The overall objective of this multi-project HIVRAD program application is to elicit neutralizing antibodies that target the CD4 binding site (CD4bs) of primary HIV-1 envelope (Env) glycoproteins. This P01 program proposal consists of three major projects, plus two cores to support the activities of major projects. The following is a summary of major activities as proposed in different Projects/Cores of this program. Goal 1: To organize and manage a highly interactive and productive research team (Core B). Goal 2: To understand how the variation in HIV-1 R5 Envs affect tropism, neutralization and vaccine development (Project 1). HIV-1 R5 envelopes vary extensively in their capacity to infect macrophages. We propose to investigate the impact of variation in macrophage tropism (mac-tropism) on other biological properties associated with Env including neutralization sensitivity. Goal 3: To study how the variation of antigenicity of CD4bs will affect the neutralization sensitivity and immunogenicity of primary Env proteins (Project 2). The CD4bs antigenicity of several panels of primary Envs, each with their own unique biological features, will be probed by mAbs. We will examine whether high CD4bs antigenicity and high sensitivity to CD4bs mAb mediated neutralization will lead to high immunogenicity for key representative Env using the DMA prime-protein boost immunization approach. Goal 4: To study the modification of receptor binding site as an approach to HIV-1 vaccine design (Project 3). We will test whether changes resulting from specific glycan modifications will lead to increased stability or accessibility of conserved epitopes in the receptor binding site and whether greater accessibility of these conserved sites will enhance their function as immunogen to elicit cross-reactive NAb responses. Goal 5: To provide support to major projects on structure analysis of Env and to study the structure of novel antigens, and antigen-antibody interactions (Core A).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI082274-04
Application #
8310009
Study Section
Special Emphasis Panel (ZAI1-EC-A (J2))
Program Officer
Miller, Nancy R
Project Start
2009-08-07
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$2,007,348
Indirect Cost
$549,192
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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