The emergence of serum antibody responses only after early cellular immune responses have suppressed HIV replication has led to doubts regarding the importance of humoral immunity in controlling HIV infections. Nonetheless, rare, broadly cross-reactive antibodies are capable of neutralizing multiple isolates of HIV-1 in vitro, and when passively administered to monkeys, prevent experimental infection by SHIV. Why are such antibodies rarely produced by HIV- infected patients? Recently, several of these rare, HIV neutralizing antibodies were shown to react with self-antigens leading to the possibility that effective HIV humoral responses are constrained by the tolerization of HIV-reactive B cells that also recognize self-antigens. We shall test the hypothesis that B cells that recognize phylogenetically conserved, neutralizing epitopes of the HIV-1 gp-41 membrane proximal external region (MPER) are present in early, developmentally immature B cells but are tolerized and lost during their subsequent development/maturation.

Public Health Relevance

These experiments will determine whether the failure to make protective antibody responses to HIV-1 antigens is a consequence of cross-reactive tolerization. B cells capable of producing protective antibodies may be deleted in development as they also react to self-antigens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI081579-04
Application #
8306271
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Conley, Tony J
Project Start
2009-08-11
Project End
2014-05-31
Budget Start
2012-08-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$386,100
Indirect Cost
$138,600
Name
Duke University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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