Abstract
The human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), a neoplasm of CD4+CD25+ T cells that occurs in 2–5% of infected individuals after decades of asymptomatic latent infection. Multiple HTLV-1-encoded regulatory proteins, including Tax and HTLV-1 basic leucine zipper factor (HBZ), play key roles in viral persistence and latency. The HTLV-1 Tax oncoprotein interacts with a plethora of host cellular proteins to regulate viral gene expression and also promote the aberrant activation of signaling pathways such as NF-κB to drive clonal proliferation and survival of T cells bearing the HTLV-1 provirus. Tax undergoes various post-translational modifications such as phosphorylation and ubiquitination that regulate its function and subcellular localization. Tax shuttles in different subcellular compartments for the activation of anti-apoptotic genes and deregulates the cell cycle with the induction of DNA damage for the accumulation of genomic instability that can result in cellular immortalization and malignant transformation. However, Tax is highly immunogenic and therefore HTLV-1 has evolved numerous strategies to tightly regulate Tax expression while maintaining the pool of anti-apoptotic genes through HBZ. In this review, we summarize the key findings on the oncogenic mechanisms used by Tax that set the stage for the development of ATLL, and the strategies used by HTLV-1 to tightly regulate Tax expression for immune evasion and viral persistence.
Highlights
The human T-cell lymphotropic virus type 1 (HTLV-1) is the first oncogenic retrovirus discovered in humans in the early 1980s by two independent research groups in Japan and America [1,2]
HTLV-1 is the causative agent of a neoplasm of CD4+CD25+ T cells known as adult T-cell leukemia/lymphoma (ATLL), which consists of four clinical subtypes: smoldering, chronic, lymphoma, and acute
Aberrant expression of NF-κB-inducing kinase (NIK) and persistent NF-κB activation may be linked to miR-31 repression in ATLL [111]; it remains unclear if Tax plays any role in miR-31 suppression
Summary
The human T-cell lymphotropic virus type 1 (HTLV-1) is the first oncogenic retrovirus discovered in humans in the early 1980s by two independent research groups in Japan and America [1,2]. HTLV-1 is an enveloped complex retrovirus that belongs to the family Retroviridae and genus deltaretrovirus. This genus includes three additional HTLV members, HTLV-2, -3, and -4 [3,4,5]. 10 million HTLV-1-infected people world-wide remain asymptomatic throughout life; 2–5% of infected individuals develop aggressive ATLL. The oncogenic ability of HTLV-1 is mediated by viral gene products and their interaction with host proteins to alter their function and favor viral infection and persistence. We will discuss recent findings on the mechanisms of HTLV-1-mediated transformation of T lymphocytes by the viral oncoprotein Tax
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