Despite significantly reduced incidence rates in the combined antiretroviral therapy (cART) era, Diffuse Large B-Cell Lymphoma (DLBCL) remains one of the most common Acquired Immunodeficiency Syndrome (AIDS) defining cancers to occur in Human Immunodeficiency Virus (HIV) infected individuals. Compared to DLBCL that arises in uninfected individuals, HIV associated DLBCL frequently present at advanced stages, with high tumor burdens and poor prognoses. In addition, DLBCL is comprised of distinct molecular subtypes, namely GCB and ABC subtypes, that further complicate understanding of the therapeutic responsiveness of HIV infected patients. In line with the NIH mission to decipher the differences between malignancies arising in HIV infected and uninfected individuals, the overarching goal of this project is to elucidate the molecular mechanisms underlying both HIV associated GCB-DLBCL (specific aim 1) and HIV associate ABC-DLBCL (specific aim 2), and to examine how these diseases differ from that that arises in uninfected patients. To do this, the project will employ a range of molecular techniques including digital gene expression profiling to investigate transcriptional signatures, array comparative genomic hybridization to determine DNA copy number landscapes, and immunohistochemistry to assess protein expression in the largest cohort, to date, of molecularly subtyped HIV associated DLBCL patient materials. It is hypothesized that the HIV associated DLBCL subtypes are distinct entities not only from each other but also their counterparts in immunocompetent patients. It is expected that integrated bioinformatic analyses will identify signatures composed of key genes and proteins associated with each subtype, and that these signatures will provide the springboard for the development of novel and/or the repositioning of existing therapeutic drugs to better treat these immunocompromised patients.