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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Conley, Tony J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Schools of Medicine
United States
Zip Code
Verkoczy, Laurent; Kelsoe, Garnett; Haynes, Barton F (2014) HIV-1 envelope gp41 broadly neutralizing antibodies: hurdles for vaccine development. PLoS Pathog 10:e1004073
Holl, T Matt; Yang, Guang; Kuraoka, Masayuki et al. (2014) Enhanced antibody responses to an HIV-1 membrane-proximal external region antigen in mice reconstituted with cultured lymphocytes. J Immunol 192:3269-79
Kim, Mikyung; Song, Likai; Moon, James et al. (2013) Immunogenicity of membrane-bound HIV-1 gp41 membrane-proximal external region (MPER) segments is dominated by residue accessibility and modulated by stereochemistry. J Biol Chem 288:31888-901
Yang, Guang; Holl, T Matt; Liu, Yang et al. (2013) Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies. J Exp Med 210:241-56
Cain, Derek W; Sanders, Sergio E; Cunningham, Michael M et al. (2013) Disparate adjuvant properties among three formulations of "alum". Vaccine 31:653-60
Moody, M Anthony; Yates, Nicole L; Amos, Joshua D et al. (2012) HIV-1 gp120 vaccine induces affinity maturation in both new and persistent antibody clonal lineages. J Virol 86:7496-507
Verkoczy, Laurent; Kelsoe, Garnett; Moody, M Anthony et al. (2011) Role of immune mechanisms in induction of HIV-1 broadly neutralizing antibodies. Curr Opin Immunol 23:383-90
Verkoczy, Laurent; Chen, Yao; Bouton-Verville, Hilary et al. (2011) Rescue of HIV-1 broad neutralizing antibody-expressing B cells in 2F5 VH x VL knockin mice reveals multiple tolerance controls. J Immunol 187:3785-97
Holl, T Matt; Haynes, Barton F; Kelsoe, Garnett (2010) Stromal cell independent B cell development in vitro: generation and recovery of autoreactive clones. J Immunol Methods 354:53-67
Cain, Derek; Kondo, Motonari; Chen, Huaiyong et al. (2009) Effects of acute and chronic inflammation on B-cell development and differentiation. J Invest Dermatol 129:266-77