Abstract
Human T-cell leukemia virus type 1 (HTLV-1) is the only identified oncogenic human retrovirus. HTLV-1 infects approximately 5–10 million people worldwide and is the infectious cause of adult T-cell leukemia/lymphoma (ATL) and several chronic inflammatory diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), dermatitis, and uveitis. Unlike other oncogenic retroviruses, HTLV-1 does not capture a cellular proto-oncogene or induce proviral insertional mutagenesis. HTLV-1 is a trans-activating retrovirus and encodes accessory proteins that induce cellular transformation over an extended period of time, upwards of several years to decades. Inarguably the most important viral accessory protein involved in transformation is Tax. Tax is a multifunctional protein that regulates several different pathways and cellular processes. This single viral protein is able to modulate viral gene expression, activate NF-κB signaling pathways, deregulate the cell cycle, disrupt apoptosis, and induce genomic instability. The summation of these processes results in cellular transformation and virus-mediated oncogenesis. Interestingly, HTLV-1 also encodes a protein called Hbz from the antisense strand of the proviral genome that counters many Tax functions in the infected cell, such as Tax-mediated viral transcription and NF-κB activation. However, Hbz also promotes cellular proliferation, inhibits apoptosis, and disrupts genomic integrity. In addition to viral proteins, there are other cellular factors such as MEF-2, superoxide-generating NAPDH oxidase 5-α (Nox5α), and PDLIM2 which have been shown to be critical for HTLV-1-mediated T-cell transformation. This review will highlight the important viral and cellular factors involved in HTLV-1 transformation and the available in vitro and in vivo tools used to study this complex process.
Highlights
Human T-cell leukemia virus type 1 (HTLV-1) is a complex delta retrovirus within the Orthoretrovirinae subfamily
Transformation of HTLV-1-infected T-cells is mediated by a wide variety of both viral and cellular proteins. Viral proteins such as Tax and Hbz play an important role in T-cell transformation, there are several additional cellular factors that contribute to this process (Table 2)
Serving as the primary driving force for viral transformation, the HTLV-1-encoded Tax oncoprotein is critical for viral gene expression, immortalization, and pathogenesis
Summary
Human T-cell leukemia virus type 1 (HTLV-1) is a complex delta retrovirus within the Orthoretrovirinae subfamily. The transformation of HTLV-1-infected T-cells is dependent on other viral proteins in addition to Tax. A promoter on the antisense strand in the 3’ LTR of the proviral genome drives expression of Hbz, the only viral protein derived from an anti-sense transcript in HTLV-1. Viral proteins such as Tax and Hbz play an important role in T-cell transformation, there are several additional cellular factors that contribute to this process (Table 2) These cellular factors become increasingly relevant later during viral infection, as Tax expression is typically silenced in the majority of ATL patient samples (94). Cellular factors and miRNAs have a wide variety of diverse functions that can serve to either promote or suppress HTLV-1-mediated T-cell transformation independent of Tax or Hbz
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