# Interaction of HTLV-1 Tax & Hbz in Transformation

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2021 · $184,078

## Abstract

Interaction of HTLV-1 Tax & Hbz in Transformation
Abstract
 Human T-cell leukemia virus type 1 (HTLV-1) is the cause of a refractory T cell lymphoproliferative disorder,
designated adult T-cell leukemia lymphoma (ATLL). HTLV-1 encodes two oncogenes, Tax and Hbz, each of
which induces T cell lymphoma in transgenic mice. Tax is a potent transcriptional trans activator protein that
also induces genetic instability. However, Tax is immunogenic and its expression is down-regulated after
ATLL develops. Hbz RNA and protein have separable activities that promote T cell activation and proliferation.
Hbz is continuously expressed throughout infection. We hypothesize that the predominant role of Tax is T cell
lymphoma initiation, and the predominant role of Hbz is a T cell lymphoma promoter. We developed three
animal models to test this hypothesis and elucidate the underlying molecular mechanisms for the roles of these
oncogenes and their interactions. In our Tax+Hbz- transgenic mice, Tax is under the regulation of a
doxycycline inducible promoter. T cell lymphomas develop in the presence of doxycycline, and regress in its
absence. In our Tax-Hbz+ transgenic mice, full length Hbz RNA and functional epitope tagged Hbz protein are
expressed in activated T cells and induce T cell lymphomas. Double transgenic Tax+Hbz+ mice develop
tumors more rapidly than either single transgenic model. These animals have imaging markers to monitor
doxycycline induction and Tax activity. In Aim 1, we will compare full exon genomics and transcriptomics by
RNAseq of Tax+Hbz-, Tax-Hbz+, and Tax+Hbz+ mice all maintained on doxycycline in order to determine if
Tax induces genetic instability in our mouse model and whether mutations occur in genes that are frequently
mutated in ATLL. We will use RNAseq to identify genes responsible for the unique features of each transgene,
and if there are distinct alterations in double transgenic animals compared to single transgenic animals. In Aim
2, we will withdraw doxycycline in order to determine if tumors continue to proliferate in Tax+Hbz+ animals, but
regress in Tax+Hbz- animals, and to determine, by RNAseq, the genes responsible for the different biological
results. We will compare our transcriptomic alterations to those in ATLL. In Aim 3, we will use shRNAs or
lentivirus expression of key genes identified in the transgenic models, to test high priority candidates from our
murine model in short-term cultured ATLL cell lines. These studies will provide new insights into how Tax and
Hbz mediate transformation, which could lead to new therapies for ATLL and identification of novel biomarkers
for this disease.

## Key facts

- **NIH application ID:** 10189192
- **Project number:** 1R21CA252869-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Lee Ratner
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $184,078
- **Award type:** 1
- **Project period:** 2021-05-10 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189192

## Citation

> US National Institutes of Health, RePORTER application 10189192, Interaction of HTLV-1 Tax & Hbz in Transformation (1R21CA252869-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10189192. Licensed CC0.

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