Transformation to continuous growth of primary human T lymphocytes by human T-cell leukemia virus type I X-region genes transduced by a Herpesvirus saimiri vector.

Abstract

The role of the X region of the genome of the human T-cell leukemia virus type I (HTLV-I) in the hmmortalization of lymphocytes has been difficult to distinguish from its role in viral replication as this region encodes at least two genes, tax and rex, required for replication and the expression of viral proteins. To determine whether the X region does encode immortalizing functions, a fragment of the HTLV-I provirus capable of expressing known X-region proteins was inserted into the genome of a transformation-defective, replication-competent Herpesvirus saimiri. Infection of fresh mitogen-activated human cord blood and thymocytes yielded immortal T-cell lines that had the same phenotype (CD4+, CD5+, HLA class HII, interleukin 2 receptor a-chain +) as lymphocytes transformed by cocultivation with HTLV-I. These experiments demonstrate that the X region encodes the functions of HTLV-I that immortalize a distinct subpopulation of human T cells. The experiments also demonstrate the utility of the H.saimiri vector for the transduction of heterologous genes into human T cells.

The tax protein from the primate T-cell lymphotropic virus type 3 is expressed in vivo and is functionally related to HTLV-1 Tax rather than HTLV-2 Tax

“…Several lines of evidence have demonstrated a pivotal role for the HTLV-1 Tax protein in the immortalization or transformation of the HTLV-1-infected cells. As an example, the transduction of the tax1 gene into primary human T lymphocytes using a defective simian herpes virus is sufficient to immortalize them (Grassmann et al, 1989). Likewise, the expression of Tax1 or the co-transfection of Tax1 and Ras in …”

The C-terminus of the HTLV-1 Tax oncoprotein mediates interaction with the PDZ domain of cellular proteins

“…Another interesting facet of Tax is its ability to transform cells. The oncogenic properties of this protein have been established by various assays, including transformation of primary T lymphocytes (Grassmann et al, 1989), cooperation with Ras in transformation of ®broblasts (Pozzatti et al, 1990) and induction of tumours in transgenic mice (Nerenberg et al, 1987;Benvenisty et al, 1992;Grossman et al, 1995). Tax transgenic mice are also known to develop several pathologies including thymus atrophy (Furuta et al, 1989), muscle degeneracy (Nerenberg and Wiley, 1989), arthritis (Iwakura et al, 1991) and a proliferation of ductal cells of the salivary gland resembling the SjoÈ gren syndrome (Green et al, 1989).…”

Tax protein of HTLV-1 inhibits CBP/p300-mediated transcription by interfering with recruitment of CBP/p300 onto DNA element of E-box or p53 binding site

“…The virus-encoded regulatory protein Tax is critical for HTLV-1 replication and is thought to contribute to ATL development (Yoshida, 1993). Tax has been shown to immortalize T lymphocytes and transform rodent cells (Grassmann et al, 1989;Yamaoka et al, 1996). Transgenic mice that express Tax in mature T lymphocytes developed large granular lymphocytic leukemia, showing that Tax has the capacity to induce leukemia (Grossman et al, 1995).…”