Epstein Barr virus (EBV) is a ubiquitous gamma herpes virus associated with the development of several B lymphoproliferative diseases including lymphoma in human immune deficiency virus (HIV) infected individuals. Cellular immunity plays a critical role in the control of EBV and other viral infections. However it has been difficult to boost this arm of the immune response using current approaches in humans. Dendritic cells (DCs) are specialized antigen presenting cells (APCs) capable of generating strong anti-viral immune responses. Our hypothesis is that Dcs will be effective adjuvants for the generation of EBV specific immune response for therapy and prevention of lymphoma in HIV infected individuals. Maturation of DCs ex vivo leads to an increase in their potency in vitro. We have recently demonstrated that a single injection of antigen bearing mature DCs, but not unpulsed DCs or antigens alone, generated broad CD4 and CD8+ve T cell immunity in healthy volunteers. These data provide the first controlled evidence of immunogenicity of DCs in humans. We will now examine the strength and durability of the T immunity using newer quantitative assays. In studies proposed herein, we will next determine the magnitude of EBV specific memory using DCs as APCs and EBV specific effector CTL response using newer sensitive assays (ELISPOT and MHC-tetramer binding) in patients with HIV infection, as compared to normal hosts. Using the ELISPOT assay, we will also examine the nature of CD4+ve T cell immunity to EBV in these populations. These studies will serve as a baseline for future immune therapeutic trials to boost EBV and HIV specific immune responses. Recent studies in our laboratory have demonstrated that DCs can acquire exogenous antigen from apoptotic cells and generate CD8+ CTLs. There fore we will examine if DCs are able to acquire antigen from apoptotic EBV infected cells, as a potentially novel strategy for generating EBV specific CTL responses in patients. The long term goals are to use DCs as adjuvants to boost EBV and HIV specific immune response in patients with HIV associated lymphoma. The proposed studies and career development plan will provide the necessary laboratory experience to complement the PI s prior expertise in clinical oncology research and lay the foundation for career as a physician-scientist in tumor immunology.
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