DNA Plasmid Based Vaccination Against the Oncogenic Human T Cell Leukemia Virus Type 1

  • M. G. Agadjanyan
  • B. Wang
  • S. B. Nyland
  • D. B. Weiner
  • K. E. Ugen
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 226)


The human T cell leukemia virus type 1 (HTLV-1) holds its place in history as the first human retrovirus established to be associated with disease. Since its discovery, it has been demonstrated to be the causal agent of adult T cell leukemia (ATL) and HTLV-1 associated myelopathy (HAM). In addition, more recently this retrovirus has been suggested to have a role in the etiology and/or pathogenesis of a myriad of autoimmune disorders including rheumatoid arthritis and uveitis (Ugen et al. 1996b). Also, the role of infection with HTLV in accelerating progression to acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus (HIV)-1 infected individuals has also been suggested (Kramer et al. 1989). The worldwide seropositivity of HTLV-1 and the related HTLV-2 is estimated to be at least 10 million. Coupled with its association to fatal and debilitating disorders as well as its potential role in the pathogenesis of other serious illnesses an effective vaccine is warranted. In this review we will summarize current information on HTLV-1 including immune responses to this virus, correlates of protection as well as potential vaccination strategies including DNA plasmid inoculation.


Leukemia Virus Acquire Immune Deficiency Syndrome Bovine Leukemia Virus Cell Leukemia Virus Type Inhibit Syncytium Formation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Agadjanyan M, Ugen K, Wang B, Williams W, and Weiner D (1994a) Identification of an 80-kilodalton membrane glycoprotein important for human T-cell leukemia virus type I and type II syncytium formation and infection. J Virol 68:485–493PubMedGoogle Scholar
  2. Agadjanyan M, Wang B, Ugen K, Villafana T, Merva M, et al. (1994b) DNA inoculation with an HTLV-I envelope DNA construct elicits immune responses in rabbits. In: Chanock RM, Ginsberg HS, Brown F, Lerner RA (eds) Vaccines 94: Modern approaches to new vaccines including prevention of AIDS. Cold Spring Harbor, Cold Spring Harbor, NY, pp 47–53Google Scholar
  3. Ami Y, Kushida S, Matsumura M, Yoshida Y, Kameyama T, et al. (1992) Vertical transmission of HTLV-I in HTLV-I carrier rat. Jpn J Cancer Res 83:1241–1243PubMedCrossRefGoogle Scholar
  4. Baba E, Nakamura M, Tanaka Y (1993) Multiple neutralizing B-cell epitopes recognized by human monoclonal antibodies. J Immunol 151:1013–1024PubMedGoogle Scholar
  5. Barre-Sinoussi F, Cherman JC, Rey F, Nugeyre MT, Chameret S, et al. (1983) Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220:868–871PubMedCrossRefGoogle Scholar
  6. Blattner WA, Kalyanaraman VS, Robert-Guroff M, Lister TA, Galton AG, et al. (1982) The human C retrovirus: HTLV in blacks from the Caribbean region, and relationship to adult T cell leukemia/ lymphoma. Int J Cancer 30:257PubMedCrossRefGoogle Scholar
  7. Bohnlein E, Berger J, Hauber J (1991) Functional mapping of the human immunodeficiency virus type 1 rev RNA binding domain: new insights into the domain structure of rev and rex. J Virol 65:7051–7055PubMedGoogle Scholar
  8. Bolognesi D, Montelaro R, Frank H, Schafer W (1978) Assembly of type C oncornaviruses: a model. Science 199:183–186PubMedCrossRefGoogle Scholar
  9. Boyer JD, Ugen KE, Wang B, Agadjanyan MG, Bagarazzi ML, et al. (in press) Journal of Infectious Diseases DNA vaccination as an anti-HIV immunotherapy in infected chimpanzeesGoogle Scholar
  10. Boyer JD, Ugen KE, Wang B, Agadjanyan MG, Gilbert L, et al. (1997) Protection from high dose heterologous HIV-1 challenge in chimpanzees by DNA vaccination. Nature Medicine 3:526–532PubMedCrossRefGoogle Scholar
  11. Boyer JD, Wang B, Ugen K, Agadjanyan M, Javadian A, et al. (1996) Protective anti-HIV immune responses in non-human primates through DNA immunization. J Med Primatol 25:242–250PubMedCrossRefGoogle Scholar
  12. Bunn P, Schecter G, Jaffe E (1983) Clinical course of retrovirus-associated adult T cell lymphoma in the United States. NEJM 309:257–264PubMedCrossRefGoogle Scholar
  13. Cann AJ, Chen ISY (1990) Human T-cell leukemia virus types I and II. In: Fields BN, Knipe DM, Howley PM (eds) Virology, Raven, NY, pp 1849–1880Google Scholar
  14. Clapham P, Nagy K, Cheingsong-Popov R, Exley M, Weiss RA (1983) Productive infection and cell-free transmission of human T-cell leukemia virus in a nonlymphoid cell line. Science 222:1125–1127PubMedCrossRefGoogle Scholar
  15. Clapham P, Nagy K, Weiss R (1984) Pseudotypes of human T-cell leukemia virus types 1 and 2: neu- traliztion by patient’s sera. Proc Natl Acad Sci USA 81:2886–2890PubMedCrossRefGoogle Scholar
  16. Coffin J (1986) Genetic variation in AIDS virus. Cell 46:1–4PubMedCrossRefGoogle Scholar
  17. Coffin JM (1996) Retroviridae: the viruses and their replication. In: BN Fields, DM Knipe, PM Howley (eds) Virology Lippincott-Raven, Philadelphia, pp 1767–1880Google Scholar
  18. De The G and Bomford R (1993) An HTLV-I vaccine: Why, how, whom? AIDS Res Hum Retroviruses 9:381–386PubMedCrossRefGoogle Scholar
  19. Delamarre L, Pique C, Pham D, Tursz T, Dokhelar M-C (1994) Identification of functional regions in the human T-cell leukemia virus type I SU glycoprotein. J Virol 68:3544–3549PubMedGoogle Scholar
  20. DeRossi A, Aldovani A, Franchini G, Mann D, Gallo RC (1985) Clonal selection of T-lymphocytes infected by cell-free human T-cell leukemia/lymphoma virus type I: parameters of virus integration and expression. Virology 143:640–645CrossRefGoogle Scholar
  21. Dezutti CS, Frazier FE, Huffl Y, Stromberg PC, Olsen RG (1990) Subunit vaccine protects Macaca nemestrina (pig-tailed macaque) against simian T-cell lymphotropic virus type 1 challenge. Cancer Res 50:5687–5691Google Scholar
  22. Fan N Gavalchin J, Paul B, Wells K, Lane MJ, et al. (1992) Infection of peripheral blood mononuclear cells and cell lines by cell free human T-cell lymphoma/leukemia virus type I. J Clin Microbiol 30: 905–910PubMedGoogle Scholar
  23. Franchini G, Tartaglia J, Markham P, Benson J, Fullen J, et al. (1995) Highly attenuated HTLV type I env poxvirus vaccines induce protection against a cell - associated HTLV type I challenge in rabbits. AIDS Res Hum Retroviruses 11:307–313PubMedCrossRefGoogle Scholar
  24. Gallo RC, Jay G (1991) The human retroviruses. In: Gallo RC, Jay G (eds) The human retroviruses. Academic, NY, p 421Google Scholar
  25. Gessain A, Barin F, Vernant JC, Gout O, Maurs L, et al. (1985) Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet ii: 407–410CrossRefGoogle Scholar
  26. Gessain A, Gout O (1992) Chronic myelopathy associated with human T lymphotropic virus type 1 (HTLV-1). Ann Intern Med 117:933–946PubMedGoogle Scholar
  27. Gray GS, White M, Bartman T, Mann D (1990) Envelope gene sequence of HTLV-1 isolate MT-2 and its comparison with other HTLV-1 isolates. Virology 177:391–395PubMedCrossRefGoogle Scholar
  28. Hall WW, Ishak R, Zhu SW, Novoa, P Eiraku N, et al. (1996) Human T lymphotropic virus type II (HTLV-II): epidemiology, molecular properties, and clinical features of infection. J Acquir Immune Defic Syndromes Hum Retrovirol 13:S204–S214CrossRefGoogle Scholar
  29. Hidaka M, Inoue J, Yoishida M, Seiki M (1988) Post-transcriptional regulator (rex) of HTLV-1 initiates expression of virla structural proteins but suppresses expression of regulatory proteins. EMBO J72:519–523Google Scholar
  30. Hino S, Katamine S, Miyata H, Tsuji Y, Yamabe T, et al. (1996) Primary prevention of HTLV-I in Japan. J Acquir Immune Defic Syndromes Hum Retrovirol 13:S199–S203CrossRefGoogle Scholar
  31. Hino S, Yamaguichi K, Katamine S (1985) Mother-to-child transmission of human T-cell leukemia virus type I. Jpn J Cancer Research 76:474–480Google Scholar
  32. Hinuma Y, Komoda H, Chosa T, Kondo T, Kohakura M, et al. (1982) Antibodies to adult T cell leukemia virus-associated antigen (ATLA) in sera from patients with ATL and controls in Japan: a nation-wide seroepidemiologic study. Int J Cancer 29:631–635PubMedCrossRefGoogle Scholar
  33. Hoshino H, Shinoyama M, Miwa M and Sugimura T (1983) Detection of lymphocytes producing a human retrovirus associated with adult T-cell leukemia by syncytium induction assay. Proc Natl Acad Sci USA 80:7337–7341PubMedCrossRefGoogle Scholar
  34. Hoshino H, Weiss R, Miyoshi I, Yoshida M, et al. (1985) Human T-cell leukemia virus type-I: psedotype neutralization of Japanese and American isolates with human and rabbit sera. Int J Cancer 36: 671–675PubMedCrossRefGoogle Scholar
  35. Ibrahim F, Flette L, Gessain ANB, De The G, et al. (1994) Infection of rats with human T-cell leukemia virus type 1: susceptibility of inbred strains, antibody response and provirus location. Int J Cancer 58:446–451PubMedCrossRefGoogle Scholar
  36. Inoue J, Seiki M, Taniguchi T (1986) Induction of interleukin 2 receptor gene expression of by p40x encoded by human T-cell leukemia virus type 1. EM BO J5:2883–2888Google Scholar
  37. Ishiguro N, Abe M, Seto K, Sakurai H, Ikeda H, et al. (1992) A rat model of human T lymphocyte virus type I (HTLV-I) infection. I Humoral antibody response, provirus integration and HTLV-I associated myelopathy/tropical spastic paraparesis-like myelopathy in seronegative HTLV-I carrier rats. J Exp Med 176:981–989PubMedCrossRefGoogle Scholar
  38. Kalyanaraman VC, Sarngadharan MG, Robert-Gurofif M, Miyoshi I, Blayney D, et al. (1982) A new subtype of human T-cell leukemia virus (HTLV-II) associated with a T-cell variant of hairy cell leukemia. Science 218:571–573PubMedCrossRefGoogle Scholar
  39. Kanner S, Cheng-Mayer C, Geffen R (1986) Human retroviral env and gag polypeptides: serologic assays to measure infection. J Immunol 137:674–678PubMedGoogle Scholar
  40. Kaplan JE, Khabbaz RF (1993) The epidemiology of human T-lymphotropic viruses types I and II. Med Virol 3:137–148CrossRefGoogle Scholar
  41. Kazanji M, De The G, Bessereau JL, Schulz T, Shida H, et al. (1997) Vaccination of rats with recombinant adenovirus 5, DNA plasmids and vaccinia viruses containing the HTLV-1 env gene. AIDS Res Hum Retroviruses (in press)Google Scholar
  42. Kiyokawa T, Yoshikura H, Hattori S, Seiki M, Yoshida M (1984) Envelope proteins of human T-cell leukemia virus. Expression in Escherichia coli and its applications to studies of env-gene functions. Proc Natl Acad Sci USA 81:6202–6206PubMedCrossRefGoogle Scholar
  43. Komuro A, Hayami M, Fujii H, Miyahara M (1983) Vertical transmission of adult T-cell leukemia virus. Lancet 1:240PubMedCrossRefGoogle Scholar
  44. Kramer A (1989) Spontaneous lymphocyte proliferation in symptom free HTLV-1 positive Jamaicans. Lancet 2:923–924PubMedCrossRefGoogle Scholar
  45. Lairmore MD, Rudolph DL, Roberts BD, Dezzutti CS, Lal RB (1992) Characterization of a B-cell immunodominant epitope of human T-lymphotropic virus type 1 (HTLV-I) envelope gp46. Cancer Lett 66:11–20PubMedCrossRefGoogle Scholar
  46. Lal R, Rudolph D, Lairmore M, Khabbaz R, Garfield M, et al. (1991) Serologic discrimination of human T cell lymphotropic virus infection by using a synthetic peptide-based enzyme immunoassay. J Infect Dis 163:41–46PubMedCrossRefGoogle Scholar
  47. Miyoshi I, Kubonishi I, Yoshimoto S, et al. (1981) Type C particles in a cord T cell derived by cocultivating normal human cord leukocytes and human leukemic T cells. Nature 294:770–771PubMedCrossRefGoogle Scholar
  48. Miyoshi I, Yoshimoto S, Kubonishi I, Fujishita M, Ohtsuki Y, et al. (1985) Infectious transmission of human T-cell leukemia virus to rabbits. Int J Cancer 35:81–85PubMedCrossRefGoogle Scholar
  49. Moss B (1988) Roles of vaccinia virus in the development of new vaccines. Vaccine6:161–163PubMedCrossRefGoogle Scholar
  50. Nacamura H, Hayami M, Ohta Y, Ishikawa K, Tsuimoto H, et al. (1987) Protection of cynomologus mankeys agaist infection by human T-cell leukemia virus type-I by immunization with viral env gene products produced in Escherichia coli. Int J Cancer 40:403–407CrossRefGoogle Scholar
  51. Nagashima K, Yoshida M and Seiki M (1986) A single species of pX mRNA of human T-cell leukemia virus type I encodes trans-activator p40x and two other phosphoproteins. J Virol 60:394–399PubMedGoogle Scholar
  52. Nagy K, Clapham P, Cheingsong-Popov R, Weiss R (1983) Human T-cell leukemia virus type I: induction of syncytia formation and inhibition by patients’ sera. Int J Cancer 32:321–328PubMedCrossRefGoogle Scholar
  53. Nakano S, Ando Y, Ichijo M, et al. (1984) Search for possible routes of vertical and horizontal transmission of adult T-cell leukemia virus. GANN 75:1044–1045PubMedGoogle Scholar
  54. Okochi K, Sato H, Hinuma Y (1985) A retrospective study on transmission of adult T cell leukemia virus by blood transfusion; seroconversion in recipients. Vox Sang 46:245–253CrossRefGoogle Scholar
  55. Palker JT, Riggs E, Spragion D, Muir AJ Scearge R, et al. (1992) Mapping of homologous, amino- terminal neutralizing regions of human T-cell lymphotropic virus type 1 and II gp46 envelope glycoproteins. J Virol 66:5879–5889PubMedGoogle Scholar
  56. Palker T (1990) Mapping of epitopes on human T-cell leukemia virus type I envelope glycoprotein. In: Blattner W (ed) Human retrovirology HTLV, Raven, NY, pp 435–445Google Scholar
  57. Poiesz B, Rescetti F, Gazdar A (1980) Detection and isolation of type-C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA 77:7415–7419PubMedCrossRefGoogle Scholar
  58. Poiesz BJ, Ruscetti FW, Reitz MS, Kalyanaraman VS, Gallo RC (1981) Isolation a new type-C retrovirus (HTLV) in primery uncultured cells of patient with Sezary T-cell leukemia and evidence for virus nucleic acids and antigens in fresh leukemic cells. Nature 294:268–271PubMedCrossRefGoogle Scholar
  59. Reddy EP, Mettus R, DeFreitas, E Wroblewska Z, Cisco M, et al. (1988) Molecular cloning of human T-cell lymphotropic virus type 1-like proviral genome from the peripheral lymphocyte DNA of a patient with chronic neurologic disorders. Proc Natl Acad Sci USA 85:3599–3603PubMedCrossRefGoogle Scholar
  60. Renjifo B, Chou K, Ramirez LS, Vallejo FG, Essex M (1996) Human T cell leukemia virus type I (HTLV-I) molecular genotypes and disease outcomes. J AIDS Hum Retrovirol 13:S146–S153Google Scholar
  61. Rimsky L, Hauber J, Dukovich M, Malim MH, Langlois A, et al. (1988) Functional replacement of the HIV-1 rev protein by the HTLV-1 rex protein. Nature 335:738–740PubMedCrossRefGoogle Scholar
  62. Rudolph DL, Lai RB (1993) Discrimination of human T lymphotropic virus type-1 and type II infections by synthetic peptides comprising structural epitopes from the envelope glycoproteins. Clin Chem 39:288–292PubMedGoogle Scholar
  63. Sagata N, Yasunaga T, Ikawa Y (1985) Two distinct polypeptides may betranslated from a single spliced mRNA of the genes of human T-cell leukemia and bovine leukemia viruses. FEBS Lett 192:37–42PubMedCrossRefGoogle Scholar
  64. Samuel K, Lautenberger J, Jorcyk C, Joseph S, Wong-Staal F, et al. (1984) Diagnostic potential for human malignancies of bacterially produced HTLV-I envelope protein. Science 226:1094–1097PubMedCrossRefGoogle Scholar
  65. Seiki M, Hattori S, Hirayama Y, Yoshida M (1983) Human adult T-cell leukemia virus: Complete nucleotide sequence of the provirus genome integrated in leukemia cell DNA. Proc Natl Acad Sci USA 80:3618–3622PubMedCrossRefGoogle Scholar
  66. Smith MR and Greene WC (1991) Molecular biology of the type I human T cell leukemia virus (HTLV-I) and adult-T cell leukemia. J Clin Invest 87:761–776PubMedCrossRefGoogle Scholar
  67. Suzuki T, Fujisawa JI, Toita M (1993a) The transactivator tax of human T cell leukemia virus type 1 (HTLV-1) interacts with cAMP responsive element (CRE) binding and CRE modulator proteins that bind to the 21 base pair enhancer of HTLV-1. Proc Natl Acad Sci USA 90:610–614PubMedCrossRefGoogle Scholar
  68. Suzuki T, Hirai H, Fujisawa J (1993b) A trans-activator tax of human T cell leukemia virus type 1 binds to NF-kappa B p50 and serum response factor (SRF) and associates with enhancer DNAs of the NF kappa B and CArG box. Oncogene 8:2391–2397PubMedGoogle Scholar
  69. Suzuki T, Hirai H, Yoshida M (1994) Tax protein of HTLV-1 interacts with the rel himology domain of NF-kappaB/Rel involves phosphorylation and degradation of I kappa B alpha and RelA (p65)- mediated induction of the c-rel gene. Oncogene 9:3099–3105PubMedGoogle Scholar
  70. Tajima K, Tominaga S, Suchi T, et al. (1982) Epidemiological analysis of the distribution of antibody to adult T-cell leukemia-virus-assocaited antigen: possible horizontal transmission of adult T-cell leukemia virus. Gann 73:893–901PubMedGoogle Scholar
  71. Takahashi K, Takezaki T, Oki T (1991) Inhibitory effect of maternal antibody on mother-to-child transmission of human T lymphotropic virus type 1. Int J Cancer 49:673PubMedCrossRefGoogle Scholar
  72. Takatsuki K, Uchiyama T, Ueshima Y (1982) Adult T cell leukemia: proposal as a new disease and cytogenetic, phenotypic and functional studies of leukemic cells. Gann Monogr Cancer Res 28:13–22Google Scholar
  73. Tanaka A, Takahashi C, Yamaoka S (1990) Oncogenic transformation by the tax gene of human T cell leukemia virus type 1 in vitro. Proc Natl Acad Sci USA 87:1071–1075PubMedCrossRefGoogle Scholar
  74. Tanaka Y, Tanaka R, Terada E (1994) Induction of antibody response that neutralize human T-cell leukemia virus type 1 infection in vitro and in vivo by peptide immunization. J Virol 68:6323–6231PubMedGoogle Scholar
  75. Ugen K, Boyer J, Agadjanyan M, Wang B, Javadian A, et al. (1996a) Site-specific humoral immune responses generated in chimpanzees after DNA inocualtion with HIV-1 envelope expressing constructs. In: Brown F, Burton D, Mekalanos J, Norrby E (eds) Vaccines 96: Molecular approaches to the control of infectious diseases. Cold Spring Harbor, Cold Spring Harbor, NY, pp 61–65Google Scholar
  76. Ugen KE, Agadjanyan M, Wang B, Kudchodkar S, Cho A, et al. (1995) Elicitation of immune responses in rodents after DNA inoculation with an HTLV-I envelop glycoprotein expressing construct: a model for vaccination efficacy. In: Brown F, Burton D, Mekalanos J, Norrby E (eds) Vaccines 95: Molecular approaches to the control of infectious diseases. Cold Spring Harbor, Cold Spring Harbor, NY, pp 129–134Google Scholar
  77. Ugen KE, Fernandes L, Schumacher HR, Wang B, Weiner DB, et al. (1996b) Retroviruses and autoimmunity. In: H Freedman, R Noel, M Bendenelli (eds) Microorganisms and autoimmune diseases. Plenum, NY, pp 219–231CrossRefGoogle Scholar
  78. Ugen KE, Boyer JD, Wang B, Bagarazzi ML, Agadjanyan MG, et al. (1997) Nucleic acid immunization of chimpanzees as a prophylactic/immunotherapeutic vaccination model for HIV-1: prelude to a clinical trial. Vaccine 15:927–930PubMedCrossRefGoogle Scholar
  79. Ulmer JB, Donnelly J, Parker SE, Rhodes GH, Feigner PL, et al. (1993) Heterologous protection against influenza by injection of DNA encoding a viral protein. Science 259:1745–1749PubMedCrossRefGoogle Scholar
  80. Wang B, Boyer JD, Srikantan V, Ugen KE, Gilbert L, et al. (1995) Induction of humoral and cellular immune responses to the human immunodeficiency type 1 virus in non-human primates by in vivo DNA inoculation. Virology 211:102–112PubMedCrossRefGoogle Scholar
  81. Wang B, Ugen K, Srikantan V, Agadjanyan MG, Dang K, et al. (1993) Gene inoculation generates immune responses against HIV-I. Proc Nat Acad Sci USA 90:4156–4160PubMedCrossRefGoogle Scholar
  82. Weiss RA, Clapham P, Nagy K and Hoshino H (1985) Envelope properties of human T-cell leukemia viruses. Curr Top Microbiol Immunol 115:235–246PubMedCrossRefGoogle Scholar
  83. Yamanouchi K, Kinoshita K, Moriuchi R, et al. (1985) Oral transmission of human T-cell leukemia virus type-1 into marmoset (Callithrix jacchus) as an experimental model for milk-borne transmission. Jpn J Cancer Res 76:481–487PubMedGoogle Scholar
  84. Yoshida M, Miyoshi I, Hinuma Y (1982) Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implications in the disease. Proc Natl Acad Sci USA 79:2031PubMedCrossRefGoogle Scholar
  85. Yoshida M, Seiki M (1987) Recent advances in the molecular biology of HTLV-1: transactivation of viral and cellular genes. Ann Rev Immuno 15:541–559CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • M. G. Agadjanyan
    • 1
    • 2
  • B. Wang
    • 3
  • S. B. Nyland
    • 4
  • D. B. Weiner
    • 1
  • K. E. Ugen
    • 4
  1. 1.Department of Pathology and Laboratory MedicineUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Institute of Viral PreparationsRussian Academy of Medical ScienceMoscowRussia
  3. 3.Sinogen Institute, Institute of ZoologyChinese Academy of SciencesBeijingChina
  4. 4.Department of Medical Microbiology and ImmunologyUniversity of South Florida College of MedicineTampaUSA

Personalised recommendations