Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01

  title={Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01},
  author={Tongqing Zhou and Ivelin S. Georgiev and Xueling Wu and Zhi-Yong Yang and Kaifan Dai and Andr{\'e}s Finzi and Young Do Kwon and Johannes F Scheid and Wei Shi and Ling Xu and Yongping Yang and Jiang Zhu and Michel C. Nussenzweig and Joseph G. Sodroski and Lawrence Shapiro and Gary J. Nabel and John R. Mascola and Peter D. Kwong},
  pages={811 - 817}
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… 
A Boost for HIV Vaccine Design
The isolation of particularly potent monoclonal broadly neutralizing antibodies using a novel selection strategy, and the crystal structure of the most effective of these antibodies in complex with its target gp120, a viral envelope glycoprotein are solved.
Structural Features of Broadly Neutralizing Antibodies and Rational Design of Vaccine.
  • T. Zhou, Kai Xu
  • Biology
    Advances in experimental medicine and biology
  • 2018
Accumulating information on antibody recognition of HIV-1 Env and ontogenesis suggests distinct pathways for generating effective HIV- 1 vaccine based on specific antibody ontogeny or specific target site.
Structural survey of HIV-1-neutralizing antibodies targeting Env trimer delineates epitope categories and suggests vaccine templates
All 206 broadly neutralizing antibody-HIV-1 Env complexes in the PDB were analyzed with resolution suitable to define their interaction chemistries and the CD4-binding site antibody IOMA appeared to be a promising candidate for lineage-based vaccine design.
A Derivative of the D5 Monoclonal Antibody That Targets the gp41 N-Heptad Repeat of HIV-1 with Broad Tier-2-Neutralizing Activity
D5_AR, a more potent variant of the anti-NHR antibody D5, is engineered and established its ability to inhibit HIV-1 strains that are more difficult to neutralize and are more representative of circulating strains (tier-2 strains), which bolster efforts to target the gp41 NHR and the PHI for vaccine development.
Antibody epitope exposure and neutralization of HIV-1.
Increased understanding of antibody epitope exposure on Env should provide new impulses for efforts to elicit nAbs that can protect against HIV-1 infection, and Crystal structures of Env-derived antigens, most in complex with antibodies, along with structure-function studies and molecular modeling, have provided significant further insight.
Reverse Immunology Approach to Define a New HIV-gp41-Neutralizing Epitope
These findings provide new insights into the molecular design of immunogens to elicit antibodies with neutralizing properties and binding and molecular docking studies revealed that F8 interacts similarly with W614A-3S and a Mim_F8-1 mimotope, despite their lack of sequence homology, suggesting structural mimicry.
Delineating Antibody Recognition in Polyclonal Sera from Patterns of HIV-1 Isolate Neutralization
Serum characterization and antibody isolation are transforming the understanding of the humoral immune response to viral infection, and it is shown that epitope specificities of HIV-1–neutralizing antibodies in serum can be elucidated from the serum pattern of neutralization against a diverse panel ofAIDS-1 isolates.
How HIV-1 entry mechanism and broadly neutralizing antibodies guide structure-based vaccine design
This work highlights consideration of the appropriate structural context from the HIV-1-entry mechanism and extraordinary progress with replicating template B-cell ontogenies in the structure-based design of vaccine immunogens and immunization regimens.
Elicitation of antibody responses against the HIV-1 gp41 Membrane Proximal External Region (MPER)
This dissertation focuses on the gp41 MPER segment given its highly conserved amino acid sequence among all HIV-1 clades and viral strain isolates and essential function in Env-mediated fusion and HIV entry.


Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1
Three broadly neutralizing antibodies are identified, 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.
Structural Basis of Immune Evasion at the Site of CD4 Attachment on HIV-1 gp120
Co-crystal structures for two poorly neutralizing, CD4–binding site (CD4BS) antibodies, F105 and b13, in complexes with gp120 are determined, finding these conformations to be poorly compatible with the viral spike.
Structural definition of a conserved neutralization epitope on HIV-1 gp120
A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1.
Maturation Pathways of Cross-Reactive HIV-1 Neutralizing Antibodies
Evidence is presented that a germline-like b12 (monovalent and bivalent scFv as an Fc fusion protein or IgG) lacks measurable binding to an Env as measured by ELISA with a sensitivity in the μM range and that identifying antibodies that are intermediates in the pathways to maturation could help design novel vaccine immunogens to guide the immune system for their enhanced elicitation.
Analysis of Memory B Cell Responses and Isolation of Novel Monoclonal Antibodies with Neutralizing Breadth from HIV-1-Infected Individuals
This study reveals that by using appropriate screening methods, a large proportion of memory B cells can be isolated that produce mAbs with HIV-1 neutralizing activity, and three of these mAbs show unusual breadth of neutralization and therefore add to the current panel of HIV- 1 neutralizing antibodies with potential for passive protection and template-based vaccine design.
The antigenic structure of the HIV gp120 envelope glycoprotein
The spatial organization of conserved neutralization epitopes on gp120 is described, using epitope maps in conjunction with the X-ray crystal structure of a ternary complex that includes a gp120 core, CD4 and a neutralizing antibody.
Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals
The IgG memory B-cell compartment in the selected group of patients with broad serumneutralizing activity to HIV is comprised of multiple clonal responses with neutralizing activity directed against several epitopes on gp120.
Analysis of Neutralization Specificities in Polyclonal Sera Derived from Human Immunodeficiency Virus Type 1-Infected Individuals
A systematic analysis of the NAb specificities of a panel of HIV-1-positive sera is presented, using methodologies that identify both conformational and continuous neutralization determinants on the HIV-2 Env protein and finds evidence that regions of the gp120 coreceptor binding site may also be a target of neutralizing activity.
Dissecting the Neutralizing Antibody Specificities of Broadly Neutralizing Sera from Human Immunodeficiency Virus Type 1-Infected Donors
Overall, the data suggest that broad neutralization results from more than one specificity in the sera but that the number of these specificities is likely small.