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

From AIDS Clinical Care
Dan H. Barouch, MD, PhD
Posted: 08/30/2010; AIDS Clinical Care © 2010 Massachusetts Medical Society

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.

Comment
 
Another study published last year described the isolation and characterization of two other new broadly reactive mAbs, PG9 and PG16, which were also derived from an HIV-1–infected individual with broadly reactive serum neutralizing antibodies (Science 2009; 326:285). These mAbs exhibit substantial breadth and potency, and they have been shown to bind to conserved portions of the variable V2 and V3 loops on the intact HIV-1 Env trimer — a previously undescribed epitope that could represent a potential new HIV-1 vaccine target.

Taken together, these studies demonstrate that exceptionally broadly reactive neutralizing antibodies with substantial potency can indeed be generated in HIV-1–infected humans, probably at higher frequencies than previously recognized. As basic research tools, these new mAbs will prove invaluable. Moreover, their identification and characterization may lead to insights into HIV-1 vaccine design by identifying new targets and defining mechanisms of action. A major challenge now is to use this knowledge to improve HIV-1 vaccine immunogens — a daunting task, given how difficult it has been in the past to translate increased understanding of mAbs into improved vaccine immunogens. Nevertheless, these recent advances offer increased hope that an HIV-1 vaccine may indeed be possible.

References

• Wu X et al. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 2010 Jul 8.

• Zhou T et al. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 2010 Jul 8.
 
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