While the HIV and SIV envelope glycoprotein (Env) subunits, gp120and gp4 1, have been characterized in their receptor-bound and/or fusogenic states, little is known about the conformation of the native """"""""pre-triggered"""""""" Env complex on the surface of virions. Moreover, how interactions between gp120and gp41 contribute to the structure and function of oligomeric Env remain poorly understood. The overall goal of this proposal is to better understand the native Env complex and the cooperative gp120-gp41 interactions that are relevant to its structure and function. We have characterized two prototypic Envs, one HIV-1 and one SIV, each with novel gp4 1-mediated phenotypes. The SIV/CPmac gp41 confers remarkable stability to virion-associated Env compared to the closely related SIVmac25l. In the HIV model, the HIV-118x gp4l induces exposure of CD4-induced epitopes in the associated gpl20 and confers a highly fusogenic phenotype when compared to the parental HXBc2 Env. We will employ a combination of molecular, biochemical, and biophysical techniques to characterize the gp120-gp41 interaction in these Envs.
The Specific Aims of the proposed research are: 1. To identify the mutations in the SIV CPmac gp4l that are responsible for stabilizing the native envelope glycoprotein complex and use protein dissection to identify contact regions in gp120and gp4 1. 2. To define the determinants and mechanisms whereby the HIV-1/8x gp4l modulates envelope glycoprotein conformation and fusogenicity. 3. To apply concepts derived from these models to understand and stabilize the gp120-gp41 interactions on primary isolate envelope glycoproteins By increasing our understanding of gp120/gp41 interactions of native, pretriggered Env proteins, this proposal will provide new insights into Env structure and function that could be relevant to the development of novel antiviral agents as well as Env-based immunogens for vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050504-04
Application #
6747341
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (01))
Program Officer
Sharma, Opendra K
Project Start
2001-07-01
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
4
Fiscal Year
2004
Total Cost
$308,000
Indirect Cost
Name
Duke University
Department
Surgery
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Liu, Jie; Wang, Shilong; Hoxie, James A et al. (2002) Mutations that destabilize the gp41 core are determinants for stabilizing the simian immunodeficiency virus-CPmac envelope glycoprotein complex. J Biol Chem 277:12891-900