The Role of Human T Cell Lymphotropic Virus Type I Tax in the Development of Cutaneous T Cell Lymphoma

Abstract

Although it has been well established that the human T cell lymphotropic virus type I (HTLV‐I) causes adult T cell leukemia/lymphoma (ATLL) in regions of the world where this virus is endemic, its role in the pathogenesis of cutaneous T cell lymphoma (CTCL) in the Western world has been less well established. Most patients with CTCL are negative for antibodies to the structural proteins of HTLV‐I, and thus a causative role for this virus is usually dismissed. However, the Tax sequence of HTLV‐I has been found in the peripheral blood mononuclear cells of practically all patients with CTCL. Such patients express Tax mRNA and have antibodies to p40Tax, the protein encoded by this sequence. Sequence analysis of a 159‐bp region of Tax extracted from CTCL cells proved to be homologous with the same region prepared from a cell line infected with prototypic HTLV‐I. By in situ PCR, Tax has been demonstrated in the lymphocytes infiltrating the skin as well as in the keratinocytes of such patients. Apart from the pathophysiologic and clinical interest of these studies, these observations may have therapeutic implications. In vitro, the proliferation of HTLV‐I‐transformed cells can be inhibited by antisense to HTLV‐I Tax. Since Tax has not been identified in the normal human genome, antisense to Tax deserves serious consideration as a treatment modality for patients whose cells have been demonstrated to harbor Tax.

Current views in HTLV-I-associated adult T-cell leukemia/lymphoma

“…Most patients with CTCL are negative for antibodies to the structural proteins of HTLV-I, and thus a causative role for this virus is usually dismissed. However, numerous studies have found HTLV-I-related proviral tax sequence or deleted proviruses in tumor samples from CTCL patients [27][28][29][30][31][32][33][34]. Recently a study on the northeastern coast of Brazil found HTLV-I integrated proviral sequences by southern blot in several mycosis fungoides-like cutaneous lymphomas, and CD30 + largecell anaplastic lymphomas [35].…”

Incidence of Cutaneous T-Cell Lymphoma in the United States, 1973-2002

“…Several studies have suggested that infectious agents [12][13][14] or environmental exposures [15][16][17] may play a role in CTCL. While the unusual geographic differences seen in our data could be explained by an environmental or viral exposure, our data neither directly support nor contradict such hypotheses.…”

A novel high throughput quantum dot-based fluorescence assay for quantitation of virus binding and attachment

“…T cells represent the primary susceptible population in vivo while progenitor cells, monocytes, and dendritic cells have also been reported to be susceptible to infection by HTLV-1 (Ali et al, 1993;Makino et al, 1999) and were hence assessed for their relative binding affinity to HTLV-1. HTLV-1 has been shown to play a role in the pathogenesis of cutaneous T cell lymphoma (Zucker-Franklin, 2001), therefore, vaginal keratinocyte (VK-2) cells were also examined with respect to binding. The P4R5 cell line, a derivative of the epithelial cell line HeLa engineered to express HIV receptor (CD4) and co-receptors (CCR5 and CXCR4) were examined to determine if receptors for HIV-1 also played a role in HTLV-1 binding.…”