Wednesday, April 2, 2025
4/2/2025
Epstein-Barr virus LMP1 mediated oncogenicity - Abstract Epstein-Barr virus (EBV) is highly associated with multiple types of lymphomas, which occur at elevated frequencies in people living with HIV. These include Hodgkin, Burkitt, post- transplant, plasmablastic, primary central nervous system and diffuse large B-cell lymphomas, which cause a large burden of disease in the HIV+ population. Despite highly active antiretroviral therapy, HIV+ individuals have elevated risk for EBV+ malignancies, in particular Hodgkin lymphoma. In people living with HIV, nearly all Hodgkin lymphoma and over 40% of immunoblastic lymphomas are EBV+. The EBV oncogene Latent Membrane Protein 1 (LMP1) is highly expressed in many HIV-associated lymphomas, including Hodgkin lymphoma. Yet, much remains to be learned about critical LMP1 roles in lymphomagenesis, in particular with HIV co-infection. Relatedly, much has remained unknown about specific LMP1 roles in germinal center B-cells, a key B-cell state from which most EBV+ lymphomas arise, and how HIV co- infection alters LMP1-dependent lymphomagenesis. Our preliminary data highlights that two LMP1 C-terminal tail domains are non-redundantly important for primary human B-cell transformation at distinct early timepoints post-infection, that each blocks distinct programmed cell death pathways, that they synergistically induces PD-L1 checkpoint signaling, and that germinal center cytokines are important determinants of LMP1 expression level. We have also constructed recombinant EBV with point mutants that abrogate signaling by either or both LMP1 transformation essential (TES) regions and developed a novel model of EBV/HIV co-infection of a novel secondary lymphoid microenvironment. Our aims test the central hypothesis that HIV co-infection dysregulates germinal center B-cell LMP1 expression and signaling, resulting in altered EBV+ B-cell reservoirs, checkpoint signaling and contributing to the observed elevated rates of EBV+ lymphomas. In Aim 1, we will define key LMP1 TES1 and TES2 signaling roles in B-cell oncogenic transformation and their relationship with HIV co-infection. In Aim 2, we will identify how the secondary lymphoid microenvironment and HIV coinfection alter LMP1 expression and oncogenic effects on LMP1 target gene expression. In Aim 3, we will identify how HIV/EBV co-infection alter checkpoint signaling, B-cell development and activation, and responses to checkpoint blockade. Collectively, these studies will newly characterize key aspects of LMP1 signaling in oncogenic B-cell transformation, including with HIV co-infection, and will lay the foundation for novel therapeutic approaches.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).