Two papers published in Science Express today are receiving extensive coverage in the mainstream media. The studies, conducted by researchers at the NIH’s Vaccine Research Center (VRC), reveal the discovery of three new broadly neutralizing antibodies, one of which has activity against 91% of the viruses in a panel containing 190 different HIV variants from every known clade. The Wall Street Journal has an excellent article covering the research by Mark Schoofs. The antibodies are named VRC01, VRC02 and VRC03, and it is VRC01 that has the greatest breadth and potency of neutralization.
The work bears some similarities to the discovery of two broadly neutralizing antibodies reported last year by researchers associated with the International AIDS Vaccine Initiative (IAVI). Those antibodies, PG9 and PG16, neutralized around 70-80% of a similar panel of HIV variants. One important difference is that in the second paper published today, a VRC team led by Peter Kwong provides a detailed description of the target of VRC01 (the exact targets of PG9 and PG16 have not yet been uncovered). VRC01 targets a part of the HIV envelope protein that binds to the CD4 receptor, and the breadth of neutralization indicates that this part of the virus is highly conserved.
Kwong’s research group also looks in detail at the B cell responsible for making VRC01, which was sampled from an African American gay man with HIV infection. Importantly, the antibody-producing genes in the B cell do not appear to be rare or unusual, suggesting that it should be possible to prompt production of VRC01-like antibodies in uninfected people – if the right vaccine can be designed. However, the paper also shows that the B cell had undergone an unusually extensive process of “affinity maturation.” This process involves the stepwise accumulation of mutations (or deletions) in the B cell’s antibody-producing genes, resulting in the production of an antibody that is much better at glomming onto its target than the one the B cell started out producing. In fact, when the researchers reverted all the mutations that had occurred during affinity maturation (there were 66 in total), the antibody that was produced did not have any neutralizing activity.
In sum, the new VRC data appears to represent another significant step forward on the path toward an antibody-based HIV vaccine. It was once unclear whether broad neutralization of HIV by antibodies was possible at concentrations that could be achieved by vaccination, but the discovery of VRC01, PG9, PG16 and several other similarly potent candidates has addressed this uncertainty. The next challenge – and it is not insignificant – involves designing vaccines that can induce similar antibodies. In the case of VRC01, this will also require trying to recapitulate the complex process of B cell affinity maturation that led to the generation of the antibody. A more typical number of mutations associated with affinity maturation is around nine, so the 66 changes that led to the production of VRC01 may be a difficult path to retrace.
UPDATE: Heidi Ledford's story at Nature News provides additional information on the targeting and affinity maturation issues related to VRC01.
Science Express, Published Online July 8, 2010
Science DOI: 10.1126/science.1187659
REPORTS
Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1
Xueling Wu,1,* Zhi-Yong Yang,1,* Yuxing Li,1,* Carl-Magnus Hogerkorp,1, William R. Schief,4 Michael S. Seaman,5 Tongqing Zhou,1 Stephen D. Schmidt,1 Lan Wu,1 Ling Xu,1 Nancy S. Longo,1 Krisha McKee,1 Sijy O’Dell,1 Mark K. Louder,1 Diane L. Wycuff,1 Yu Feng,1, Martha Nason,2 Nicole Doria-Rose,3 Mark Connors,3 Peter D. Kwong,1 Mario Roederer,1 Richard T. Wyatt,1,Gary J. Nabel,1, John R. Mascola1
Cross-reactive neutralizing antibodies (NAbs) are found in the sera of many HIV-1–infected subjects, but the virologic basis of their neutralization remains poorly understood. We used knowledge of HIV-1 envelope (Env) structure to develop antigenically resurfaced glycoproteins specific for the structurally conserved site of 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 gp120, an important insight for future HIV-1 vaccine design.
1 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
2 Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
3 Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
4 Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
5 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
* These authors contributed equally to this work.
Science Express, Published Online July 8, 2010
Science DOI: 10.1126/science.1192819
RESEARCH ARTICLES
Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01
Tongqing Zhou,1 Ivelin Georgiev,1,* Xueling Wu,1,* Zhi-Yong Yang,1,* Kaifan Dai,1 Andrés Finzi,2 Young Do Kwon,1 Johannes Scheid,3 Wei Shi,1 Ling Xu,1 Yongping Yang,1 Jiang Zhu,1 Michel C. Nussenzweig,3 Joseph Sodroski,2,4 Lawrence Shapiro,1,5 Gary J. Nabel,1 John R. Mascola,1 Peter D. Kwong1
During HIV-1 infection, antibodies are generated against the region of the viral gp120 envelope glycoprotein that binds CD4, the primary receptor for HIV-1. Among these antibodies, VRC01 achieves broad neutralization of diverse viral strains. Here, we determine the crystal structure of VRC01 in complex with an HIV-1 gp120 core. VRC01 partially mimics CD4 interaction with gp120. A shift from the CD4-defined orientation, however, focuses VRC01 onto the vulnerable site of initial CD4 attachment, allowing it to overcome the glycan and conformational masking that diminishes the neutralization potency of most CD4-binding-site antibodies. To achieve this recognition, VRC01 contacts gp120 mainly through V-gene–derived regions substantially altered from their genomic precursors. Partial receptor mimicry and extensive affinity maturation thus facilitate neutralization of HIV-1 by natural human antibodies.
1 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
2 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Pathology, Division of AIDS, Harvard Medical School, Boston, MA 02115, USA.
3 Laboratory of Molecular Immunology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
4 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
5 Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
* These authors contributed equally to this work.
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