Approximately 90% of healthy adults are infected with Epstein Barr Virus (EBV), but in AIDS patients the diminished cytotoxic T lymphocyte response allows the expression of additional EBV proteins (type III latency). These viral proteins alter cel signaling to drive proliferation and inhibit apoptosis;suggesting a role in tumorigenesis that could contribute to the ?60-fold higher rate of Diffuse Large B Cell Lymphoma (DLBCL) and other Non-Hodgkin's Lymphomas in AIDS patients. Supporting this idea, EBV is present in nearly 100% of DLBCLs in AIDS patients, but only about 3% of DLBCLs in patients who are not immunocompromised. Our project is guided by the expectation that EBV+ AIDS patients require fewer changes in the cellular genome than non-immunocompromised patients to develop DLBCL. Using in vivo transcriptome and genetic information derived from DLBCL patient biopsies, we will use a strategy to determine the distinct cancer pathways in DLBCL patients with and without AIDS. This is important because it will highlight common and unique pathways that can be used to guide the development of therapeutics that are appropriately effective against these subclasses of DLBCLs.
Non-Hodgkin's Lymphoma has been considered an AIDS-defining illness for more than twenty years, and DLBCL especially remains a major concern for AIDS patients. We plan to identify tumor specific gene expression profiles and genetic signatures that are at the root of disrupted signaling pathways in EBV/AIDS-associated and EBV/AIDS-negative DLBCLs. This work will allow us to determine the contribution of EBV in DLBCL development in AIDS patients and mechanistic explanations for the high incidence of EBV associated malignancies in AIDS patients.
|O'Grady, Tina; Cao, Subing; Strong, Michael J et al. (2014) Global bidirectional transcription of the Epstein-Barr virus genome during reactivation. J Virol 88:1604-16|