Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1

TLDR

Cross‑reactive neutralizing antibodies are present in many HIV‑1–infected individuals, yet the virologic basis of their activity remains poorly understood. By exploiting HIV‑1 envelope structure, the authors engineered antigenically resurfaced glycoproteins that target the conserved CD4‑binding site, used these probes to isolate CD4bs‑reactive sera and individual B cells from an infected donor. Cloning immunoglobulin genes from these B cells yielded three monoclonal antibodies, including somatic variants, that neutralized over 90 % of circulating HIV‑1 isolates, demonstrating that broadly neutralizing activity can be achieved by targeting the CD4‑binding site and informing future vaccine design.

Abstract

Cross-reactive neutralizing antibodies (NAbs) are found in the sera of many HIV-1-infected individuals, but the virologic basis of their neutralization remains poorly understood. We used knowledge of HIV-1 envelope structure to develop antigenically resurfaced glycoproteins specific for the structurally conserved site of initial CD4 receptor binding. These probes were used to identify sera with NAbs to the CD4-binding site (CD4bs) and to isolate individual B cells from such an HIV-1-infected donor. By expressing immunoglobulin genes from individual cells, we identified three monoclonal antibodies, including a pair of somatic variants that neutralized over 90% of circulating HIV-1 isolates. Exceptionally broad HIV-1 neutralization can be achieved with individual antibodies targeted to the functionally conserved CD4bs of glycoprotein 120, an important insight for future HIV-1 vaccine design.