Dendritic cells (DCs) are professional antigen-presenting cells (APCs) with a unique ability to prime naive T and B immune cells, thus inducing primary immune responses and permitting establishment of immunological memory. This unique ability of DCs has been utilized to enhance immune responses by modulating the Ag to be targeted to DC surface molecules. However, their intrinsic small number in peripheral tissues limits the use of DCs as immunotherapy or vaccine targets. Increasing DC populations would provide a rational way to enhance immune responses. This proposal is designed to test the hypothesis that incorporation of DC growth factors (FL, GM-CSF) or an activator (CD40L) into virus-like particles (VLPs) will lead to enhancement of immune responses by expanding and/or activating DCs as well as targeting of the VLPs to DC populations simultaneously. Hematopoietic growth factors such as fit3 ligand (FL) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were shown to expand subsets of DCs and thus to increase immune responses. CD40 ligand (CD40L) was also demonstrated to bind to CD40 on DCs. Interaction of CD40L induces the activation of DCs into professional APCs. In addition, direct activation of DCs by CD40L does not require a CD4+ T helper (Th) cell in enhancing immune responses, which has therapeutic implications for AIDS patients. Coexpression of HIV gag and env genes in cells results in production of VLPs containing Env protein with Gag protein core. Lacking nucleic acids,VLPs are safe and known to induce both cellular and humoral immune responses. For both targeting SHIV VLPs (SIV Gag core and HIV SF162 Env protein) to DCs and expanding DC populations, we will express FL,GM-CSF, or CD40L in membrane-bound form and produce FL, GM-CSF, or CD40L incorporated into SHIVVLPs (specific aim 1). Immune responses in mice after immunization with SHIV VLPs containing membrane-anchored DC growth factors (FL, GM-CSF) or CD40L will be examined by determining HIV Env protein specific antibody titers, cytokine production, and CTL activities specific to HIV Env and SIV Gag as well as by analyzing subpopulations of DC subsets (specific aim 2). As a long-term objective, the efficacy of targeting VLPs to DCs will be tested in a non-human primate model for designing a more effective AIDS vaccine.
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