The molecular basis for development of highly neutralizing antibodies against HIV is still poorly understood. New approaches are needed to define the molecular and genetic basis for development of B cells specific for HIV, and the antibodies they secrete. We have assembled a strong consortium to attack this research problem. We have developed novel viral and immunologic tools for exploration of the HIV-specific B cell repertoire. The Pi's laboratory has developed efficient techniques for the physical isolation of single virus-specific B cells, and the cloning and expression of antibody genes from these single cells, resulting in panels of human monoclonal antibodies. The Spearman laboratory at Emory has developed production systems for HIV pseudovirion particles that contain fluorescent proteins, allowing presentation of Env sequences of interest in a multivalent display that is conformationally correct and labeled. Dr. Kalams at Vanderbilt has assembled a strong clinical cohort of HIV infected controllers and access to rapid progressors, from whom we will obtain blood specimens for comparative purposes. We will test the hypothesis that HIV controllers exhibit a B cell repertoire characterized by broader use of VH segments than the oligoclonal repertoire of rapid progressors, and more importantly, a greater degree of somatic hypermutation that results in higher affinity antibodies with more neutralizing potency. We will determine the molecular genetics of the antibody genes from HIV-specific cells from these two subject classes, and determine the repertoire changes over time. We will determine the effect of the genetic changes observed on the neutralizing function of the monoclonal antibodies that we isolate. A major """"""""collateral benefit"""""""" of these basic science studies aimed at understanding repertoire development is that the work also will result in production of large panels of human monoclonal antibodies that could be of therapeutic or prophylactic benefit. The most potent antibodies also will be used to define epitopes of interest, guiding vaccine design efforts. Public health: These studies will define how effective antibodies to HIV are generated in humans. The studies will help us to understand if it is feasible to find antibodies in infected humans that kill virus. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AI078407-01
Application #
7464062
Study Section
Special Emphasis Panel (ZAI1-KS-I (J3))
Program Officer
Bradac, James A
Project Start
2008-03-15
Project End
2013-02-28
Budget Start
2008-03-15
Budget End
2009-02-28
Support Year
1
Fiscal Year
2008
Total Cost
$619,313
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Boehme, Karl W; Ikizler, Mine'; Iskarpatyoti, Jason A et al. (2016) Engineering Recombinant Reoviruses To Display gp41 Membrane-Proximal External-Region Epitopes from HIV-1. mSphere 1:
Hicar, Mark D; Chen, Xuemin; Kalams, Spyros A et al. (2016) Low frequency of broadly neutralizing HIV antibodies during chronic infection even in quaternary epitope targeting antibodies containing large numbers of somatic mutations. Mol Immunol 70:94-103
Chukwuma, Valentine U; Hicar, Mark D; Chen, Xuemin et al. (2015) Association of VH4-59 Antibody Variable Gene Usage with Recognition of an Immunodominant Epitope on the HIV-1 Gag Protein. PLoS One 10:e0133509
Willis, Jordan R; Sapparapu, Gopal; Murrell, Sasha et al. (2015) Redesigned HIV antibodies exhibit enhanced neutralizing potency and breadth. J Clin Invest 125:2523-31
Aiyegbo, Mohammed S; Eli, Ilyas M; Spiller, Benjamin W et al. (2014) Differential accessibility of a rotavirus VP6 epitope in trimers comprising type I, II, or III channels as revealed by binding of a human rotavirus VP6-specific antibody. J Virol 88:469-76
Willis, Jordan R; Briney, Bryan S; DeLuca, Samuel L et al. (2013) Human germline antibody gene segments encode polyspecific antibodies. PLoS Comput Biol 9:e1003045
Aiyegbo, Mohammed S; Sapparapu, Gopal; Spiller, Benjamin W et al. (2013) Human rotavirus VP6-specific antibodies mediate intracellular neutralization by binding to a quaternary structure in the transcriptional pore. PLoS One 8:e61101
Briney, Bryan S; Crowe Jr, James E (2013) Secondary mechanisms of diversification in the human antibody repertoire. Front Immunol 4:42
Briney, Bryan S; Willis, Jordan R; Crowe Jr, James E (2012) Human peripheral blood antibodies with long HCDR3s are established primarily at original recombination using a limited subset of germline genes. PLoS One 7:e36750
Briney, B S; Willis, J R; Crowe Jr, J E (2012) Location and length distribution of somatic hypermutation-associated DNA insertions and deletions reveals regions of antibody structural plasticity. Genes Immun 13:523-9

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