Development of broadly neutralizing antibodies from autologous neutralizing antibody responses in HIV infection

Abstract

Purpose of review: Detailed genetic and structural characterization has revealed that broadly neutralizing antibodies (bnAbs) against HIV-1 have unusually high levels of somatic hypermutation, long CDRH3 domains, and the ability to target one of four sites of vulnerability on the HIV-1 envelope (Env) glycoproteins. A current priority is to understand how bnAbs are generated during natural infection, and translate this information into immunogens that can elicit bnAb following vaccination.

Recent findings: Strain-specific neutralizing antibodies can acquire broad neutralizing capacity when the transmitted/founder Env or a specific Env variant is recognized by an unmutated rearranged germline that has the capacity to develop bnAb-like features. This event could be relatively infrequent, as only certain germlines appear to possess inherent features needed for bnAb activity. Furthermore, the glycosylation pattern and diversity of circulating HIV-1 Envs, as well as the state of the B-cell compartment, may influence the activation and maturation of certain antibody lineages.

Summary: Collectively, studies over the last year have suggested that the development of HIV-1 Env immunogens that bind and activate bnAb-like germlines is feasible. However, more information about the features of Env variants and the host factors that lead to breadth during natural infection are needed to elicit bnAbs through immunization.

Figure 1. The pathway to neutralization breadth

Maturation of a CD4bs lineage required somatic hypermutation for both strain-specific and broad neutralizing capacity (19). This is consistent with high levels of somatic hypermutation seen in other CD4bs bnAbs e.g. VRC01. In contrast, V1V2 directed bnAbs selected a germline with preexisting long CDRH3s and had the inherent ability to bind and neutralize the founder virus. Additional levels of somatic hypermutation were needed to mediate broad neutralizing activity (20).

Figure 2. Model for the maturation of strain-specific plasma responses to acquire breadth

Strain-specific antibodies (gray) recognize defined epitopes (shown in blue, in a lock-and-key schematic). These antibodies drive viral escape mutations (represented as multi-colored shapes) within epitopes. The emergence of sequential escape mutations creates multiple immunotypes (or epitope variants) within a single infected subject. Maturation of nAbs to tolerate multiple residues at a given position (e.g. either a triangle or a square) or to recognize a smaller core epitope (e.g. the invariant sphere at the second position within the epitope, highlighted in the gray box) thereby better encompasses the global epitope variants in heterologous viruses (shown on the right), and enables the development of broad neutralization antibodies (red).