Human immunodeficiency virus (HIV-1) is the major cause of acquired immunodeficiency syndrome (AIDS) in humans. A prophylactic vaccine is urgently needed to curb the HIV-1 pandemic. The elicitation of virus-neutralizing antibodies by an HIV-1 vaccine would be desirable. The HIV-1 envelope glycoproteins, gp120 and gp41, are the only targets on the virion accessible to neutralizing antibodies. The HIV-1 envelope glycoproteins are contained in trimeric complexes on the viral surface, and mediate receptor binding and membrane fusion. The structure of the HIV-1 envelope glycoproteins, particularly those of primary isolates, has evolved to minimize the elicitation and efficacy of neutralizing antibodies. Nonetheless, several examples exist of antibodies directed against different envelope glycoprotein epitopes that potently neutralize even primary HIV-1 isolates. Our preliminary results suggest that the elicitation of antibodies that neutralize primary HIV-1 isolates is feasible given the correct immunogen. The overall goal of this work is to understand the interaction of antibodies, particularly potent neutralizing antibodies, with the HIV-1 envelope glycoproteins and to use this understanding to improve the elicitation of neutralizing antibodies.
The specific aims of the proposal are: To investigate the mechanistic and structural basis for differences in neutralizing potency among antibodies recognizing CD4-induced (CD4i) epitopes. To create homogeneous preparations of HIV-1 envelope glycoprotein trimers suitable for analysis of antibody-trimer interactions by macromolecular electron microscopy. To test whether viral strain, variable loop modification and/or stabilization of the conformational flexibility of the gp120 core affect the ability of HIV-1 envelope glycoprotein trimers to elicit neutralizing antibodies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI031783-13
Application #
6653665
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Wassef, Nabila M
Project Start
1991-07-15
Project End
2008-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
13
Fiscal Year
2003
Total Cost
$415,829
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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