Over the past couple of years, several new antibodies capable of neutralizing a broad array of HIV isolates have been discovered. As mentioned in prior posts about these discoveries, one common feature of these antibodies is that the B cells that produce them have undergone an unusual degree of somatic hypermutation—a process in which the cell’s antibody-producing genetic code is progressively revised in order to increase the affinity of the antibody for its target. The genetic code that the B cell starts out with is called the germline sequence, and it is typically altered by around 5-15% to produce antibodies against common infections, whereas this figure ranges from 19-46% for the broadly neutralizing antibodies against HIV that have been identified. Antibodies targeting the part of the HIV envelope that binds to the CD4 receptor, such as the recently discovered VRC01, are at the extreme end of this scale (showing sequence alterations of 40-46%).
Yesterday in Science Express, researchers from the Vaccine Research Center (VRC), the Center for HIV/AIDS Vaccine Immunology (CHAVI) and the International AIDS Vaccine Initiative (IAVI) published the latest results from their collaborative effort to better understand how these antibodies are generated. The work involves analyses of mind-boggling numbers of B cell genetic sequences, and identifies several new broadly neutralizing antibodies from infected individuals that target HIV’s CD4 binding site. Of potential importance for vaccine design, the B cell sequences that give rise to the antibodies are not uncommon, and although a similarly extensive degree of somatic hypermutation is involved in their generation, it appears that the mutations do not have to be exactly the same to produce structurally similar antibodies. The researchers are hopeful that these data can be used as a map for guiding the development of broadly neutralizing antibodies using vaccines.
NIAID Press Release: NIH-Led Team Maps Route for Eliciting HIV Neutralizing Antibodies
Published Online 11 August 2011
Science DOI: 10.1126/science.1207532
Xueling Wu1,*, Tongqing Zhou1,*, Jiang Zhu1,*, Baoshan Zhang1, Ivelin Georgiev1, Charlene Wang1, Xuejun Chen1, Nancy S. Longo1, Mark Louder1, Krisha McKee1, Sijy O’Dell1, Stephen Perfetto1, Stephen D. Schmidt1, Wei Shi1, Lan Wu1, Yongping Yang1, Zhi-Yong Yang1, Zhongjia Yang1, Zhenhai Zhang1,2, Mattia Bonsignori3, John A. Crump4,5, Saidi H. Kapiga6, Noel E. Sam5,6, Barton F. Haynes3, Melissa Simek7, Dennis R. Burton8, Wayne C. Koff7, Nicole Doria-Rose9, Mark Connors9, NISC Comparative Sequencing Program10, James C. Mullikin10, Gary J. Nabel1, Mario Roederer1, Lawrence Shapiro1,2, Peter D. Kwong1,†, John R. Mascola1
1 Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA.
2 Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
3 The Duke Human Vaccine Institute, Duke University School of Medicine, and Duke University Medical Center, Durham, NC 27710, USA.
4 Division of Infectious Diseases and International Health, Department of Medicine, and Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
5 Christian Medical Center and Kilimanjaro Christian Medical College, Tumaini University, Moshi, Tanzania.
6 Kilimanjaro Reproductive Health Programme, Moshi, Tanzania.
7 International AIDS Vaccine Initiative (IAVI), New York, NY 10038, USA.
8 Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, and Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02129, USA.
9 Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
10 NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
* These authors contributed equally to this work.
Antibody VRC01 is a human immunoglobulin that neutralizes ~90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1–infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of antibody–heavy chain maturation, confined to the IGHV1-2*02 lineage, involving dozens of somatic changes, and capable of pairing with different light chains. Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies thus involves the evolution of antibodies to a highly affinity-matured state required to recognize an invariant viral structure, with lineages defined from thousands of sequences providing genetic roadmaps of their development.