HIV and SIV virions shed a significant fraction of their gp120 glycoproteins. The immune system responds to these envelope fragments, creating non-neutralizing antibodies that are usually incapable of binding to the native envelope glycoprotein complex. The goal of this initial independent research project is to generate and test the comparative imunogenicity of non-infectious virus-like particles (VLP) that contain disulfide-stabilized envelope glycoprotein complexes (SOS proteins). The envelope glycoprotein mutants that will be expressed on these particles have a disulfide bond between the gp120 and gp41 subunits which prevent gp120 shedding. These SOS envelope glycoproteins mimic the antigenic configuration of the native complex. Thus, their presentation on a multivalent array of VLPs might be advantageous enabling the SOS-VLPs to be a potential component in a combination vaccine.
Two Specific Aims are proposed:
Specific Aim 1 : The SOS mutations will be introduced into the SIVmne envelope (Env) gene to create a disulfide bond between the gp120 and gp41 subunits. The immunochemical, biophysical and morphological properties of the resulting SOS-VLPs will be compared to wild type VLPs. An emphasis will be to determine the glycoprotein retention on particles as well as assessment of its antigenic configuration.
Specific Aim 2 : Test the immunogenicity of the SOS-VLPs in rabbits in comparison with wild type VLPs and soluble SOS gp140 proteins. The most important end point will be to measure the breadth and potency of neutralizing antibodies against matched virus isolates as well as against more diverse isolates providing an indication of worth of VLP immunogens as vaccine components. If SOS-VLPs seem promising, the investigator proposes to generate a recombinant vaccinia capable of expressing VLPs. The SOS-VLPs then will be used in a prime-boost vaccination and SIVmne challenge studies in macaques. Ultimately, the information obtained in these studies will be applied to those to make HIV-1, SOS-VLPs as components of a combination vaccine against HIV-1 infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI049566-01
Application #
6333057
Study Section
Special Emphasis Panel (ZRG1-AARR-2 (01))
Program Officer
Bradac, James A
Project Start
2000-09-01
Project End
2001-02-28
Budget Start
2000-09-01
Budget End
2001-02-28
Support Year
1
Fiscal Year
2000
Total Cost
$125,430
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Crooks, Emma T; Jiang, Pengfei; Franti, Michael et al. (2008) Relationship of HIV-1 and SIV envelope glycoprotein trimer occupation and neutralization. Virology 377:364-78
Crooks, Emma T; Moore, Penny L; Franti, Michael et al. (2007) A comparative immunogenicity study of HIV-1 virus-like particles bearing various forms of envelope proteins, particles bearing no envelope and soluble monomeric gp120. Virology 366:245-62
Moore, Penny L; Crooks, Emma T; Porter, Lauren et al. (2006) Nature of nonfunctional envelope proteins on the surface of human immunodeficiency virus type 1. J Virol 80:2515-28
Crooks, Emma T; Moore, Penny L; Richman, Douglas et al. (2005) Characterizing anti-HIV monoclonal antibodies and immune sera by defining the mechanism of neutralization. Hum Antibodies 14:101-13
Binley, James M; Cayanan, Charmagne S; Wiley, Cheryl et al. (2003) Redox-triggered infection by disulfide-shackled human immunodeficiency virus type 1 pseudovirions. J Virol 77:5678-84
Labrijn, Aran F; Poignard, Pascal; Raja, Aarti et al. (2003) Access of antibody molecules to the conserved coreceptor binding site on glycoprotein gp120 is sterically restricted on primary human immunodeficiency virus type 1. J Virol 77:10557-65
Schulke, Norbert; Vesanen, Mika S; Sanders, Rogier W et al. (2002) Oligomeric and conformational properties of a proteolytically mature, disulfide-stabilized human immunodeficiency virus type 1 gp140 envelope glycoprotein. J Virol 76:7760-76
Binley, James M; Sanders, Rogier W; Master, Aditi et al. (2002) Enhancing the proteolytic maturation of human immunodeficiency virus type 1 envelope glycoproteins. J Virol 76:2606-16