Identification of New Broadly Reactive HIV-1–Specific Monoclonal Antibodies

Dan H. Barouch, MD, PhD

Disclosures

AIDS Clinical Care 

In This Article

Abstract and Introduction

Abstract

One monoclonal antibody neutralizes >90% of worldwide circulating HIV-1 isolates.

Introduction

One of the major roadblocks in the development of an HIV-1 vaccine has been the inability of vaccine immunogens to elicit broadly reactive HIV-1 Env–specific neutralizing antibodies. Some investigators have questioned whether the human immune system is even capable of generating such broadly reactive antibodies, given the extent of virus variability worldwide and the immune evasion tactics employed by the virus.

Researchers now describe the isolation and structural analysis of a new broadly reactive HIV-1 Env–specific monoclonal antibody (mAb) called VRC01, which was derived from an HIV-1–infected individual with broadly reactive serum neutralizing antibodies. Prior work from these investigators and others identified the CD4 binding site as a largely conserved site on HIV-1 Env that was the target of a different mAb (b12). VRC01 also targets the CD4 binding site, but it exhibits greater breadth, neutralizing >90% of HIV-1 isolates circulating worldwide. Moreover, it neutralizes these isolates with substantial potency. Interestingly, VRC01 partially mimics CD4 binding to HIV-1 Env, but the crystal structure shows that its orientation differs slightly from that of CD4, allowing it to target the vulnerable site of initial CD4 binding very precisely. Molecular sequence analysis also reveals that the variable loops of VRC01 have undergone extensive somatic hypermutation and affinity maturation — factors that likely contribute to the breadth and potency of this mAb.

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