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Research Summary

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus and the causative infectious agent of both HAM/TSP, a chronic inflammatory disease of the central nervous system, and ATL, an aggressive and fatal disease of CD4+ T-cells. HTLV-1-associated disease development occurs after an extensive clinical latency period upwards of several decades and lacks ideal therapeutic strategies. Not only is prognosis poor, but the molecular mechanism(s) behind disease development are not greatly understood. My lab utilizes molecular tools, coupled with both in vitro and in vivo models of infection and disease, to understand the cellular and viral players involved in genetic and epigenetic regulation of HTLV-1 gene expression and oncogenesis.

Project 1. Role of HTLV-1 Envelope in Transformation and Disease:

HTLV-2 is genetically and immunologically related to HTLV-1. However, unlike HTLV-1, HTLV-2 is generally not associated with disease. Comparative studies between these related viruses have been, and continue to be, extremely informative for identifying specific virus-host interactions associated with the pathogenic process.

Both HTLV-1 and HTLV-2 preferentially transform T-cells in vitro. HTLV-1 mainly transforms CD4+ T-cells, while HTLV-2 largely transforms CD8+ T-cells. Previous work mapped the genetic determinant for transformation tropism to the viral envelope protein (Env) and found transformation tropism is not solely conferred at the level of entry, but ensues during the cellular transformation process that occurs several weeks after infection. My lab utilizes comparative studies between Env-1 and Env-2 to identify and target the molecular mechanism(s) of HTLV-1 CD4+ T-cell transformation tropism using both in vitro and in vivo approaches.

Project 2. Role of PRMT5 in HTLV-1 Transformation and T-Cell Proliferation:

Modification of chromatin plays a central role in regulating various gene expression programs required during different stages of cell growth and development. One such chromatin modification is arginine methylation. PRMT5 is a type II PRMT enzyme that may act as either a transcriptional activator or repressor through symmetric dimethylation of arginine residues on histone proteins H4 (H4R3) and H3 (H3R8). During my postdoctoral training, I found PRMT5 expression was upregulated during HTLV-1-mediated T-cell transformation, as well as in established lymphocytic leukemia/lymphoma cell lines and ATL patient PBMCs. Interestingly, inhibition of PRMT5 by a novel small molecule inhibitor had selective toxicity in HTLV-1-transformed T-cells. Therefore, we hypothesize that PRMT5 could be an important epigenetic regulator of the HTLV-1 T-cell transformation process. We currently study how PRMT5 regulates HTLV-1-mediated T-cell transformation and pathogenesis.

Ongoing Collaborations:

Genome Editing to Prevent HTLV-1 Disease: Several studies have shown at least two viral genes, tax and hbz, are individually linked to cytokine activation, cell proliferation, and eventual oncogenic transformation. Tax is the major driver of viral transcription, transformation, and immune dysregulation, while HBZ supports proliferation and survival of HTLV-1-transformed cells in vivo and in vitro. HTLV-1 ATL tumor cells typically do not express tax, while hbz is always expressed in HTLV-1-infected cells, PBMCs of HTLV-1-infected individuals, and ATL tumor cells. Together, these two viral proteins are essential to the pathophysiology of both HAM/TSP and ATL. Our work will test the hypothesis that CRISPR/Cas9 genomic editing will be an effective method to disable the HTLV-1 provirus and its proliferative-inducing and tumorigenic effects on infected T-cells both in vitro, using cell culture-based assays, and in vivo, using a transplantation model in NOG mice. This work is part of a NIH-funded R21 Grant (Collaborators: Dr. Patrick Green & Dr. Kristine Yoder).

Contributions of HBZ to HTLV-1 Pathobiology: A mounting body of evidence suggests HBZ protein expression is critical throughout HTLV-1-mediated tumorigenesis. Tax is frequently silenced (by epigenetic modifications or deletion of the 5’ LTR) in ATL patients, presumably through CTL-mediated host immune-surveillance pressure. Therefore, HBZ-targeting strategies have strong potential for ATL and HAM/TSP therapeutics. Our group is focused on identification and characterization of HBZ cellular binding partners and their effects within T-cells. Insight of these roles will allow us to not only refine the role of HBZ in T-cell transformation and development of disease, but also explore HBZ cellular targets as potential marks for disease prevention and treatment. This project is one of two Aims from a NIH Program Project Grant (Collaborator: Dr. Patrick Green).