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Genetic and Structural Analyses of Multiple Powerfully Neutralizing HIV Antibodies Reveal Similar Evolutionary Pathways

NIAID intramural scientists previously identified a human antibody capable of neutralizing about 90 percent of circulating strains of HIV. This broadly neutralizing antibody was discovered at the NIAID Dale and Betty Bumpers Vaccine Research Center (VRC) and was thus called VRC01. With this antibody in hand, the researchers sought to determine if antibody VRC01 was unique or if similar broadly neutralizing antibodies develop in other HIV-infected individuals.

Using methods such as monoclonal identification and X-ray crystallography, the researchers found that VRC01 was not unique. Antibodies in other individuals evolved in similar ways to recognize the VRC01-identified site of vulnerability on HIV. The presence of VRC01-like antibodies in other individuals suggests that similar antibodies might be elicited by vaccination. VRC01-like antibodies thus could serve as helpful guides in HIV vaccine design.

The scientists previously found that the genes for VRC01-like antibodies undergo an unusually high number of mutations—70 to 90—between the first draft that codes for a weak antibody and the final version that codes for an antibody that can neutralize HIV.

An in-depth sequence analysis of the genetic transcripts (RNA molecules) that code for VRC01-like antibodies revealed the genetic lineages and pathways by which these antibodies evolve into their mature forms. Defining these pathways provides insights into how to design vaccines that could coach antibody-producing white blood cells to evolve their antibodies from infancy into a mature, HIV-fighting form.

Image of the VRC01 antibody bound to HIV
This image shows the atomic-level protein structure of the antibody VRC01 (blue and green) binding to HIV (grey and red). The precise site of VRC01-HIV binding (red) is a subset of the area that the virus uses to attach to immune cells.
Credit: NIAID


Wu X, Zhou T, Zhu J, Zhang B, Georgiev I, Wang C, Chen X, Longo NS, Louder M, McKee K, O'Dell S, Perfetto S, Schmidt SD, Shi W, Wu L, Yang Y, Yang ZY, Yang Z, Zhang Z, Bonsignori M, Crump JA, Kapiga SH, Sam NE, Haynes BF, Simek M, Burton DR, Koff WC, Doria-Rose NA, Connors M; NISC Comparative Sequencing Program, Mullikin JC, Nabel GJ, Roederer M, Shapiro L, Kwong PD, Mascola JR. Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science. 2011 Sep 16;333(6049):1593-602.​

Last Updated December 28, 2012

Last Reviewed December 28, 2012