Introduction

Research Background:

HTLV-1 (Human T Cell Leukemia/Lymphoma Virus type 1) was the first human retrovirus to be discovered in 1980, followed by HTLV-2 in 1983 and HTLV-3 in 2005 discovered by our team. The origin of most of HTLV-1 subtypes appears to be linked to episodes of interspecies transmission between STLV-1 (simian homologue of HTLV-1) infected monkeys and humans, followed by variable period of evolution in the human host. Among HTLVs, HTLV-1 is certainly the most studied and is etiologically linked to two main diseases: Adult T Leukemia/Lymphoma defined as a monoclonal proliferation of leukemic CD4+ T lymphocytes and Tropical Spastic Paraparesis/HTLV-1 associated myelopathy, characterized by the invasion of the central nervous system by HTLV-1 infected lymphocytes. Epidemiological studies have established a correlation between neonatal infection and development of ATL, several decades later. Our team was the first to put forward the fact that the infection of T cell progenitors in the thymus by this human retrovirus might be an important starting event in the initiation of the T- cell leukemogenic process.

The HTLV-1 proviral genome encompasses a unique set of non-structural regulatory proteins that have been shown to intervene in viral replication, and in the immortalization/transformation process. One of them, the Tax protein, a 40-kDa phosphoprotein, has the ability to trans-activate the proviral promoter but also to modulate a wide-array of cellular genes including regulators of the cell cycle, of apoptosis, cytokines or their receptor. All these genes play a crucial role in T-lymphocyte growth and function. Numerous observations have underlined the fact that Tax exerts these activities during the early steps of the leukemogenic process. Another viral protein, HBZ (HTLV-1 bZIP factor) encoded by the complementary strand of the HTLV-1 provirus has been shown to down-regulate Tax-mediated viral transcription. HBZ is the only regulatory protein expressed in leukemic cells and is therefore supposed to play a crucial effect during the late steps of the leukemogneic process. Experiments using either HBZ transgenic mice or rabbits infected with wild-type or HBZ-deficient HTLV-1 viruses have suggested that HBZ was responsible for (1) the proliferation of CD4+ lymphocytes cells and (2) the viral persistence in vivo.