various complexes with 2-domain CD4 [13-16], and these have been placed in the context of the entire 4-domain extracellular portion of CD4 [17].

Figure 2. Antibody recognition at the CD4-binding site of HIV-1 gp120

The structures of gp120 in complex with CD4-binding site antibodies (a-c) or CD4 (d) are shown in cartoon diagrams with HIV-1 gp120 colored in gray, antibody-heavy chain colored in green, antibody-light chain colored in blue, and CD4 colored in yellow. The epitopes of antibodies are highlighted in red on gp120 surface with the outer domain-contact site for CD4 outlined in yellow (a-c). The site of vulnerability defined as the outer domain contact of CD4 on HIV-1 gp120 is shown as a yellow surface (d). Effective neutralizers, either VH1-2-derived VRC01-class antibodies [6,31] or canonical CDR H3-utilizing antibodies [30,32], target this vulnerable site with high precision. In contrast, non-neutralizing CD4-binding site antibodies, such as b13 and F105 [33], only partially contact the site of vulnerability and induce significant conformational changes on monomeric gp120.

Figure 3. Immunogens to elicit CD4-binding site–directed neutralizing antibodies

A number of HIV-1 envelope glycoprotein oligomers have been tested for their ability to elicit neutralizing antibodies (as reviewed in [41]), and we highlight here a particularly promising soluble HIV-1 gp140 “SOSIP” variant [8,9,42-44], which is displayed with electron microscopy-determined density and modeled gp120-outer domain. Other promising HIV-1 immunogens include core HIV-1 gp120 ([45,46], outer domain gp120 (OD4.2.2) [47,48], b12-epitope scaffold [49],and b12-epitope peptide [50]••, which are shown in cartoon and semi-transparent surface representation (grey), with CD4-, VRC-PG04-, or b12-sites of binding highlighted in red. While vaccination with HIV-1 Env immunogens containing the CD4-binding site and capable of binding broadly neutralizing antibodies have in select cases elicited encouraging titers of HIV-1 neutralizing antibodies (for example, [50]••), such neutralization remains to be confirmed at the monoclonal antibody level.

Figure 4. Schematic of a general procedure for immunogen design for a target antibody class, and current progress for the VRC01 class

(top) Initial definition of target antibody class. By using known antibody templates (based on both identified antibodies and their structures in complex with antigen), sera can be interrogated for antibodies from the given class can and selected for next-generation sequencing analysis of the antibodyome. (middle) Analysis of antibody ontogeny for delineation of germline, intermediate, and mature antibodies. (bottom) Design of immunogens for elicitation (germline immunogen), guided affinity maturation (intermediate immunogen), and clonal expansion (expansion immunogen) of the class antibodies. Germline immunogens should possess sufficient affinity to allow antibody elicitation, while the increased affinity of the intermediate and expansion immunogens for their target antibodies versus less mutated variants can effect maturation and clonal expansion.