A cluster of overlapping quaternary neutralizing epitopes (QNEs) is present on the HIV-1 virus protein envelope spikes. They are composed of portions of the V2 and V3 variable regions of gpl 20 and appear to be stabilized by the intermolecular interactions in the gpl 20 trimer. The goal of Project 2 of this HIVRAD is to create immunogens that can elicit potent neutralizing anti-QNE Abs. Anti-QNE monoclonal antibodies (mAbs) are extremely potent, being 1,000-fold more potent than previously described HIV mAbs. Our team is in a unique position to pursue and achieve this goal since: (i) we have generated and characterized >100 human anti-HIV mAbs, (ii) we described the first human QNE mAb, 2909, (iii) we have successfully developed and used a structure-based rational immunogen design strategy for the production of a panel of V3-scaffold immunogens, and (iv) we have shown these rationally designed immunogens to be capable of inducing cross-clade neutralizing Abs in animals. It is a natural and logical extension of our work to apply our rational design strategy to the development of QNE-scaffold immunogens. Having already determined the crystal structures of two QNE mAbs, human mAb 2909 and rhesus mAb 2.5B, and having created a 3D structural model of the QNE in the context of gpl 20, we now propose to design, engineer, synthesize and test the immunogenicity of QNE-scaffold proteins. We will, in Aim 2.1. refine our model of the QNE by investigating the antigen-antibody interactions of QNE mAbs using biophysical and biochemical methods.
In Aim 2. 2. we will design and create QNE-scaffold proteins by identifying suitable protein scaffolds and grafting the components of QNE into them. After testing for antigenicity with appropriate mAbs and HIV+ sera, we will, in Aim 2.3, use the recombinant QNE-scaffold proteins to select and characterize new QNE mAbs.
In Aim 2. 4, we will test the recombinant QNE antigens for immunogenicity in non-human primates to determine their ability to induce potent Abs with protective anti-viral functions. These studies will potentially provide an invaluable reagent for inclusion in an HIV/AIDS vaccine.

Public Health Relevance

Current data suggest a vaccine targeting quaternary structures on the surface protein spikes of HIV could provide potent protection against infection. An immunogen, rationally designed to mimic the epitope cluster recognized by extremely potent monoclonal antibodies specific for these quaternary structures, should constitute an important component of an efficacious vaccine.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-JBS-A (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York University
New York
United States
Zip Code
Wu, Xueling; Kong, Xiang-Peng (2016) Antigenic landscape of the HIV-1 envelope and new immunological concepts defined by HIV-1 broadly neutralizing antibodies. Curr Opin Immunol 42:56-64
McFarren, Alicia; Lopez, Lillie; Williams, Dionna W et al. (2016) A fully human antibody to gp41 selectively eliminates HIV-infected cells that transmigrated across a model human blood brain barrier. AIDS 30:563-72
Hessell, Ann J; McBurney, Sean; Pandey, Shilpi et al. (2016) Induction of neutralizing antibodies in rhesus macaques using V3 mimotope peptides. Vaccine 34:2713-21
Jiang, Xunqing; Totrov, Max; Li, Wei et al. (2016) Rationally Designed Immunogens Targeting HIV-1 gp120 V1V2 Induce Distinct Conformation-Specific Antibody Responses in Rabbits. J Virol 90:11007-11019
Zolla-Pazner, Susan (2016) Non-neutralizing antibody functions for protection and control HIV in humans and SIV and SHIV in non-human primates. AIDS 30:2551-2553
Zolla-Pazner, Susan; Cohen, Sandra Sharpe; Boyd, David et al. (2016) Structure/Function Studies Involving the V3 Region of the HIV-1 Envelope Delineate Multiple Factors That Affect Neutralization Sensitivity. J Virol 90:636-49
Moody, M Anthony; Gao, Feng; Gurley, Thaddeus C et al. (2015) Strain-Specific V3 and CD4 Binding Site Autologous HIV-1 Neutralizing Antibodies Select Neutralization-Resistant Viruses. Cell Host Microbe 18:354-62
Pan, Ruimin; Chen, Yuxin; Vaine, Michael et al. (2015) Structural analysis of a novel rabbit monoclonal antibody R53 targeting an epitope in HIV-1 gp120 C4 region critical for receptor and co-receptor binding. Emerg Microbes Infect 4:e44
Kwon, Young Do; Pancera, Marie; Acharya, Priyamvada et al. (2015) Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env. Nat Struct Mol Biol 22:522-31
Pan, Ruimin; Gorny, Miroslaw K; Zolla-Pazner, Susan et al. (2015) The V1V2 Region of HIV-1 gp120 Forms a Five-Stranded Beta Barrel. J Virol 89:8003-10

Showing the most recent 10 out of 36 publications