The HIV/AIDS epidemic remains a significant public health problem, affecting more than 36 million people worldwide. Plasmablastic lymphoma is an AIDS-defining malignancy and among the most lethal cancers affecting HIV-infected patients who account for over two-thirds of the cases worldwide (1 ). Plasmablastic lymphoma is a particularly lethal disease with a median survival of 6-9 months. The central goal of this proposal is to conduct a well-powered genomic study of plasmablastic lymphoma that serves as a lasting resource for defining the biology of this disease. In spite of the poor outcomes associated with plasmablastic lymphoma, their genomic landscape remains mostly unknown. Defining the genetic landscape of plasmablastic lymphoma in both HIV positive and negative cases would allow us to identify specific features of plasmablastic lymphoma that emerge from the interactions between HIV infection and genetic factors underlying lymphomagenesis. We have enrolled a large cohort of plasmablastic lymphoma patients (N=148) that comprise both HIV positive (N=108) and HIV-negative (N=40) Aim 1. Comprehensively define the genomic profiles of plasmablastic lymphomas In this aim, we propose to define the genetic alterations and gene expression profiles of plasmablastic lymphomas using whole exome sequencing and RNA sequencing and compare them to HIV-negative cases. Aim 2: Define the role of the microenvironment in plasmablastic lymphomas In this aim, we propose to define the composition of the tumor microenvironment in plasmablastic lymphomas using single cell sequencing.