) The main objectives of this study are (1) to understand the role of the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) in stimulating the development of non-Hodgkin's lymphoma in patients who are infected with the human immunodeficiency virus (HIV) and (2) to identify specific deficits in the T helper responses of the HIV-infected host which lead to the development of EBV-positive NHL. In an effort to understand the role of the EBV latent membrane protein 1 (LMP1) transforming protein in stimulating the abnormal growth and proliferation of malignant B lymphocytes, LMP1-mediated activation of the NF-kappa-B transcription factor will be studied immunohistochemically on tumor specimens. The determination will also be made of which members of the tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are expressed in these tumors using multiplex reverse transcriptase-linked polymerase chain reaction (RT-PCR). In an effort to identify other cellular genes which contribute to the malignant phenotype of the cell, chromosomal abnormalities which are present in HIV-NHL will be studied using standard clinical cytogenetic methods. Another important aspect to LMP1 immunobiology is its role as a major direct target of T cell immunity of the host against EBV-infected B cells. Additionally, LMP1 enhances immunosurveillance against all viral targets of the immune system in latently infected cells by increasing the level of the adhesion molecule LFA-3 on the surface, thereby increasing the efficiency with which EBV infected cells adhere to T cells which express the LFA-3 ligand CD2. In this regard, the baseline T-helper (TH) subset profile and the baseline T cell responses against EBV will be measured in patients with HIV-NHL. In an effort to understand the immunological deficits which lead to the development of EBV-positive HIV-NHL, the relative frequencies and absolute number of TH1 and TH2 cells will be determined. The TH subset profile of T helper responses against autologous EBV- transformed lymphoblastoid cell lines (LCLs) will also be determined in these patients. These measurements will be made using in vitro assays which allow T helper cells to proliferate in response to antigen. The TH subsets will be determined using ELISA assays to measure secreted cytokines specific to different subsets of TH cells. The cytokines granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin-2 (IL-2), IL-4, IL-12, interferon-alpha (IFN-alpha) and IFN-gamma will be tested for their ability to modulate the responses of these patients T lymphocytes against autologous EBV-transformed LCLS. This may provide an important step in the rational development of immunomodulatory therapeutic modalities for these patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Special Emphasis Panel (SRC (C2))
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Cremer, Kenneth J
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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