The human immunodeficiency virus (HIV-1) is the cause of AIDS. The primary target for antibodies capable of neutralizing the HIV-1 infection process is the exterior envelope glycoprotein, gp120. Very recently the applicants, in collaboration with Dr. Wayne Hendrickson's laboratory at Columbia University, solved the crystal structure of a gp120 core protein in complex with the primary virus receptor, CD4 and a neutralizing antibody. This new structural information provides a unique opportunity to test several hypotheses that may significantly impact HIV-1 vaccine design. A major obstacle in HIV-1 vaccine development is the efficient elicitation of broadly neutralizing antibodies using HIV-1 envelope l glycoproteins as immunogens. This difficulty may be in part due to the extensive degree of gp12 l glycosylation, which accounts for roughly one-half of its apparent molecular weight. It is likely the extensive glycosylation affects the manner in which gp120 is """"""""viewed"""""""" by the host immune system. The carbohydrates may shield much of the glycoprotein surface, including conserved, functional neutralization targets, and present many sugar epitopes to the humoral immune system as self-antigens. The applicants propose, based upon structural analysis, to selectively delete specific sugar residues that may mask conserved, receptor binding regions and to test if these mutant envelope glycoproteins can better elicit neutralizing antibodies compared to wild-type gp120. They also plan to utilize the remaining sugar residues to orient gp120 on antigen presenting cells to better expose receptor binding regions to the humoral immune system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI044328-02
Application #
2887891
Study Section
Special Emphasis Panel (ZAI1-PRJ-A (S1))
Program Officer
Bende, Steve M
Project Start
1998-09-29
Project End
2000-09-28
Budget Start
1999-09-29
Budget End
2000-09-28
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215
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