294
Views
0
CrossRef citations to date
0
Altmetric
Invited Reviews

Pathogenicity and virulence of human T lymphotropic virus type-1 (HTLV-1) in oncogenesis: adult T-cell leukemia/lymphoma (ATLL)

ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 189-211 | Received 07 Apr 2022, Accepted 08 Dec 2022, Published online: 02 Jan 2023

References

  • Gessain A, Cassar O. Epidemiological aspects and world distribution of HTLV-1 infection. Front Microbiol. 2012;3:388.
  • Gallo RC. History of the discoveries of the first human retroviruses: HTLV-1 and HTLV-2. Oncogene. 2005;24(39):5926–5930.
  • Verdonck KG, Van Dooren S, Vandamme AM, et al. Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis. 2007;7(4):266–281.
  • Bangham CR, Araujo A, Yamano Y, et al. HTLV-1-associated myelopathy/tropical spastic paraparesis. Nat Rev Dis Primers. 2015;1:15012.
  • Bangham CRM. Human T cell leukemia virus type 1: persistence and pathogenesis. Annu Rev Immunol. 2018;36:43–71.
  • Higuchi Y, Yasunaga J-I, Mitagami Y, et al. HTLV-1 induces T cell malignancy and inflammation by viral antisense factor-mediated modulation of the cytokine signaling. Proc Natl Acad Sci U S A. 2020;117(24):13740–13749.
  • Ahmadi Ghezeldasht S, Shamsian SAA, Gholizadeh Navashenaq J, et al. HTLV-1 oncovirus–host interactions: from entry to the manifestation of associated diseases. Rev Med Virol. 2021;31(6):e2235.
  • Rosadas C, Taylor GP. Mother-to-child HTLV-1 transmission: unmet research needs. Front Microbiol. 2019;10:999.
  • Baratella M, Forlani G, Accolla RS. HTLV-1 HBZ viral protein: a key player in HTLV-1 mediated diseases. Front Microbiol. 2017;8:2615.
  • Klinkon M, Černe M. Cutaneous T‐cell lymphoma in a heifer with increased serum lactate dehydrogenase activity. Vet Clin Pathol. 2006;35(2):231–234.
  • Ghezeldasht SA, Shirdel A, Assarehzadegan MA, et al. 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). Iran J Basic Med Sci. 2013;16(3):179–195.
  • Tsukasaki K, Hermine O, Bazarbachi A, et al. Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia–lymphoma: a proposal from an international consensus meeting. J Clin Oncol. 2009;27(3):453–459.
  • Ashrafi F, Rahimzada M, Parandi M, et al. Molecular insight into the study of adult T-cell leukemia/lymphoma (ATLL): ten-year studies on HTLV-1 associated diseases in an endemic region. Gene. 2022;847:146885.
  • Razavi Pashabayg C, Momenifar N, Malekpour SA, et al. Phylogenetic and phylodynamic study of human T-cell lymphotropic virus type 1 (HTLV-1) in Iran. Infect Genet Evol. 2020;85:104426.
  • Hedayati-Moghaddam MR, Jafarzadeh Esfehani R, El Hajj H, et al. Updates on the epidemiology of the human T-cell leukemia virus type 1 infection in the countries of the Eastern Mediterranean Regional Office of the World Health Organization with special emphasis on the situation in Iran. Viruses. 2022;14(4):664.
  • Hedayati-Moghaddam MR, Tehranian F, Bayati M. Human T-lymphotropic virus type I (HTLV-1) infection among Iranian blood donors: first case-control study on the risk factors. Viruses. 2015;7(11):5736–5745.
  • Farid R, Etemadi M, Baradaran H, et al. Seroepidemiology and virology of HTLV-1 in the city of Mashhad, northeastern Iran. Serodiagn Immunother Infect Dis. 1993;5(4):251–252.
  • Georgieva ER. Non-structural proteins from human T-cell leukemia virus type 1 in cellular membranes—mechanisms for viral survivability and proliferation. Int J Mol Sci. 2018;19(11):3508.
  • Kataoka K, Nagata Y, Kitanaka A, et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat Genet. 2015;47(11):1304–1315.
  • Ratner L. Molecular biology of human T cell leukemia virus. Semin Diagn Pathol. 2020;37(2):104–109.
  • Martinez MP, Al-Saleem J, Green PL. Comparative virology of HTLV-1 and HTLV-2. Retrovirology. 2019;16(1):21.
  • Donhauser N, Socher E, Millen S, et al. Transfer of HTLV-1 p8 and gag to target T-cells depends on VASP, a novel interaction partner of p8. PLoS Pathog. 2020;16(9):e1008879.
  • Bhatt V, Shi K, Salamango DJ, et al. Structural basis of host protein hijacking in human T-cell leukemia virus integration. Nat Commun. 2020;11(1):3121.
  • Martin JL, Mendonça LM, Marusinec R, et al. Critical role of the human T-cell leukemia virus type 1 capsid N-terminal domain for Gag–Gag interactions and virus particle assembly. J Virol. 2018;92(14):e00333-18.
  • Makiyama J, Kobayashi S, Watanabe E, et al. CD4(+) CADM1(+) cell percentage predicts disease progression in HTLV-1 carriers and indolent adult T-cell leukemia/lymphoma. Cancer Sci. 2019;110(12):3746–3753.
  • Rowan AG, Dillon R, Witkover A, et al. Evolution of retrovirus-infected premalignant T-cell clones prior to adult T-cell leukemia/lymphoma diagnosis. Blood. 2020;135(23):2023–2032.
  • Tanaka Y, Mukai R, Ohshima T. HTLV-1 viral oncoprotein HBZ contributes to the enhancement of HAX-1 stability by impairing the ubiquitination pathway. J Cell Physiol. 2021;236(4):2756–2766.
  • Forlani G, Baratella M, Tedeschi A, et al. HTLV-1 HBZ protein resides exclusively in the cytoplasm of infected cells in asymptomatic carriers and HAM/TSP patients. Front Microbiol. 2019;10:819.
  • Rushing AW, Hoang K, Polakowski N, et al. The human T-cell leukemia virus type 1 basic leucine zipper factor attenuates repair of double-stranded DNA breaks via nonhomologous end joining. J Virol. 2018;92(15):e00672-18.
  • Manel N, Kim FJ, Kinet S, et al. The ubiquitous glucose transporter GLUT-1 is a receptor for HTLV. Cell. 2003;115(4):449–459.
  • Uchiyama T. Human T cell leukemia virus type I (HTLV-I) and human diseases. Annu Rev Immunol. 1997;15:15–37.
  • Nagai M, Brennan MB, Sakai JA, et al. CD8(+) T cells are an in vivo reservoir for human T-cell lymphotropic virus type I. Blood. 2001;98(6):1858–1861.
  • Jones KS, Petrow-Sadowski C, Huang YK, et al. Cell-free HTLV-1 infects dendritic cells leading to transmission and transformation of CD4(+) T cells. Nat Med. 2008;14(4):429–436.
  • Demontis MA, Sadiq MT, Golz S, et al. HTLV-1 viral RNA is detected rarely in plasma of HTLV-1 infected subjects. J Med Virol. 2015;87(12):2130–2134.
  • Pique C, Jones KS. Pathways of cell–cell transmission of HTLV-1. Front Microbiol. 2012;3:378.
  • Jin J, Sherer N, Mothes W. Surface transmission or polarized egress? Lessons learned from HTLV cell-to-cell transmission. Viruses. 2010;2(2):601–605.
  • Gross C, Thoma-Kress AK. Molecular mechanisms of HTLV-1 cell-to-cell transmission. Viruses. 2016;8(3):74.
  • Pinto DO, DeMarino C, Pleet ML, et al. HTLV-1 extracellular vesicles promote cell-to-cell contact. Front Microbiol. 2019;10:2147.
  • Oliveira PD, Kachimarek AC, Bittencourt AL. Early onset of HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATL): systematic search and review. J Trop Pediatr. 2018;64(2):151–161.
  • Take H, Umemoto M, Kusuhara K, et al. Transmission routes of HTLV‐I: an analysis of 66 families. Jpn J Cancer Res. 1993;84(12):1265–1267.
  • Varandas CMN, da Silva JLS, Primo JRL, et al. Early juvenile human T-cell lymphotropic virus type-1-associated myelopathy/tropical spastic paraparesis: study of 25 patients. Clin Infect Dis. 2018;67(9):1427–1433.
  • Yamano Y, Sato T. Clinical pathophysiology of human T-lymphotropic virus-type 1-associated myelopathy/tropical spastic paraparesis. Front Microbiol. 2012;3:389.
  • Carneiro-Proietti A, Amaranto-Damasio M, Leal-Horiguchi C, et al. Mother-to-child transmission of human T-cell lymphotropic viruses-1/2: what we know, and what are the gaps in understanding and preventing this route of infection. J Pediatr Infect Dis Soc. 2014;3(Suppl. 1):S24–S29.
  • Gerdes H-H, Bukoreshtliev NV, Barroso JF. Tunneling nanotubes: a new route for the exchange of components between animal cells. FEBS Lett. 2007;581(11):2194–2201.
  • Baratella M, Forlani G, Raval GU, et al. Cytoplasmic localization of HTLV-1 HBZ protein: a biomarker of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). PLoS Negl Trop Dis. 2017;11(1):e0005285.
  • Yamaguchi K, Takatsuki K. Adult T cell leukaemia–lymphoma. Baillieres Clin Haematol. 1993;6(4):899–915.
  • Alvarez C, Gotuzzo E, Vandamme AM, et al. Family aggregation of human T-Lymphotropic virus 1-associated diseases: a systematic review. Front Microbiol. 2016;7:1674.
  • Mendes MS, Costa MC, Costa IM. Human T-cell lymphotropic virus-1 infection: three infected generations in the same family. Rev Soc Bras Med Trop. 2016;49(5):660–662.
  • Iwanaga M, Watanabe T, Utsunomiya A, et al. Human T-cell leukemia virus type I (HTLV-1) proviral load and disease progression in asymptomatic HTLV-1 carriers: a nationwide prospective study in Japan. Blood. 2010;116(8):1211–1219.
  • Kannagi M, Ohashi T, Harashima N, et al. Immunological risks of adult T-cell leukemia at primary HTLV-I infection. Trends Microbiol. 2004;12(7):346–352.
  • Yoshizumi T, Shirabe K, Ikegami T, et al. Impact of human T cell leukemia virus type 1 in living donor liver transplantation. Am J Transplant. 2012;12(6):1479–1485.
  • Yamauchi J, Yamano Y, Yuzawa K. Risk of human T-cell leukemia virus type 1 infection in kidney transplantation. N Engl J Med. 2019;380(3):296–298.
  • Paiva AM, Assone T, Haziot MEJ, et al. Risk factors associated with HTLV-1 vertical transmission in Brazil: longer breastfeeding, higher maternal proviral load and previous HTLV-1-infected offspring. Sci Rep. 2018;8(1):7742.
  • Alarcón Villaverde J, Romaní Romaní F, Montano Torres S, et al. Vertical transmission of HTLV-1 in Peru. Rev Peru Med Exp Salud Publica. 2011;28(1):101–108.
  • Mello MA, da Conceição AF, Sousa SM, et al. HTLV-1 in pregnant women from the Southern Bahia, Brazil: a neglected condition despite the high prevalence. Virol J. 2014;11:28.
  • Proietti FA, Carneiro-Proietti AB, Catalan-Soares BC, et al. Global epidemiology of HTLV-I infection and associated diseases. Oncogene. 2005;24(39):6058–6068.
  • Forlani G, Shallak M, Tedeschi A, et al. Dual cytoplasmic and nuclear localization of HTLV-1-encoded HBZ protein is a unique feature of adult T-cell leukemia. Haematologica. 2021;106(8):2076–2085.
  • Raval GU, Bidoia C, Forlani G, et al. Localization, quantification and interaction with host factors of endogenous HTLV-1 HBZ protein in infected cells and ATL. Retrovirology. 2015;12:59.
  • Gazon H, Chauhan PS, Porquet F, et al. Epigenetic silencing of HTLV-1 expression by the HBZ RNA through interference with the basal transcription machinery. Blood Adv. 2020;4(21):5574–5579.
  • Macnamara A, Rowan A, Hilburn S, et al. HLA class I binding of HBZ determines outcome in HTLV-1 infection. PLoS Pathog. 2010;6(9):e1001117.
  • Suemori K, Fujiwara H, Ochi T, et al. HBZ is an immunogenic protein, but not a target antigen for human T-cell leukemia virus type 1-specific cytotoxic T lymphocytes. J Gen Virol. 2009;90(Pt 8):1806–1811.
  • Gaudray G, Gachon F, Basbous J, et al. The complementary strand of the human T-cell leukemia virus type 1 RNA genome encodes a bZIP transcription factor that down-regulates viral transcription. J Virol. 2002;76(24):12813–12822.
  • Lemasson I, Lewis MR, Polakowski N, et al. Human T-cell leukemia virus type 1 (HTLV-1) bZIP protein interacts with the cellular transcription factor CREB to inhibit HTLV-1 transcription. J Virol. 2007;81(4):1543–1553.
  • Clerc I, Polakowski N, André-Arpin C, et al. An interaction between the human T cell leukemia virus type 1 basic leucine zipper factor (HBZ) and the KIX domain of p300/CBP contributes to the down-regulation of Tax-dependent viral transcription by HBZ. J Biol Chem. 2008;283(35):23903–23913.
  • Cook LB, Melamed A, Demontis MA, et al. Rapid dissemination of human T-lymphotropic virus type 1 during primary infection in transplant recipients. Retrovirology. 2016;13:3.
  • Carpentier A, Barez PY, Hamaidia M, et al. Modes of human T cell leukemia virus type 1 transmission, replication and persistence. Viruses. 2015;7(7):3603–3624.
  • Bangham CR, Cook LB, Melamed A. HTLV-1 clonality in adult T-cell leukaemia and non-malignant HTLV-1 infection. Semin Cancer Biol. 2014;26(100):89–98.
  • Hanon E, Hall S, Taylor GP, et al. Abundant Tax protein expression in CD4+ T cells infected with human T-cell lymphotropic virus type I (HTLV-I) is prevented by cytotoxic T lymphocytes. Blood. 2000;95(4):1386–1392.
  • Bangham CR. CTL quality and the control of human retroviral infections. Eur J Immunol. 2009;39(7):1700–1712.
  • Kulkarni A, Bangham CR. HTLV-1: regulating the balance between proviral latency and reactivation. Front Microbiol. 2018;9:449.
  • Maldarelli F, Wu X, Su L, et al. HIV latency. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science. 2014;345(6193):179–183.
  • Mohammadi FS, Mosavat A, Shabestari M, et al. HTLV-1–host interactions facilitate the manifestations of cardiovascular disease. Microb Pathog. 2019;134:103578.
  • Mota TM, Jones RB. HTLV-1 as a model for virus and host coordinated immunoediting. Front Immunol. 2019;10:2259.
  • Niewiesk S, Daenke S, Parker CE, et al. Naturally occurring variants of human T-cell leukemia virus type I Tax protein impair its recognition by cytotoxic T lymphocytes and the transactivation function of tax. J Virol. 1995;69(4):2649–2653.
  • Bangham CR, Osame M. Cellular immune response to HTLV-1. Oncogene. 2005;24(39):6035–6046.
  • Nejmeddine M, Bangham CR. The HTLV-1 virological synapse. Viruses. 2010;2(7):1427–1447.
  • Manivannan K, Rowan AG, Tanaka Y, et al. CADM1/TSLC1 identifies HTLV-1-infected cells and determines their susceptibility to CTL-mediated lysis. PLoS Pathog. 2016;12(4):e1005560.
  • Furukawa Y, Fujisawa J, Osame M, et al. Frequent clonal proliferation of human T-cell leukemia virus type 1 (HTLV-1)-infected T cells in HTLV-1-associated myelopathy (HAM-TSP). Blood. 1992;80(4):1012–1016.
  • Gillet NA, Malani N, Melamed A, et al. The host genomic environment of the provirus determines the abundance of HTLV-1-infected T-cell clones. Blood. 2011;117(11):3113–3122.
  • Imaizumi Y, Iwanaga M, Tsukasaki K, et al. Natural course of HTLV-1 carriers with monoclonal proliferation of T lymphocytes ("pre-ATL") in a 20-year follow-up study. Blood. 2005;105(2):903–904.
  • Tsukasaki K, Tsushima H, Yamamura M, et al. Integration patterns of HTLV-I provirus in relation to the clinical course of ATL: frequent clonal change at crisis from indolent disease. Blood. 1997;89(3):948–956.
  • Laydon DJ, Melamed A, Sim A, et al. Quantification of HTLV-1 clonality and TCR diversity. PLoS Comput Biol. 2014;10(6):e1003646.
  • Currer R, Van Duyne R, Jaworski E, et al. HTLV Tax: a fascinating multifunctional co-regulator of viral and cellular pathways. Front Microbiol. 2012;3:406.
  • Giam CZ, Semmes OJ. HTLV-1 infection and adult T-cell leukemia/lymphoma—a tale of two proteins: Tax and HBZ. Viruses. 2016;8(6):161.
  • Ramezani S, Shirdel A, Rafatpanah H, et al. Assessment of HTLV-1 proviral load, LAT, BIM, c-FOS and RAD51 gene expression in adult T cell leukemia/lymphoma. Med Microbiol Immunol. 2017;206(4):327–335.
  • Moore SPG, Kruchten J, Toomire KJ, et al. Transcription factors and DNA repair enzymes compete for damaged promoter sites. J Biol Chem. 2016;291(11):5452–5460.
  • Mozhgani SH, Zarei-Ghobadi M, Teymoori-Rad M, et al. Human T-lymphotropic virus 1 (HTLV-1) pathogenesis: a systems virology study. J Cell Biochem. 2018;119(5):3968–3979.
  • Tarokhian H, Rahimi H, Mosavat A, et al. HTLV-1–host interactions on the development of adult T cell leukemia/lymphoma: virus and host gene expressions. BMC Cancer. 2018;18(1):1287.
  • Ashrafi F, Nassiri M, Javadmanesh A, et al. Epigenetics evaluation of the oncogenic mechanisms of two closely related bovine and human deltaretroviruses: a system biology study. Microb Pathog. 2020;139:103845.
  • Futsch N, Prates G, Mahieux R, et al. Cytokine networks dysregulation during HTLV-1 infection and associated diseases. Viruses. 2018;10(12):691.
  • Maeda M, Tanabe-Shibuya J, Miyazato P, et al. IL-2/IL-2 receptor pathway plays a crucial role in the growth and malignant transformation of HTLV-1-infected T cells to develop adult T-cell leukemia. Front Microbiol. 2020;11:356.
  • Cook LB, Rowan AG, Melamed A, et al. HTLV-1-infected T cells contain a single integrated provirus in natural infection. Blood. 2012;120(17):3488–3490.
  • Kamihira S, Sugahara K, Tsuruda K, et al. Proviral status of HTLV-1 integrated into the host genomic DNA of adult T-cell leukemia cells. Clin Lab Haematol. 2005;27(4):235–241.
  • Derse D, Crise B, Li Y, et al. Human T-cell leukemia virus type 1 integration target sites in the human genome: comparison with those of other retroviruses. J Virol. 2007;81(12):6731–6741.
  • Artesi M, Hahaut V, Cole B, et al. PCIP-seq: simultaneous sequencing of integrated viral genomes and their insertion sites with long reads. Genome Biol. 2021;22(1):97.
  • Artesi M, Marçais A, Durkin K, et al. Monitoring molecular response in adult T-cell leukemia by high-throughput sequencing analysis of HTLV-1 clonality. Leukemia. 2017;31(11):2532–2535.
  • Ley TJ, Mardis ER, Ding L, et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature. 2008;456(7218):66–72.
  • Tamiya S, Matsuoka M, Etoh K, et al. Two types of defective human T-lymphotropic virus type I provirus in adult T-cell leukemia. Blood. 1996;88(8):3065–3073.
  • Miyazaki M, Yasunaga J, Taniguchi Y, et al. Preferential selection of human T-cell leukemia virus type 1 provirus lacking the 5′ long terminal repeat during oncogenesis. J Virol. 2007;81(11):5714–5723.
  • Furukawa Y, Kubota R, Tara M, et al. Existence of escape mutant in HTLV-I Tax during the development of adult T-cell leukemia. Blood. 2001;97(4):987–993.
  • Takeda S, Maeda M, Morikawa S, et al. Genetic and epigenetic inactivation of Tax gene in adult T‐cell leukemia cells. Int J Cancer. 2004;109(4):559–567.
  • Koiwa T, Hamano-Usami A, Ishida T, et al. 5′-Long terminal repeat-selective CpG methylation of latent human T-cell leukemia virus type 1 provirus in vitro and in vivo. J Virol. 2002;76(18):9389–9397.
  • Katsuya H, Islam S, Tan BJY, et al. The nature of the HTLV-1 provirus in naturally infected individuals analyzed by the viral DNA-capture-seq approach. Cell Rep. 2019;29(3):724–735.e4.
  • Hollsberg P. Mechanisms of T-cell activation by human T-cell lymphotropic virus type I. Microbiol Mol Biol Rev. 1999;63(2):308–333.
  • Yoshida M. Multiple viral strategies of HTLV-1 for dysregulation of cell growth control. Annu Rev Immunol. 2001;19(1):475–496.
  • Arainga M, Takeda E, Aida Y. Identification of bovine leukemia virus Tax function associated with host cell transcription, signaling, stress response and immune response pathway by microarray-based gene expression analysis. BMC Genomics. 2012;13:121.
  • Fochi S, Mutascio S, Bertazzoni U, et al. HTLV deregulation of the NF-kappaB pathway: an update on Tax and antisense proteins role. Front Microbiol. 2018;9:285.
  • Sun SC, Yamaoka S. Activation of NF-kappaB by HTLV-I and implications for cell transformation. Oncogene. 2005;24(39):5952–5964.
  • Iwakura Y, Itagaki K, Ishitsuka C, et al. The development of autoimmune inflammatory arthropathy in mice transgenic for the human T cell leukemia virus type-1 env-pX region is not dependent on H-2 haplotypes and modified by the expression levels of fas antigen. J Immunol. 1998;161(12):6592–6598.
  • Mitra-Kaushik S, Harding J, Hess J, et al. Enhanced tumorigenesis in HTLV-1 Tax-transgenic mice deficient in interferon-gamma. Blood. 2004;104(10):3305–3311.
  • Rauch D, Gross S, Harding J, et al. Imaging spontaneous tumorigenesis: inflammation precedes development of peripheral NK tumors. Blood. 2009;113(7):1493–1500.
  • Habu K, Nakayama-Yamada J, Asano M, et al. The human T cell leukemia virus type I-Tax gene is responsible for the development of both inflammatory polyarthropathy resembling rheumatoid arthritis and noninflammatory ankylotic arthropathy in transgenic mice. J Immunol. 1999;162(5):2956–2963.
  • Mahieux R. HTLV-I, tax: fox hunting still allowed. Blood. 2008;111(12):5418.
  • Gao L, Deng H, Zhao H, et al. HTLV-1 Tax transgenic mice develop spontaneous osteolytic bone metastases prevented by osteoclast inhibition. Blood. 2005;106(13):4294–4302.
  • Koizumi A, Mizukami H, Inoue M. pX gene causes hypercholesterolemia in hypercholesterolemia-resistant BALB/c mice. Biol Pharm Bull. 2005;28(9):1731–1735.
  • Gachon F, Thebault S, Peleraux A, et al. Molecular interactions involved in the transactivation of the human T-cell leukemia virus type 1 promoter mediated by Tax and CREB-2 (ATF-4). Mol Cell Biol. 2000;20(10):3470–3481.
  • Azran I, Schavinsky-Khrapunsky Y, Aboud M. Role of Tax protein in human T-cell leukemia virus type-I leukemogenicity. Retrovirology. 2004;1(1):20.
  • Lenzmeier BA, Giebler HA, Nyborg JK. Human T-cell leukemia virus type 1 Tax requires direct access to DNA for recruitment of CREB binding protein to the viral promoter. Mol Cell Biol. 1998;18(2):721–731.
  • Franchini G, Fukumoto R, Fullen JR. T-cell control by human T-cell leukemia/lymphoma virus type 1. Int J Hematol. 2003;78(4):280–296.
  • Zhao T, Matsuoka M. HBZ and its roles in HTLV-1 oncogenesis. Front Microbiol. 2012;3:247.
  • Seiki M, Eddy R, Shows TB, et al. Nonspecific integration of the HTLV provirus genome into adult T-cell leukaemia cells. Nature. 1984;309(5969):640–642.
  • Lemoine FJ, Wycuff DR, Marriott SJ. Transcriptional activity of HTLV-I Tax influences the expression of marker genes associated with cellular transformation. Dis Markers. 2001;17(3):129–137.
  • Jacobson S, Shida H, McFarlin DE, et al. Circulating CD8+ cytotoxic T lymphocytes specific for HTLV-I pX in patients with HTLV-I associated neurological disease. Nature. 1990;348(6298):245–248.
  • Kfoury Y, Nasr R, Journo C, et al. The multifaceted oncoprotein tax: subcellular localization, posttranslational modifications, and NF-kappaB activation. Adv Cancer Res. 2012;113:85–120.
  • Chu ZL, Shin YA, Yang JM, et al. IKKgamma mediates the interaction of cellular IkappaB kinases with the Tax transforming protein of human T cell leukemia virus type 1. J Biol Chem. 1999;274(22):15297–15300.
  • Chu Z-L, DiDonato JA, Hawiger J, et al. The Tax oncoprotein of human T-cell leukemia virus type 1 associates with and persistently activates IκB kinases containing IKKα and IKKβ. J Biol Chem. 1998;273(26):15891–15894.
  • Peloponese J-M, Yeung ML, Jeang K-T. Modulation of nuclear factor-ϰB by human T cell leukemia virus type 1 Tax protein. Immunol Res. 2006;34(1):1–12.
  • Sun SC, Ballard DW. Persistent activation of NF-kappaB by the Tax transforming protein of HTLV-1: hijacking cellular IkappaB kinases. Oncogene. 1999;18(49):6948–6958.
  • Hironaka N, Mochida K, Mori N, et al. Tax-independent constitutive IkappaB kinase activation in adult T-cell leukemia cells. Neoplasia. 2004;6(3):266–278.
  • Harhaj EW, Giam CZ. NF-kappaB signaling mechanisms in HTLV-1-induced adult T-cell leukemia/lymphoma. FEBS J. 2018;285(18):3324–3336.
  • Dewan MZ, Terashima K, Taruishi M, et al. Rapid tumor formation of human T-cell leukemia virus type 1-infected cell lines in novel NOD-SCID/gammac(null) mice: suppression by an inhibitor against NF-kappaB. J Virol. 2003;77(9):5286–5294.
  • Mori N, Fujii M, Ikeda S, et al. Constitutive activation of NF-kappaB in primary adult T-cell leukemia cells. Blood. 1999;93(7):2360–2368.
  • Sun SC. The non-canonical NF-kappaB pathway in immunity and inflammation. Nat Rev Immunol. 2017;17(9):545–558.
  • Azimi N, Brown K, Bamford RN, et al. Human T cell lymphotropic virus type I Tax protein trans-activates interleukin 15 gene transcription through an NF-kappaB site. Proc Natl Acad Sci U S A. 1998;95(5):2452–2457.
  • Mariner JM, Lantz V, Waldmann TA, et al. Human T cell lymphotropic virus type I Tax activates IL-15R alpha gene expression through an NF-kappa B site. J Immunol. 2001;166(4):2602–2609.
  • Munoz E, Israël A. Activation of NF-κB by the Tax protein of HTLV-1. Immunobiology. 1995;193(2–4):128–136.
  • Millen S, Meretuk L, Göttlicher T, et al. A novel positive feedback-loop between the HTLV-1 oncoprotein Tax and NF-κB activity in T-cells. Retrovirology. 2020;17(1):30.
  • Fujikawa D, Nakagawa S, Hori M, et al. Polycomb-dependent epigenetic landscape in adult T-cell leukemia. Blood. 2016;127(14):1790–1802.
  • Watanabe T. Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1-infected T cells. Blood. 2017;129(9):1071–1081.
  • Horie R, Watanabe T, Morishita Y, et al. Ligand-independent signaling by overexpressed CD30 drives NF-κB activation in Hodgkin–Reed-Sternberg cells. Oncogene. 2002;21(16):2493–2503.
  • Kannagi M, Harada S, Maruyama I, et al. Predominant recognition of human T cell leukemia virus type I (HTLV-I) pX gene products by human CD8+ cytotoxic T cells directed against HTLV-I-infected cells. Int Immunol. 1991;3(8):761–767.
  • Inoue J, Yoshida M, Seiki M. Transcriptional (p40x) and post-transcriptional (p27x-III) regulators are required for the expression and replication of human T-cell leukemia virus type I genes. Proc Natl Acad Sci U S A. 1987;84(11):3653–3657.
  • Parker CE, Daenke S, Nightingale S, et al. Activated, HTLV-1-specific cytotoxic T-lymphocytes are found in healthy seropositives as well as in patients with tropical spastic paraparesis. Virology. 1992;188(2):628–636.
  • Jeang KT, Giam CZ, Majone F, et al. Life, death, and Tax: role of HTLV-I oncoprotein in genetic instability and cellular transformation. J Biol Chem. 2004;279(31):31991–31994.
  • Robek MD, Ratner L. Immortalization of CD4(+) and CD8(+) T lymphocytes by human T-cell leukemia virus type 1 Tax mutants expressed in a functional molecular clone. J Virol. 1999;73(6):4856–4865.
  • Endo K, Hirata A, Iwai K, et al. Human T-cell leukemia virus type 2 (HTLV-2) Tax protein transforms a rat fibroblast cell line but less efficiently than HTLV-1 tax. J Virol. 2002;76(6):2648–2653.
  • Feuer G, Green PL. Comparative biology of human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2. Oncogene. 2005;24(39):5996–6004.
  • Kusano S, Yoshimitsu M, Hachiman M, et al. I-mfa domain proteins specifically interact with HTLV-1 Tax and repress its transactivating functions. Virology. 2015;486:219–227.
  • Thébault S, Gachon F, Lemasson I, et al. Molecular cloning of a novel human I-mfa domain-containing protein that differently regulates human T-cell leukemia virus type I and HIV-1 expression. J Biol Chem. 2000;275(7):4848–4857.
  • Cigognini D, Corneo G, Fermo E, et al. HIC gene, a candidate suppressor gene within a minimal region of loss at 7q31.1 in myeloid neoplasms. Leuk Res. 2007;31(4):477–482.
  • Watanabe T, Yamashita S, Ureshino H, et al. Targeting aberrant DNA hypermethylation as a driver of ATL leukemogenesis by using the new oral demethylating agent OR-2100. Blood. 2020;136(7):871–884.
  • Charostad J, Astani A, Goudarzi H, et al. DNA methyltransferases in virus-associated cancers. Rev Med Virol. 2019;29(2):e2022.
  • Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol. 2006;6(8):595–601.
  • Waldmann TA. The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy. Cancer Immunol Res. 2015;3(3):219–227.
  • Yamada O, Ozaki K, Akiyama M, et al. JAK-STAT and JAK-PI3K-mTORC1 pathways regulate telomerase transcriptionally and posttranslationally in ATL cells. Mol Cancer Ther. 2012;11(5):1112–1121.
  • Vanhaesebroeck B, Waterfield MD. Signaling by distinct classes of phosphoinositide 3-kinases. Exp Cell Res. 1999;253(1):239–254.
  • Cereseto A, Parks RW, Rivadeneira E, et al. Limiting amounts of p27 Kip1 correlates with constitutive activation of cyclin E-CDK2 complex in HTLV-I-transformed T-cells. Oncogene. 1999;18(15):2441–2450.
  • Iwanaga R, Ohtani K, Hayashi T, et al. Molecular mechanism of cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I. Oncogene. 2001;20(17):2055–2067.
  • Okkenhaug K, Patton DT, Bilancio A, et al. The p110δ isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells. J Immunol. 2006;177(8):5122–5128.
  • Ahmad A, Biersack B, Li Y, et al. Targeted regulation of PI3K/Akt/mTOR/NF-κB signaling by indole compounds and their derivatives: mechanistic details and biological implications for cancer therapy. Anticancer Agents Med Chem. 2013;13(7):1002–1013.
  • Xiang J, Rauch DA, Huey DD, et al. HTLV-1 viral oncogene HBZ drives bone destruction in adult T cell leukemia. JCI Insight. 2019;4(19):e128713.
  • Matsuoka M, Mesnard JM. HTLV-1 bZIP factor: the key viral gene for pathogenesis. Retrovirology. 2020;17(1):2.
  • Yoshida M, Satou Y, Yasunaga J, et al. Transcriptional control of spliced and unspliced human T-cell leukemia virus type 1 bZIP factor (HBZ) gene. J Virol. 2008;82(19):9359–9368.
  • Nakagawa M, Shaffer AL, Ceribelli M, et al. Targeting the HTLV-I-regulated BATF3/IRF4 transcriptional network in adult T cell leukemia/lymphoma. Cancer Cell. 2018;34(2):286–297.e10.
  • Tanaka A, Matsuoka M. HTLV-1 alters T cells for viral persistence and transmission. Front Microbiol. 2018;9:461.
  • Satou Y, Yasunaga J, Yoshida M, et al. HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells. Proc Natl Acad Sci U S A. 2006;103(3):720–725.
  • Taniguchi Y, Nosaka K, Yasunaga J, et al. Silencing of human T-cell leukemia virus type I gene transcription by epigenetic mechanisms. Retrovirology. 2005;2:64.
  • Matsumoto J, Ohshima T, Isono O, et al. HTLV-1 HBZ suppresses AP-1 activity by impairing both the DNA-binding ability and the stability of c-Jun protein. Oncogene. 2005;24(6):1001–1010.
  • Saito M, Matsuzaki T, Satou Y, et al. In vivo expression of the HBZ gene of HTLV-1 correlates with proviral load, inflammatory markers and disease severity in HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Retrovirology. 2009;6(1):19.
  • Kawatsuki A, Yasunaga JI, Mitobe Y, et al. HTLV-1 bZIP factor protein targets the Rb/E2F-1 pathway to promote proliferation and apoptosis of primary CD4(+) T cells. Oncogene. 2016;35(34):4509–4517.
  • Carvalho EM, Da Fonseca Porto A. Epidemiological and clinical interaction between HTLV-1 and Strongyloides stercoralis. Parasite Immunol. 2004;26(11–12):487–497.
  • LaGrenade L, Hanchard B, Fletcher V, et al. Infective dermatitis of Jamaican children: a marker for HTLV-I infection. Lancet. 1990;336(8727):1345–1347.
  • Sugata K, Satou Y, Yasunaga J, et al. HTLV-1 bZIP factor impairs cell-mediated immunity by suppressing production of Th1 cytokines. Blood. 2012;119(2):434–444.
  • Arnold J, Yamamoto B, Li M, et al. Enhancement of infectivity and persistence in vivo by HBZ, a natural antisense coded protein of HTLV-1. Blood. 2006;107(10):3976–3982.
  • Vandermeulen C, O'Grady T, Wayet J, et al. The HTLV-1 viral oncoproteins Tax and HBZ reprogram the cellular mRNA splicing landscape. PLoS Pathog. 2021;17(9):e1009919.
  • Tsukahara T, Kannagi M, Ohashi T, et al. Induction of Bcl-x(L) expression by human T-cell leukemia virus type 1 Tax through NF-kappaB in apoptosis-resistant T-cell transfectants with tax. J Virol. 1999;73(10):7981–7987.
  • Higuchi M, Takahashi M, Tanaka Y, et al. Downregulation of proapoptotic Bim augments IL-2-independent T-cell transformation by human T-cell leukemia virus type-1 tax. Cancer Med. 2014;3(6):1605–1614.
  • Ashrafi F, Ghezeldasht SA, Ghobadi MZ. Identification of joint gene players implicated in the pathogenesis of HTLV-1 and BLV through a comprehensive system biology analysis. Microb Pathog. 2021;160:105153.
  • Mori N, Fujii M, Cheng G, et al. Human T-cell leukemia virus type I Tax protein induces the expression of anti-apoptotic gene bcl-xL in human T-cells through nuclear factor-kappaB and c-AMP responsive element binding protein pathways. Virus Genes. 2001;22(3):279–287.
  • Brauweiler A, Garrus JE, Reed JC, et al. Repression of bax gene expression by the HTLV-1 Tax protein: implications for suppression of apoptosis in virally infected cells. Virology. 1997;231(1):135–140.
  • Mühleisen A, Giaisi M, Köhler R, et al. Tax contributes apoptosis resistance to HTLV-1-infected T cells via suppression of Bid and Bim expression. Cell Death Dis. 2014;5(12):e1575.
  • Tanaka-Nakanishi A, Yasunaga J, Takai K, et al. HTLV-1 bZIP factor suppresses apoptosis by attenuating the function of FoxO3a and altering its localization. Cancer Res. 2014;74(1):188–200.
  • Valletti A, Marzano F, Pesole G, et al. Targeting chemoresistant tumors: could TRIM proteins-p53 axis be a possible answer? Int J Mol Sci. 2019;20(7):1776.
  • Jaworska AM, Wlodarczyk NA, Mackiewicz A, et al. The role of TRIM family proteins in the regulation of cancer stem cell self-renewal. Stem Cells. 2020;38(2):165–173.
  • Liu Y, Dong Y, Zhao L, et al. TRIM59 overexpression correlates with poor prognosis and contributes to breast cancer progression through AKT signaling pathway. Mol Carcinog. 2018;57(12):1792–1802.
  • Pise-Masison CA, Radonovich M, Dohoney K, et al. Gene expression profiling of ATL patients: compilation of disease-related genes and evidence for TCF4 involvement in BIRC5 gene expression and cell viability. Blood. 2009;113(17):4016–4026.
  • Suzuki S, Kofune H, Uozumi K, et al. A survivin-responsive, conditionally replicating adenovirus induces potent cytocidal effects in adult T-cell leukemia/lymphoma. BMC Cancer. 2019;19(1):516.
  • Zhao P, Meng Q, Liu LZ, et al. Regulation of survivin by PI3K/Akt/p70S6K1 pathway. Biochem Biophys Res Commun. 2010;395(2):219–224.
  • Dequiedt F, Kettmann R, Burny A, et al. Mutations in the p53 tumor-suppressor gene are frequently associated with bovine leukemia virus-induced leukemogenesis in cattle but not in sheep. Virology. 1995;209(2):676–683.
  • Dutartre H, Claviere M, Journo C, et al. Cell-free versus cell-to-cell infection by human immunodeficiency virus type 1 and human T-lymphotropic virus type 1: exploring the link among viral source, viral trafficking, and viral replication. J Virol. 2016;90(17):7607–7617.
  • Rosewick N, Durkin K, Artesi M, et al. Cis-perturbation of cancer drivers by the HTLV-1/BLV proviruses is an early determinant of leukemogenesis. Nat Commun. 2017;8:15264.
  • Siegel RS, Gartenhaus RB, Kuzel TM. Human T-cell lymphotropic-I-associated leukemia/lymphoma. Curr Treat Options Oncol. 2001;2(4):291–300.
  • Taylor GP, Matsuoka M. Natural history of adult T-cell leukemia/lymphoma and approaches to therapy. Oncogene. 2005;24(39):6047–6057.
  • Kato K, Akashi K. Recent advances in therapeutic approaches for adult T-cell leukemia/lymphoma. Viruses. 2015;7(12):6604–6612.
  • Waldmann TA. T-cell receptors for cytokines: targets for immunotherapy of leukemia/lymphoma. Ann Oncol. 2000;11(1):101–106.
  • Waldmann TA, Goldman CK, Bongiovanni KF, et al. Therapy of patients with human T-cell lymphotrophic virus I-induced adult T-cell leukemia with anti-Tac, a monoclonal antibody to the receptor for interleukin-2. Blood. 1988;72(5):1805–1816.
  • Wang TT, Yang J, Zhang Y, et al. IL-2 and IL-15 blockade by BNZ-1, an inhibitor of selective γ-chain cytokines, decreases leukemic T-cell viability. Leukemia. 2019;33(5):1243–1255.
  • Katsuya H, Ishitsuka K, Utsunomiya A, et al. Treatment and survival among 1594 patients with ATL. Blood. 2015;126(24):2570–2577.
  • Soltani A, Hashemy SI, Zahedi Avval F, et al. Molecular targeting for treatment of human T-lymphotropic virus type 1 infection. Biomed Pharmacother. 2019;109:770–778.
  • Kchour G, Rezaee R, Farid R, et al. The combination of arsenic, interferon-alpha, and zidovudine restores an "immunocompetent-like" cytokine expression profile in patients with adult T-cell leukemia lymphoma. Retrovirology. 2013;10(1):91.
  • Kchour G, Tarhini M, Kooshyar MM, et al. Phase 2 study of the efficacy and safety of the combination of arsenic trioxide, interferon alpha, and zidovudine in newly diagnosed chronic adult T-cell leukemia/lymphoma (ATL). Blood. 2009;113(26):6528–6532.
  • Yared JA, Kimball AS. Optimizing management of patients with adult T cell leukemia–lymphoma. Cancers. 2015;7(4):2318–2329.
  • Berkowitz JL, Janik JE, Stewart DM, et al. Safety, efficacy, and pharmacokinetics/pharmacodynamics of daclizumab (anti-CD25) in patients with adult T-cell leukemia/lymphoma. Clin Immunol. 2014;155(2):176–187.
  • Montoni A, Robu M, Pouliot E, et al. Resistance to PARP-Inhibitors in cancer therapy. Front Pharmacol. 2013;4:18.
  • Du Y, Yamaguchi H, Hsu JL, et al. PARP inhibitors as precision medicine for cancer treatment. Natl Sci Rev. 2017;4(4):576–592.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.