Human T Lymphotropic Virus Type I (HTLV-I) Oncogenesis: Molecular Aspects of Virus and Host Interactions in Pathogenesis of Adult T cell Leukemia/Lymphoma (ATL) (original) (raw)
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Human T Lymphotropic Virus Type 1 (HTLV-1): Molecular Biology and Oncogenesis
Viruses, 2010
Human T lymphotropic viruses (HTLVs) are complex deltaretroviruses that do not contain a proto-oncogene in their genome, yet are capable of transforming primary T lymphocytes both in vitro and in vivo. There are four known strains of HTLV including HTLV type 1 (HTLV-1), HTLV-2, HTLV-3 and HTLV-4. HTLV-1 is primarily associated with adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-2 is rarely pathogenic and is sporadically associated with neurological disorders. There have been no diseases associated with HTLV-3 or HTLV-4 to date. Due to the difference in the disease manifestation between HTLV-1 and HTLV-2, a clear understanding of their individual pathobiologies and the role of various viral proteins in transformation should provide insights into better prognosis and prevention strategies. In this review, we aim to summarize the data accumulated so far in the transformation and pathogenesis of HTLV-1, focusing on the viral Tax...
BMC Cancer, 2018
Background: Adult T-cell leukemia/lymphoma (ATLL) is a lymphoproliferative disorder of HTLV-1-host interactions in infected TCD4+ cells. In this study, the HTLV-1 proviral load (PVL) and HBZ as viral elements and AKT1, BAD, FOXP3, RORγt and IFNλ3 as the host factors were investigated. Methods: The study was conducted in ATLLs, HTLV-1-associated myelopathy/tropical spastic paraparesis patients (HAM/TSPs) and HTLV-1-asympthomatic carriers (ACs). The DNA and mRNA from peripheral blood mononuclear cells were extracted for gene expression assessments via qRT-PCR, TaqMan assay, and then confirmed by western blotting. Results: As it was expected, the HTLV-1-PVL were higher in ATLLs than ACs (P = 0.002) and HAM/TSP (P = 0.041). The HBZ expression in ATLL (101.76 ± 61.3) was radically higher than in ACs (0.12 ± 0.05) and HAM/ TSP (0.01 ± 0.1) (P = 0.001). Furthermore, the AKT1 expression in ATLLs (13.52 ± 4.78) was higher than ACs (1.17 ± 0.27) (P = 0.05) and HAM/TSPs (0.72 ± 0.49) (P = 0.008). However, BAD expression in ATLL was slightly higher than ACs and HAM/TSPs and not significant. The FOXP3 in ATLLs (41.02 ± 24.2) was more than ACs (1.44 ± 1) (P = 0.007) and HAM/TSP (0.45 ± 0.15) (P = 0.01). However, RORγt in ATLLs (27.43 ± 14.8) was higher than ACs (1.05 ± 0.32) (P = 0.02) but not HAM/TSPs. Finally, the IFNλ3 expression between ATLLs (31.92 ± 26.02) and ACs (1.46 ± 0.63) (P = 0.01) and ACs and HAM/TSPs (680.62 ± 674.6) (P = 0.02) were statistically different, but not between ATLLs and HAM/TSPs. Conclusions: The present and our previous study demonstrated that HTLV-1-PVL and HBZ and host AKT1 and Rad 51 are novel candidates for molecular targeting therapy of ATLL. However, high level of RORγt may inhibit Th1 response and complicated in ATLL progressions.
Human T-cell lymphotropic virus type 1 oncogenesis and cell-to-cell spread
European Journal of Biology
Exploring host-HTLV-1 interactions and the molecular processes underpinning HTLV-1-mediated carcinogenesis is crucial for establishing effective treatments for viral infection and associated leukemia/lymphoma. Several HTLV-1 proteins have been shown to play important roles in the cellular transformation and immortalization of infected T cells. Through interactions with MAVS, STING, and RIP1, the HTLV-1 oncoprotein Tax suppresses the innate IFN response, resulting in the inhibition of TBK1-mediated phosphorylation of IRF3/IRF7. The HTLV-1 protein HBZ affects genomic integrity and inhibits target cell death and autophagy. Furthermore, it has been discovered that HBZ promotes the growth of ATL cells and aids in the evasion of infected cells from immunosurveillance. It currently appears that the efficacy of an individual's cytotoxic T cell (CTL) response to HTLV-1 is the most important single predictor of that person's provirus load, which can differ by more than 10,000-fold amo...
HTLV‐1 oncovirus‐host interactions: From entry to the manifestation of associated diseases
Reviews in Medical Virology, 2021
Human T lymphotropic virus type‐1 (HTLV‐1) is a well‐known human oncovirus, associated with two life‐threatening diseases, adult T cell leukaemia/lymphoma (ATL) and HTLV‐1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The study of this oncogenic virus is significant from two different aspects. First, HTLV‐1 can be considered as a neglected public health problem, which may spread slowly worldwide. Second, the incidence of HTLV‐1 associated diseases due to oncogenic effects and deterioration of the immune system towards autoimmune diseases are not fully understood. Furthermore, knowledge about viral routes of transmission is important for considering potential interventions, treatments or vaccines in endemic regions. In this review, novel characteristics of HTLV‐1, such as the unusual infectivity of virions through the virological synapse, are discussed in the context of the HTLV‐1 associated diseases (ATL and HAM/TSP).
Human T cell leukemia virus type I-induced disease: pathways to cancer and neurodegeneration
Virology, 2003
Retroviral infection is associated with a number of pathologic abnormalities, including a variety of cancers, immunologic diseases, and neurologic disorders. Shortly after its discovery in 1980, human T cell leukemia virus type I (HTLV-I) was found to be the etiologic agent of both adult T cell leukemia (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a neurologic disease characterized by demyelinating lesions in both the brain and the spinal cord. Approximately 5-10% of HTLV-I-infected individuals develop either ATL or HAM/TSP. Interestingly, the two diseases have vastly different pathologies and have rarely been found to occur within the same individual. While a number of host and viral factors including virus strain, viral load, and HLA haplotype have been hypothesized to influence disease outcome associated with HTLV-I infection, the relative contributions of such factors to disease pathogenesis have not been fully established. Recent research has suggested that the route of primary viral infection may dictate the course of disease pathogenesis associated with HTLV-I infection. Specifically, mucosal exposure to HTLV-I has been associated with cases of ATL, while primary viral infection based in the peripheral blood has been correlated with progression to HAM/TSP. However, the cellular and molecular mechanisms regulating disease progression resulting from primary viral invasion remain to be elucidated. Although a variety of factors likely influence these mechanisms, the differential immune response mounted by the host against the incoming virus initiated in either the peripheral blood or the mucosal compartments likely plays a key role in determining the outcome of HTLV-I infection. It has been proposed that the route of infection and size of the initial viral inoculum allows HTLV-I to infect different target cell populations, in turn influencing the breadth of the immune response mounted against HTLV-I and affecting disease pathogenesis. A model of HTLV-I-induced disease progression is presented, integrating information regarding the role of several host and viral factors in the genesis of both neoplasia and neurologic disease induced following HTLV-I infection, focusing specifically on differential viral invasion into the bone marrow (BM) and the influence of this event on the virus-specific CD8 ϩ cytotoxic T lymphocyte (CTL) response that is initiated following HTLV-I infection.
Molecular and cellular aspects of HTLV-1 associated leukemogenesis in vivo
Leukemia, 2003
Most cancers and leukemias are preceded by a prolonged period of clinical latency during which cellular, chromosomal and molecular aberrations help move normal cell towards the malignant phenotype. The problem is that premalignant cells are usually indistinguishable from their normal counterparts, thereby ruling out the possibility to investigate the events that govern early leukemogenesis in vivo. Adult T cell leukemia/lymphoma (ATLL) is a T cell malignancy that occurs after a 40-60-year period of clinical latency in about 3-5% of HTLV-1-infected individuals. ATLL cells are monoclonally expanded and harbor an integrated provirus. A persistent oligo/polyclonal expansion of HTLV-1-bearing cells has been shown to precede ATLL, supporting the fact that in ATLL tumor cells arise from a clonally expanding non-malignant cell. It is possible to isolate infected, ie preleukemic, cells during the premalignant asymptomatic phase of the infection, thus providing an exceptional system to study the mechanisms underlying human cancers. Here we review some of the consequences of HTLV-1 on its host cell in vivo, at different stages of infection.
The Exceptional Oncogenicity of HTLV-1
Frontiers in Microbiology, 2017
Human T-cell leukemia virus-1 (HTLV-1) is the first pathogenic human retrovirus identified in 1979 by the Gallo group. HTLV-1 causes fatal T-cell leukemia (adult T cell leukemia) and a progressive myelopahy (HTLV-1-associated myelopathy/ tropical spastic paraparesis, HAM/TSP) and other disorders. Since the discovery of HTLV-1, several other microorganisms are demonstrated to cause cancer in humans. In this article, we investigated the oncogenic capacity of HTLV-1, in comparison with those of other oncoviruses and one oncobacterium (Helicobacter pylori, H. Pylori) based on published literature. We conclude here that HTLV-1 is one of the most and may be the most carcinogenic among them and arguably one of the most potent of the known human carcinogens. This fact has not been noted before and is particularly important to justify why we need to study HTLV-1 as an important model of human viral oncogenesis.
Human T-Cell Leukemia Virus Type 1 (HTLV-1)
2017
Human T-Cell Leukemia Virus Type 1 (HTLV-1) is the first human retrovirus lacking a cell-derived oncogene yet is more complex than other oncogenic retroviruses. In addition to essential structural and enzymatic genes (gag, pro, pol, and env) shared by all retroviral family members, HTLV-1 encodes a unique pX region, which generates two regulatory (Tax, Rex) and five accessory (HBZ, p30, p12, p13, p8) proteins. Among them, Tax and HBZ affect expression levels of several host genes, thereby playing pivotal roles in leukemogenesis. The modes of action of Tax and HBZ involve a variety of cell signaling pathways including CREB/ATF, NF-κB, and PI3K/AKT that lead to accelerated cell proliferation concurrently with induction of genomic lesions. Tax is no longer expressed in most ATL cases but the growth-promoting activities are taken over by mutated host genes closely associated with Tax functions, while HBZ is constitutively expressed to maintain the transforming phenotype.