The goal of this proposal is to elucidate the mechanisms by which HIV-1 evades humoral immunity. Antibody responses, including class switch DNA recombination (CSR) and somatic hypermutation (SHM), are essential to block HIV-1 entry and spread. CSR substitutes IgM with IgG or IgA, thereby endowing antibodies with novel effector functions that enhance viral clearance systemically and at mucosal sites of entry. SHM introduces point mutations in genes encoding the antigen-binding variable region of antibodies, thereby providing the structural correlate for selection by viral antigens of higher affinity IgG and IgA mutants. CSR and SHM require activation-induced cytidine deaminase (AID), an enzyme expressed by B cells in the germinal center (GC) of secondary lymphoid organs. This specialized microenvironment comprises CD4+ T cells that activate B cells through CD154 and IL-4. Ultimately, GC B cells differentiate into plasma cells, which secrete large amounts of IgG and IgA antibodies. HIV-1 impairs systemic and mucosal IgG and IgA responses to viral antigens, opportunistic pathogens and vaccines through mechanisms that remain poorly understood. Although progressive loss of CD4+ T cells is certainly important, B cell-intrinsic abnormalities, including poor responsiveness of B cells to CD154, are also involved. In this proposal, we argue that the HIV-1 protein Nef contributes to the genesis of B cell-intrinsic defects arising during HIV-1 infection. We contend that Nef attenuates CD154-dependent CSR, SHM as well as virus-specific IgG and IgA production in systemic and mucosal GCs. We also hypothesize that Nef targets B cells by traveling through long-range tunneling nanotubules emanating from HIV-1-infected cells. Finally, we propose that multiple Nef domains contribute to the inhibition of kinases transducing CD154 and IL-4 signaling in B cells.
Three specific aims are proposed.
Aim 1 is to determine the ability of Nef-sufficient and Nef-deficient HIV-1 to attenuate CSR, SHM and antigen-specific IgG and IgA production in systemic and mucosal B cells.
Aim 2 is to assess the ability of long- distance tunneling nanotubules to shuttle membrane-bound and vesicle-associated Nef from infected cells to B cells.
Aim 3 is to elucidate the molecular interactions involved in Nef-mediated inhibition of CD154 and IL-4 signaling in B cells. Findings resulting from these studies should lead to a better understanding of the mechanisms whereby HIV-1 evades the antibody response. In addition, the proposed studies might facilitate the development of novel therapeutic and vaccine strategies against HIV-1. HIV-1 profoundly impairs antibody responses against viral proteins, opportunistic agents and vaccines. Growing evidence indicates that this antibody deficiency is caused not only by loss of CD4+ T cells, but also by B cell-intrinsic defects. The goal of this application is to elucidate the mechanisms by which HIV-1 causes B cell dysfunctions. Ultimately, findings deriving from the proposed studies should help develop more effective vaccines against HIV-1.
|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 15:354-364|
|Almejun, Maria B; Cols, Montserrat; Zelazko, Marta et al. (2013) Naturally occurring mutation affecting the MyD88-binding site of TNFRSF13B impairs triggering of class switch recombination. Eur J Immunol 43:805-14|
|Shan, Meimei; Gentile, Maurizio; Yeiser, John R et al. (2013) Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science 342:447-53|
|Cerutti, Andrea; Cols, Montserrat; Puga, Irene (2013) Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nat Rev Immunol 13:118-32|
|Cerutti, Andrea; Puga, Irene; Cols, Montserrat (2012) New helping friends for B cells. Eur J Immunol 42:1956-68|
|Cerutti, Andrea; Cols, Montserrat; Puga, Irene (2012) Activation of B cells by non-canonical helper signals. EMBO Rep 13:798-810|
|Chorny, Alejo; Puga, Irene; Cerutti, Andrea (2012) Regulation of frontline antibody responses by innate immune signals. Immunol Res 54:4-13|
|Klasse, Per Johan; Sanders, Rogier W; Cerutti, Andrea et al. (2012) How can HIV-type-1-Env immunogenicity be improved to facilitate antibody-based vaccine development? AIDS Res Hum Retroviruses 28:1-15|
|Boiocchi, Leonardo; Witter, Rosanny Espinal; He, Bing et al. (2012) Composite chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma are biclonal lymphomas: a report of two cases. Am J Clin Pathol 137:647-59|
|Chorny, Alejo; Cerutti, Andrea (2012) CEACAM1-S: the virtues of alternative splicing in gut immunity. Immunity 37:768-70|
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