Neurologic complications of HIV infection are common. Among the most devastating of these is primary CNS lymphoma, an AIDS-defining illness which is highly aggressive and usually associated with short survival. Establishing the pathologic basis of focal brain lesions in the setting of HIV infection can be difficult for a number of reasons, including the fact that results of neuro-imaging and DNA PCR evaluations are non-specific and cytological testing of cerebrospinal fluid is highly insensitive. Moreover, the standard interventions used to treat AIDS-related primary CNS lymphoma, dexamethasone, methotrexate and whole brain irradiation, have not been improved upon in decades. The goal of this proposal is to apply new technologies to the diagnosis and treatment of AIDS-related primary CNS lymphoma. We will apply proteomic methods to identify novel biomarkers which we hypothesize will enhance the diagnostic armamentarium used to evaluate focal brain lesions in HIV infection. We will also perform the first global metabolomic profiling of cerebrospinal fluid in AIDS in order to identify pathways which are disrupted in AIDS-related CNS lymphoma. We hypothesize that this pilot metabolomic analysis may not only lead to the identification of novel biomarkers with superior diagnostic utility, but may also provide biological insight into the pathogenesis of this type of brain tumor and potentially lead to the development of novel and more effective therapies. Finally, we will develop and apply murine models of AIDS-related primary CNS lymphoma to systematically evaluate small molecule compounds which we hypothesize will disrupt lymphoma survival signaling pathways and improve outcomes in this disease. If results from this pilot analysis are successful, we will proceed to their evaluation in the multicenter setting through the AIDS Malignancy Consortium.