This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. CD154 (CD40 ligand) is a costimulatory molecule expressed by activated CD4+ T cells that binds to the cell-surface molecule CD40, present on dendritic cells, B cells, and macrophages. This proposal will study mechanisms that affect cellular immune responses to SIV infection. Specifically, we will study the role of the costimulatory molecule CD154 during infection of rhesus macaques with a recombinant live-attenuated SIV that expresses rhesus CD154 (SIVCD154). We already showed that SIVCD154 is able to express CD154 on the surface of infected rhesus T cells. We hypothesize that signaling by CD154 is dysregulated during SIV infection, and that expression of CD154 by SIVCD154-infected cells may restore the activation pathway for T cell-dependent antigens: 1) SIVCD154-infected DCs will engage CD154 and CD40 at the cell surface and upregulate other costimulatory molecules; 2) SIVCD154-infected CD4+ T cells will engage their CD154 with CD40 on B cells, leading to B cell activation and expansion; and 3) SIVCD154-infected macrophages will engage CD154 and CD40 at the cell surface, leading to activation, release cytokines and NO, and APC function. Results from these experiments may lead to improvements in HIV vaccine design in at least two ways: i) better understanding of the mechanisms of immune dysregulation during HIV infection, or ii) prospect for safer live-attenuated vaccines.
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