Vaccines are the only feasible tool for effectively controlling the HIV pandemic. However, efforts to produce effective HIV vaccines have not yet been successful. This proposal focuses on an entirely new approach to designing HIV vaccines and will provide data directly applicable to the on-going efforts to develop safe, potent, and effective HIV vaccines. HIV envelope gp120 and gp41 are among the important antigens that must be targeted by the host immune system to fight HIV infection. While many studies have focused on antibodies and cytolytic CDS T cells specific for these antigens, very little work has been done to study CD4 T helper responses which are needed to elicit and maintain effective antibody and CD8 T cell responses. In the majority of HIV infected patients, CD4 T helper responses to gp120 are undetectable. Gp120 also elicits weak lymphoproliferation in HIV-seronegative vaccine recipients. While many factors contribute to the poor CD4 T cell responses to gp120, two factors specifically interfere with class II MHC presentation of gp120 antigens to CD4 T cells: 1) antibodies to the CD4-binding site of gp120 which, upon binding to gp120, hinder gp120 proteolytic processing necessary for class II antigen presentation, and 2) the exceedingly rich glycosylation of gp120 which also deters the processing and presentation of this antigen. The goal of this application is to design gp120 immunogens that overcome the inherent properties of the native gp120 protein that suppress its processing and presentation. We propose to introduce mutations which alter the CD4-binding site or remove the N-glycosylation sites around the T helper epitope sites, or both (Aim 1). The mutated gp120 antigens will be expressed as soluble proteins and as membrane-bound proteins on HIV pseudovirions and analyzed for reactivity with a panel of human anti-gp120 monoclonal antibodies (Aim 2). The mutated antigens will be tested first in vitro for their capacity to stimulate gp120-specific CD4 T cell responses using established human T cell lines and PBMCs (Aim 3). Subsequently, we will use the gp120 plasmids and soluble proteins or pseudovirions for priming and boosting mice, and compare the capacity of the wild type and mutant constructs to elicit anti-gp120 CD4 T cell responses and the effector CDS and antibody responses (Aim 4). These studies will provide information about how to design more immunogenic forms of gp120, how to better stimulate gp120-specific CD4 T cell responses, and how to use the mutated gp120 constructs as HIV vaccines. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI048371-05
Application #
7006235
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Wassef, Nabila M
Project Start
2000-10-01
Project End
2011-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
5
Fiscal Year
2006
Total Cost
$363,000
Indirect Cost
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Weiden, Michael D; Hoshino, Satomi; Levy, David N et al. (2014) Adenosine deaminase acting on RNA-1 (ADAR1) inhibits HIV-1 replication in human alveolar macrophages. PLoS One 9:e108476
Kumar, Rajnish; Tuen, Michael; Liu, Jianping et al. (2013) Elicitation of broadly reactive antibodies against glycan-modulated neutralizing V3 epitopes of HIV-1 by immune complex vaccines. Vaccine 31:5413-21
Kumar, Rajnish; Visciano, Maria Luisa; Li, Hualin et al. (2012) Targeting a Neutralizing Epitope of HIV Envelope Gp120 by Immune Complex Vaccine. J AIDS Clin Res S8:
Kumar, Rajnish; Tuen, Michael; Li, Hualin et al. (2011) Improving immunogenicity of HIV-1 envelope gp120 by glycan removal and immune complex formation. Vaccine 29:9064-74
Hioe, Catarina E; Visciano, Maria Luisa; Kumar, Rajnish et al. (2009) The use of immune complex vaccines to enhance antibody responses against neutralizing epitopes on HIV-1 envelope gp120. Vaccine 28:352-60
Li, Hualin; Xu, Chong-Feng; Blais, Steven et al. (2009) Proximal glycans outside of the epitopes regulate the presentation of HIV-1 envelope gp120 helper epitopes. J Immunol 182:6369-78
Li, Hualin; Chien Jr, Peter C; Tuen, Michael et al. (2008) Identification of an N-linked glycosylation in the C4 region of HIV-1 envelope gp120 that is critical for recognition of neighboring CD4 T cell epitopes. J Immunol 180:4011-21
Visciano, Maria Luisa; Tuen, Michael; Gorny, Miroslaw K et al. (2008) In vivo alteration of humoral responses to HIV-1 envelope glycoprotein gp120 by antibodies to the CD4-binding site of gp120. Virology 372:409-20
Kaur, Gurvinder; Tuen, Michael; Virland, Diana et al. (2007) Antigen stimulation induces HIV envelope gp120-specific CD4(+) T cells to secrete CCR5 ligands and suppress HIV infection. Virology 369:214-25