The influence of htlv-1 DNA elements on viral… (F31AI197799) – Project Grant to The Ohio State University

Abstract: Human t-cell leukemia virus type 1 (htlv-1) is a retrovirus that infects CD4 t cells and causes a persistent, life- long infection leading to the development of adult t-cell leukemia/lymphoma (atll) in ~5% of infected individuals. IT is currently unclear why only a portion of infected individuals develop disease. The integrated htlv-1 DNA genome (termed the provirus) is flanked by DNA elements called long terminal repeats (ltrs) at both the 5' and 3' ends. The ltrs contain promoter and regulatory elements that drive sense (5' LTR) and antisense (3' LTR) viral gene expression. Disease progression by htlv-1 has been attributed to the viral gene tax (sense gene, initiated from 5' LTR). A viral gene termed HBZ (antisense gene, initiated from 3' LTR) was recently shown to play a critical role throughout infection by promoting survival and proliferation of infected cells (i.e. persistence). Tax is silenced in ~70% of atll samples, while HBZ is consistently expressed in all infected cells. Htlv-1 leukemogenesis is also characterized by clonal expansion of infected t cells. Clonal abundance in htlv-1 infected individuals differs, whereas asymptomatic carriers contain multiple low abundance clones (polyclonal) and atll patients show monoclonal expansion and contain one or a few dominant malignant clones. However, the mechanism(s) responsible for the establishment of dominant malignant clones is unknown. Recently, DNA elements have been identified within the htlv-1 provirus that have potential roles in htlv-1 pathogenesis. These DNA elements include the viral enhancer element (venhancer) and the insulator element that contains the viral ccctc binding factor binding site (vctcf-BS). The venhancer element, which binds SRF and ELK-1 transcription factors, can influence HBZ antisense transcript abundance in vitro and in vivo. Studies show binding of host ctcf protein to the vctcf-BS prevents the spread of repressive DNA methylation from the insulator element to the 3' LTR. In addition, the presence of the vctcf-BS insulator element increased venhancer activity in vitro, specifically at the 3' LTR promoter. I hypothesize venhancer and vctcf-BS DNA elements play a combinatorial role in persistence by regulating HBZ gene expression and the subsequent selection and formation of a dominant malignant clone. I have generated proviral mutant clones which lack venhancer, vctcf-BS, or the combination. My preliminary studies demonstrate these mutant viruses can infect and immortalize t cells in vitro. In aim 1, i will determine the combined effect of the venhancer and vctcf-BS on viral gene expression and persistence using newly immortalized cells and a well-established rabbit model of infection. In aim 2, i will determine effects of the venhancer and/or vctcf-BS on htlv-1 clonal abundance and disease progression in humanized mice. These studies are expected to further elucidate the roles of both vctcf- BS and venhancer in htlv-1 pathogenesis. The proposed project provides an excellent training opportunity and environment that encompasses molecular mechanisms of viral pathogenesis, professional development, and mentorship that supports my goals and growth as an independent research scientist.

Action	Obligated	Date
Amendment	$0	Aug 31, 2026
Original award	$41,912	Aug 14, 2026

The influence of htlv-1 DNA elements on viral persistence and clonality

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