The rationally-designed immunogens developed in Projects 1 and 2 and produced in Core B will be tested in vivo in this Core for their ability to induce Abs in rabbits and/or non-human primates that are broadly reactive against HIV-1 isolates of different clades. The experiments will utilize an established DNA prime/protein boost protocol in which the DNA priming constructs will include Env genes, and the boosting constructs will consist of the V2-scaffold immunogen(s) and/or the QNE-scaffold immunogen(s). The work in Core C is divided into two specific aims:
Aim 1. To induce broad, potent, and long-lasting functional Ab responses in rabbits using rationally designed V2-scaffold immunogens as protein boosts subsequent to priming with Env genes. V2/V3 QNE-scaffold immunogens can only be tested in non-human primates because a) rabbits have not been shown to produce Abs carrying CDR H3 regions of the length needed for QNE-specific Abs, and b) it is not know if rabbits possess the immunoglobulin genes required to encode these Abs, whereas we have shown that SHIV-infected NHPs can produce QNE Abs. Thus, the V2/V3 QNE-scaffold immunogens will be tested in NHPs. In contrast, the V2-scaffold immunogens will first be tested in rabbits. To qualify for testing in NHPs, the V2-specific Ab responses achieved in rabbits will need to meet one or more of the following criteria: (a) Induction of Abs that neutralize the majority of Tier 1 pseudoviruses in the TZM.bl assay with titers better than 1:50;(b) Induction of Abs that neutralize >25% of Tier 2 pseudoviruses from at least two clades with titers better than 1:20 in at least one of the three neutralization assays used;(c) Induction of Abs that mediate additional anti-viral functions, and/or display neutralizing or other anti-viral activities against SHIVSFI62P3- Aim 2. To induce broad, potent, long-lasting and protective Ab responses in non-human primates using rationally designed V2- and/or V2/V3 QNEscaffold immunogens as protein boosts subsequent to priming with Env genes.

Public Health Relevance

Experiments performed by this Animal Studies Core C are essential to the success of the entire HIVRAD, as animal testing will be performed in this Core to identify which immunogens and immunization protocols are best able to induce antibodies and protect against infection with HIV-1 in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
1P01AI100151-01
Application #
8307164
Study Section
Special Emphasis Panel (ZAI1-JBS-A (J1))
Project Start
Project End
Budget Start
2012-08-15
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$630,466
Indirect Cost
$210,512
Name
New York University
Department
Type
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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