Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01
By T. Zhou, Ivelin S. Georgiev, Xueling Wu, Zhi-yong Yang, K. Dai, A. Finzi, Y. Kwon, J. Scheid, Wei Shi, Ling Xu and 8 more. Science, 2010
1,227 citations recorded by the source corpus.
Designer Anti-HIV Developing a protective HIV vaccine remains a top global health priority. One strategy to identify potential vaccine candidates is to isolate broadly neutralizing antibodies from infected individuals and then attempt to elicit the same antibody response through vaccination (see the Perspective by Burton and Weiss). Wu et al. (p. 856, published online 8 July) now report the identification of three broadly neutralizing antibodies, isolated from an HIV-1–infected individual, that exhibited great breadth and potency of neutralization and were specific for the co-receptor CD4-binding site of the glycoprotein 120 (gp120), part of the viral Env spike. Zhou et al. (p. 811, published online 8 July) analyzed the crystal structure for one of these antibodies, VRC01, in complex with an HIV-1 gp120. VRC01 focuses its binding onto a conformationally invariant domain that is the site of initial CD4 attachment, which allows the antibody to overcome the glycan and conformational masking that diminishes the neutralization potency of most CD4-binding-site antibodies. The epitopes recognized by these antibodies suggest potential immunogens that can inform vaccine design. A human antibody achieves broad neutralization by binding the viral site of recognition for the primary host receptor, CD4. 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. We determined the crystal structure of VRC01 in complex with a human immunodeficiency virus 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 immunoglobulin V-gene regions substantially altered from their genomic precursors. Partial receptor mimicry and extensive affinity maturation thus facilitate neutralization of HIV-1 by natural human antibodies.
Subfields: Immunology, Radiology, Nuclear Medicine and Imaging, Virology
View Paper: https://www.semanticscholar.org/paper/53cc5a4573883eab8e3fd86a9428120e14409e13
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Immunology
In Radiology, Nuclear Medicine and Imaging
Citations in the corpus
- Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8 (2016, methodology): “The antigen binding fragments (Fab) of all VRC01-class antibodies were generated by Lys-C (Roche) digestion of IgG as previously described [22].”
- Crystal structure of a soluble cleaved HIV-1 envelope trimer (2013, background): “High-resolution crystal structures of monomeric gp120 have been largely obtained using a core construct stabilized in the CD4-bound conformation and with the V1/V2/V3 elements truncated (1, 3, 8-10).”
- Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9 (2011, neutral): “The epitopes for antibodies b12 and VRC01, for example, are comprised of seven and six independent protein segment”
- Precursor Frequency and Affinity Determine B Cell Competitive Fitness in Germinal Centers, Tested with Germline-Targeting HIV Vaccine Immunogens (2017, background): “Inferred germline-reverted VRC01-class Abs do not measurably bind HIV Env due to the Env glycan shield, among other factors (Zhou et al., 2010).”