Identification of the gene responsible for human T-cell leukaemia virus transcriptional regulation

Abstract

Human T-cell leukaemia viruses (HTLVs) have genomic organization distinct from that of other replication-competent retroviruses, possessing four genes, gag, pol, env and chi. The unique fourth gene, chi (also referred to as lor), is located between env and the 3' long terminal repeat (LTR), encoding a protein of relative molecular mass 40,000 for HTLV-I and 37,000 for HTLV-II, located in the nucleus of infected cells. HTLV-I is the causative agent of adult T-cell leukaemia (ATL), a T-lymphocyte malignancy, while HTLV-II has been found associated with a T-cell variant of hairy cell leukaemia. Both viruses immortalize T cells in vitro. However, the mechanism of cellular transformation induced by HTLV is not known as there seems to be no common site of provirus integration in primary ATL cells and the virus contains no classical oncogene sequences. These observations have provoked speculation that the unique and strongly conserved chi protein (85% amino-acid homology between HTLV-I and -II) is involved in HTLV leukaemogenesis. Recent mutagenesis experiments in our laboratory have shown that the chi gene is essential for HTLV replication. It has also has been shown that the LTRs of HTLV and the related bovine leukaemia virus (BLV) are activated in trans in virus-infected cells, and, although such experiments did not directly demonstrate a role for the chi protein in transcriptional activation, it has been suggested that the chi protein is responsible for the transcriptional activation of the LTR and may be involved in cellular transformation. We have now developed a transient co-transfection assay which demonstrates that transcriptional activation of the HTLV LTR is mediated solely by the chi protein and that no other virus genes are required.

Detection and quantitation of HTLV-1 and HTLV-2 mRNA species by real-time RT-PCR

“…HTLV-1 and HTLV-2 express a doubly or completely-spliced mRNA that produces the positive regulatory proteins Tax from the pX open reading frame (ORF) IV and Rex from the partially overlapping ORF III. Tax increases the rate of transcription from the viral long terminal repeat (LTR) (Cann et al, 1985;Felber et al, 1985;Inoue et al, 1987) and modulates the transcription or activity of numerous cellular genes involved in cell growth and differentiation, cell cycle control, and DNA repair (Leung and Nabel, 1988;Mulloy et al, 1998;Ressler et al, 1997;Schmitt et al, 1998;Siekevitz et al, 1987). Compelling evidence indicates that the pleiotropic effects of Tax on cellular processes are required for the transforming or oncogenic capacity of HTLV (Endo et al, 2002;Grossman et al, 1995;Robek and Ratner, 1999;Ross et al, 2000;Ross et al, 1996;Wycuff and Marriott, 2005).…”

Titration of cellular export factors, but not heteromultimerization, is the molecular mechanism of trans-dominant HTLV-1 Rex mutants

“…HTLV-1 encodes at least two regulatory proteins, Tax and Rex, which are essential for virus replication (reviewed in : Cullen, 1992;Gitlin et al, 1993;Smith and Greene, 1991). Tax enhances transcription of all viral genes acting on the viral long terminal repeat promoter element (LTR) (Cann et al, 1985;Sodroski et al, 1985) and has been implicated in pathogenesis by dysregulating a number of regulatory cellular promoters and proteins (for review see : Yoshida, 1996). In contrast, the rex gene product acts at the posttranscriptional level, permitting the expression of the viral structural proteins (Hidaka et al, 1988;Inoue et al, 1986).…”

Functional interaction of the HTLV-1 transactivator Tax with activating transcription factor-4 (ATF4)

“…The Tax protein of HTLV-1 is a potent transactivator of viral gene expression (Cann et al, 1985;Felber et al, 1985;Fujisawa et al, 1985) and is capable of immortalizing human T lymphocytes in vitro (Grassmann et al, 1989;Tanaka et al, 1990). Tax is a 40 kDa nuclear protein that activates viral transcription through an enhancer element (Tax responsive element: TRE) consisting of three 21 bp repeats located within the HTLV-1 LTR (Sodroski et al, 1984;Felber et al, 1985;Brady et al, 1987;Paskalis et al, 1986).…”