The role of
Hbz in transformation and disease
Principal Investigator: Patrick Green, PhD, The Ohio State University
The study of
retroviruses has resulted in important discoveries and led to insights into
basic cell biology including mechanisms of cell signaling, regulation of gene
expression, and ultimately cellular transformation and cancer. Our
collaborative work within this PPG focuses on HTLV-1, which is associated
primarily with adult T cell leukemia (ATL) and neurological disease in a small
percentage of infected individuals, and for
comparative studies the related but non pathogenic HTLV-2.
Disease progression by HTLV-1 has been attributed to Tax, although we and
others have hypothesized and provide data that another viral gene, termed Hbz,
plays a critical role in the malignant process.
Hbz is encoded from a functional promoter present in the antisense strand at the
3’ terminus of the HTLV-1 proviral genome. We
extended our work through collaborations with Dr. Ratner (Project 2) and
Dr. Niewiesk (Core C) to show that HBZ reduces Tax-mediated viral transcription,
promotes the proliferation of HTLV-1 infected cells by altering the
transcriptional activity of multiple cellular factors, and is required for
viral persistence and tumor cell organ infiltration in vivo. This exciting work provides the basis for this
highly integrative continuation project designed to determine the role of Hbz
in transformation and disease. Our overall hypothesis is that uncovering
the mechanism of actions of Hbz and defining the interplay between Hbz and Tax
will provide important insight into HTLV-1 cellular transformation and disease
and ultimately will provide means for therapeutic targeting to erradicate
HTLV-1 persistence in the host.
Aim 1 will dissect the
mechanisms of action of Hbz examining both protein and RNA functions. These
studies will focus on identifying cellular interacting proteins and their
effects on key signaling pathways, and determining the functional role of HBZ post-translational
Aim 2 will combine in vitro and in vivo approaches to determine the interplay between Hbz and Tax
in the cellular transformation and tumor induction process.