Читать книгу The Peripheral T-Cell Lymphomas - Группа авторов - Страница 37

HTLV1, also known as human T‐lymphotropic virus type 1, was the first exogenous human deltaretrovirus discovered [92]. The 9‐kb genome of HTLV1 encodes the gag, pol, and env structural proteins, plus accessory and regulatory proteins at the 3′ end of the genome (tax, rex, p12, p21, p30, p13, and HBZ) that play an important role in the regulation of viral replication, persistence, and leukemogenesis [93].

HTLV1 infection causes ATLL, after a long latency of about 50 years after mother‐to‐child transmission. ATLL is a disease exemplifying an infectious agent‐driven lymphoma and multistep lymphomagenesis. Only a small fraction of infected individuals will ever develop ATLL, while the majority of infected individuals will remain asymptomatic carriers. Given the long latency period and low incidence of ATLL development in HTLV1‐infected individuals, it is postulated that other events are required for transformation, besides the role of HTLV1 infection itself, which is supported by its constant presence and the monoclonal integration of a single viral copy in the majority of cases. It is estimated that an asymptomatic HTLV1‐positive individual carries between 10e4 to 10e5 distinct clones of HTLV1‐infected T cells and each clone is distinguished by a unique site of integration of the provirus into the host genome [94]. Conversely, a single dominant clone is found among a background of hundreds of clones in patients with ATLL [95]. The proviral integration site of HTLV1 into the host genome is strongly biased toward certain transcription factor binding sites, notably STAT1, TP53, and HDAC6 [96].

Two viral proteins are implicated in oncogenesis: the transactivator protein (TAX) that is critical for T‐cell proliferation mainly via activation of NF‐κB and AP‐1 pathways, and is involved in tumor initiation; and the antisense gene product basic leucine zipper protein (HBZ) that may serve as a tumor promoter and play a role in tumor maintenance [97]. However, most neoplastic cells do not express oncogenic viral TAX, and only express HBZ. The other genomic events identified to drive disease pathogenesis include alterations altering in T‐cell receptor‐NF‐κB signaling, T‐cell trafficking (e.g. CCR4, CCR7), and immunosurveillance, as described above [46].