This is an application for a National Institutes of Health Research on Malignancies in the Context of HIV/AIDS R21 award for Dr. Satish Gopal, a Clinical Assistant Professor of Medicine in Hematology-Oncology and Infectious Diseases at UNC-Chapel Hill, who is based at the university's longstanding research collaboration in Malawi. Dr. Gopal is establishing himself as a young investigator in the area of HIV-associated lymphoma, and also lymphoma treatment in sub-Saharan Africa. This award will provide Dr. Gopal and his co- investigators with the support necessary to undertake the most comprehensive genomic assessment of HIV- associated lymphoma performed to date. Lymphoma is a major cause of morbidity and mortality among HIV-infected individuals in both the US and sub-Saharan Africa. Despite being curable, outcomes in both settings remain inferior to HIV-uninfected individuals. To illuminate lymphoma biology in the context of HIV, this proposal takes advantage of a combination of strengths highly unique to UNC, including participation in the Center for AIDS Research Network of Integrated Clinical Systems (CNICS), the highly successful UNC Project-Malawi clinical research program in Lilongwe, and inclusion as one of seven Data Analysis Centers for The Cancer Genome Atlas project. The proposed research additionally builds on two ongoing NIH-funded studies for which Dr. Gopal serves as principal investigator, including a large observational study of ~500 patients with HIV-associated lymphoma in CNICS, and a prospective lymphoma cohort study in Malawi. In Aim 1, the proposed research will compare genomic features using next-generation sequencing for HIV-associated lymphoma specimens occurring before and after antiretroviral therapy (ART). In Aim 2, comparisons will be made between the US and Malawi after adjustment for histology and ART status. Genomic characterizations will be done using RNAseq analyses of formalin-fixed paraffin embedded (FFPE) lymphoma specimens. These analyses will be used to define gene expression profiles (GEP) of diffuse large B-cell, Burkitt, and Hodgkin lymphoma specimens. GEP data will be compared between pre-ART and post-ART specimens, as well as between the United States and Malawi, using multivariable regression with expression variation as the outcome. The proposed research represents an important contribution to the existing literature in that GEP for lymphomas occurring specifically in the context of HIV have not previously been examined. Additionally, this work will allow for a comparative understanding of lymphoma biology in the US and Malawi, as well as before and after ART. The molecular insights gained will substantially illuminate lymphoma biology in the context of HIV, and result in improved treatments for this challenging and vulnerable population in both resource-rich and resource-limited settings.