The goal of this proposal is to elucidate the mechanisms by which the adjuvant GM-CSF enhances vaccine induced IgG and IgA responses against SIV. These studies will take advantage ofthe unique resources made available by this consortium and ofthe complementary and integrative expertise ofthe Amara and Pulendran groups, which evaluate novel Env immunogens for the induction of neutralizing Abs (NAbs) (Project 1 and Project 2). the Ahmed/Silvestri/Crotty group, which explores the regulation of Ab responses by T cells (Project 3). and the Cerutti group, which studies the regulation of B cells by innate immune cells (Project 4). B cells provide immune protection against HIV by producing NAbs to envelope (Env) spikes on the surface ofthe virus. However, eliciting robust and sustained NAb responses remains a major obstacle, because Env, the only relevant antigen for NAb induction, is characterized by sequence variation, limited antigenicity and scarce immunogenicity. An additional obstacle relates to the lack of strategies capable of effectively inducing NAbs both systemically and at mucosal sites of entry. Preliminary data from the Amara group show that GM-CSF enhances the avidity and frequency of vaccine-induced SIV-reactive IgG Abs produced in systemic lymphoid organs and elicits release of SIV-specific IgA in intestinal secretions. These effects correlate with increased protection against an intestinal challenge. In this proposal we hypothesize that GM-CSF mobilizes and activates a unique subset of splenic IL-21-producing NBH neutrophils equipped with B cell helper function. We contend that NBH cells enhance systemic IgG and intestinal IgA responses against SIV by inducing Ig heavy chain class switching, V(D)J gene somafic hypermutation and gut-homing receptors in splenic B cells, including marginal zone and memory B cells.
Three aims are proposed.
Aim 1 is to elucidate the mechanism by which GM-CSF induces IgG and IgA class switching in splenic B cells.
Aim 2 is to dissect the mechanism by which GM-CSF induces intestinal homing of splenic IgA class-switched B cells.
Aim 3 is to determine the mechanism by which GM-CSF improves the avidity of vaccine-induced systemic IgG and intestinal IgA responses against SIV..

Public Health Relevance

B cells provide immune protection against HIV infection by producing NAbs to Env spikes on the surface of the virus. Thus far, immunization with recombinant Env subunits has failed to elicit broadly NAbs. The proposed collaborative studies will take advantage of an SIV vaccination model involving GM-CSF to study a novel Ab-inducing immune pathway and help develop novel adjuvant strategies for preventive HIV vaccines.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-LR-A)
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Emory University
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Yang, Rendong; Bai, Yun; Qin, Zhaohui et al. (2014) EgoNet: identification of human disease ego-network modules. BMC Genomics 15:314
Derdeyn, Cynthia A; Moore, Penny L; Morris, Lynn (2014) Development of broadly neutralizing antibodies from autologous neutralizing antibody responses in HIV infection. Curr Opin HIV AIDS 9:210-6
Basu, Debby; Xiao, Peng; Ende, Zachary et al. (2014) Low antibody-dependent cellular cytotoxicity responses in Zambians prior to HIV-1 intrasubtype C superinfection. Virology 462-463:295-8
Magri, Giuliana; Miyajima, Michio; Bascones, Sabrina et al. (2014) Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells. Nat Immunol 15:354-64
Yu, Tianwei; Jones, Dean P (2014) Improving peak detection in high-resolution LC/MS metabolomics data using preexisting knowledge and machine learning approach. Bioinformatics 30:2941-8
Li, Shuzhao; Rouphael, Nadine; Duraisingham, Sai et al. (2014) Molecular signatures of antibody responses derived from a systems biology study of five human vaccines. Nat Immunol 15:195-204
Romberg, Neil; Chamberlain, Nicolas; Saadoun, David et al. (2013) CVID-associated TACI mutations affect autoreactive B cell selection and activation. J Clin Invest 123:4283-93
Li, Shuzhao; Nakaya, Helder I; Kazmin, Dmitri A et al. (2013) Systems biological approaches to measure and understand vaccine immunity in humans. Semin Immunol 25:209-18
Pulendran, Bali; Oh, Jason Z; Nakaya, Helder I et al. (2013) Immunity to viruses: learning from successful human vaccines. Immunol Rev 255:243-55
Cerutti, Andrea; Cols, Montserrat; Puga, Irene (2013) Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nat Rev Immunol 13:118-32

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