Project 3: Epigenomic Regulation of HTLV-1 Reactivation & Pathogenesis

$493,051P01FY2025CANIH

Washington University, Saint Louis MO

Investigators

Linked publications, trials & patents

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Abstract

PROJECT SUMMARY/ABSTRACT â Project 3: Epigenomic Regulation of HTLV-1 Reactivation & Pathogenesis Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATLL), an aggressive lymphoproliferative malignancy refractory to therapy. Our previous work showed that chromatin insulator, CTCF, binds HTLV-1 DNA at a single site (vCTCF-BS), and regulates virus gene expression in an integration site- dependent manner through effects on DNA methylation and histone modifications. In addition, we showed that a viral enhancer in the 3â portion of the genome is important for expression of the antisense viral oncogene hbz. The current project will define the role of epigenomic regulation by these key regulatory elements in the following aims to determine: AIM 1. Combined effects of vEnhancer and vCTCF-BS in HTLV-1 persistence and disease examining viral gene expression and T-cell immortalization in culture and in rabbits and in humanized immunodeficient mice. A multi-omic approach will examine proviral and T-cell receptor clonality in comparison to primary ATLL samples. AIM 2. Role of chromatin insulators in HTLV-1 infection, replication, and gene expression comparing binding sites and effects on DNA looping of CTCF, cohesin, and other interactive proteins in HTLV-1 reactivation from latency, and in primary infected clinical samples. Effects on cohesin kockdown on virus gene expression will also be examined. Transcriptional and post-transcriptional effects will be assessed by short and long read RNA sequencing. AIM 3. Impact of epigenetics on HTLV-1 pathogenesis. Effects of vCTCF-mutation will be examined in CD4+ and CD4+CD8+ lymphocytes, and in ATLL tumor samples, as well as the ability of an exogenous looping protein to reconstitute the effects of vCTCF-BS mutation. We expect that knowledge obtained from these studies can guide epigenomic therapeutic approaches for ATLL.

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