Autophagy in Human T-Cell Leukemia Virus Type 1 (HTLV-1) Induced Leukemia

Abstract

Viruses play an important role in the development of certain human cancers. They are estimated to contribute 16% to all human cancers. Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus to be discovered and is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive T-cell malignancy with poor prognosis. HTLV-1 viral proteins interact with mechanisms and proteins present in host cells for their own benefit, evading the immune system and promoting the establishment of disease. Several viruses manipulate the autophagy pathway to achieve their infective goals, and HTLV-1 is not the exception. HTLV-1 Tax viral protein engages NF-κB and autophagy pathways prone favoring viral replication and T cell transformation. In this review we focus on describing the relationship of HTLV-1 with the autophagy machinery and its implication in the development of ATLL.

Keywords: HTLV-1; NF-κB; T-cell leukemia; autophagy; tax.

Figure 1

In HTLV-1 infection, the viral protein Tax interferes at several steps of both canonical and noncanonical NF-κB pathway in order to activate it, inducing cell survival and proliferation, and eventually resulting in oncogenesis. By interaction with IKKγ/NEMO, Tax recruits and activates IKK complex (IKKγ/NEMO, IKKα, IKKβ) in lipid raft domains (LRD) on the Golgi. After IKK activation, Tax recruits the autophagy proteins BECN1, Bif-1 and the PI3KC3 complex through its direct interaction with BECN1, which in turn binds also with IKKα, IKKβ. Then, Tax deregulates the autophagy pathway fostering autophagosomes biogenesis but, at the same time, blocking the autophagosome-lysosome fusion. Autophagosomes accumulation enhances HTLV-1 replication. Moreover, recent data suggest a crosstalk between autophagic and extracellular vesicles (EVs) biogenesis pathways. EVs from HTLV-1 infected cells bearing the viral proteins Tax and HBZ among some host proteins, and transcriptional mRNA of Tax, HBZ and 5’LTR has been reported.