Abstract
The field of animal models for biomedical research has greatly benefited from the emergence of human immune system (HIS) mice. These “humanized” mice, which are sustainably engrafted with a HIS, have significantly contributed in delineating and recapitulating the immuno-pathogenesis of human infectious diseases, specifically of human lymphotropic infections, such as HIV, HTLV-1, and EBV. In this chapter, a special attention is given to HTLV-1 (Human T-cell lymphotropic virus type 1), the causative agent of adult T-cell leukemia/lymphoma (ATLL), and of inflammatory diseases such as the tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). Recent studies performed with humanized NOD/SCID IL2γ chain null (γc−/−) and BALB/c-Rag2−/−γc−/− have shown that these HIS mice are efficiently and persistently infected by HTLV-1. Interestingly, several months after infection, CD4+ T-cell lymphomas with characteristics of ATLL developed in these mice. Furthermore, the proliferation of activated human CD4+ T lymphocytes has been observed in the peripheral blood and peripheral organs, as a consequence of the early infection of progenitors in the bone marrow and/or in the thymus. As such, these HIS mice provide appropriate models for the characterization of molecular and cellular events that control the initiation and progression of the leukemogenic process. They therefore represent promising preclinical tools to investigate new therapeutic approaches against HTLV-1 associated diseases.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- ATLL:
-
Adult T-cell leukemia/lymphoma
- HIS:
-
Human immune system
- HP/HSCs:
-
Hematopoietic progenitors/hematopoietic stem cells
- HTLV-1:
-
Human T-cell leukemia virus type 1
- TSP/HAM:
-
Tropical spastic paraparesis/HTLV-1 associated myelopathy
References
Matsuoka M, Jeang KT. Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat Rev Cancer. 2007;7(4):270–80.
Duc Dodon M, Villaudy J, Gazzolo L, Haines R, Lairmore M. What we are learning on HTLV-1 pathogenesis from animal models. Front Microbiol. 2012;3:320.
Lairmore MD, Silverman L, Ratner L. Animal models for human T-lymphotropic virus type 1 (HTLV-1) infection and transformation. Oncogene. 2005;24(39):6005–15.
Manz M, Di Santo J. Renaissance for mouse models of human hematopoiesis and immunobiology. Nat immunol. 2009;10(10):1039–42.
Rongvaux A, Takizawa H, Strowig T, Willinger T, Eynon EE, Flavell RA, et al. Human hemato-lymphoid system mice: current use and future potential for medicine. Annu Rev Immunol. 2013;31:635–74.
Mesnard JM, Barbeau B, Devaux C. HBZ, a new important player in the mystery of adult T-cell leukemia. Blood. 2006;108(13):3979–82.
Tattermusch S, Bangham CR. HTLV-1 infection: what determines the risk of inflammatory disease? Trends Microbiol. 2012;20(10):494–500.
Duc Dodon M, Mesnard JM, Barbeau B. Adult T-cell leukemia induced by HTLV-1: before and after HBZ. Med Sci (Paris). 2010;26(4):391–6.
Samarut J, Gazzolo L. Target cells infected by avian erythroblastosis virus differentiate and become transformed. Cell. 1982;28(4):921–9.
Rulli K, Lenz J, Levy LS. Disruption of hematopoiesis and thymopoiesis in the early premalignant stages of infection with SL3‐3 murine leukemia virus. J Virol. 2002;76(5):2363–74.
Hasegawa H, Sawa H, Lewis MJ, Orba Y, Sheehy N, Yamamoto Y, et al. Thymus-derived leukemia-lymphoma in mice transgenic for the tax gene of human T-lymphotropic virus type I. Nat Med. 2006;12(4):466–72.
Feuer G, Fraser JK, Zack JA, Lee F, Feuer R, Chen IS. Human T-cell leukemia virus infection of human hematopoietic progenitor cells: maintenance of virus infection during differentiation in vitro and in vivo. J Virol. 1996;70(6):4038–44.
Banerjee P, Sieburg M, Samuelson E, Feuer G. Human T-cell lymphotropic virus type 1 infection of CD34+ hematopoietic progenitor cells induces cell cycle arrest by modulation of p21(cip1/waf1) and survivin. Stem cells. 2008;26(12):3047–58.
Tripp A, Banerjee P, Sieburg M, Planelles V, Li F, Feuer G. Induction of cell cycle arrest by human T-cell lymphotropic virus type 1 Tax in hematopoietic progenitor (CD34+) cells: modulation of p21cip1/waf1 and p27kip1 expression. J virol. 2005;79(22):14069–78.
Banerjee P, Tripp A, Lairmore M, Crawford L, Sieburg M, Ramos J, et al. Adult T-cell leukemia/lymphoma development in HTLV-1-infected humanized SCID mice. Blood. 2010;115(13):2640–8.
Blom B, Spits H. Development of human lymphoid cells. Ann Rev Immunol. 2006;24:287–320.
Spits H. Development of alphabeta T cells in the human thymus. Nat Rev Immunol. 2002;2(10):760–72.
Anderson MK. At the crossroads: diverse roles of early thymocyte transcriptional regulators. Immunol Rev. 2006;209:191–211.
Aifantis I, Mandal M, Sawai K, Ferrando A, Vilimas T. Regulation of T-cell progenitor survival and cell-cycle entry by the pre-T-cell receptor. Immunol Rev. 2006;209:159–69.
Wencker M, Gazzolo L, Duc Dodon M. The leukemogenic activity of TaxHTLV-1 during human alphabeta T cell development. Front Biosci (Schol Ed). 2009;1:194–204.
Wencker M, Sausse C, Derse D, Gazzolo L, Duc Dodon M. Human T-cell leukemia virus type 1 Tax protein down-regulates pre-T-cell receptor alpha gene transcription in human immature thymocytes. J Virol. 2007;81(1):301–8.
Villaudy J, Wencker M, Gadot N, Gillet N, Scoazec J-Y, Gazzolo L, et al. HTLV-1 propels thymic human T cell development in “human immune system” Rag2-/- gamma c-/- mice. PLoS pathog. 2011;7(9):e1002231.
Akkina R. New generation humanized mice for virus research: comparative aspects and future prospects. Virology. 2012;435(1):14–28.
Legrand N, Ploss A, Balling R, Becker P, Borsotti C, Brezillon N, et al. Humanized mice for modeling human infectious disease: challenges, progress, and outlook. Cell Host Microbe. 2009;6(1):5–9.
Banerjee P, Crawford L, Samuelson E, Feuer G. Hematopoietic stem cells and retroviral infection. Retrovirology. 2010;7:8.
Tezuka K, Xun R, Tei M, Ueno T, Tanaka M, Takenouchi N, et al. An animal model of adult T-cell leukemia-humanized mice with HTLV-1 specific immunity. Blood. 2013;123(3):346–55. (Epub ahead of print).
Shultz L, Saito Y, Najima Y, Tanaka S, Ochi T, Tomizawa M, et al. Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r gamma(null) humanized mice. Proc Natl Acad of Sci U S A. 2010;107(29):13022–7.
Acknowledgments
This contribution was supported in part by INSERM & CNRS, by the European Union Project “Infection and Cancer” (INCA) under the Sixth Research Framework Programme (grant number: LSHC-CT-2005-018704) and by the Fondation de France, comité “Leucémie” (nuRAF09001CCA) to MDD and by grants from the US National Institutes of Health (CA124595) and by the Empire State Stem Cell Fund through New York State Department of Health Contract (NYSTEM #C023059 and #N08G-127) to G.F.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media New York
About this chapter
Cite this chapter
Duc Dodon, M., Villaudy, J., Gazzolo, L., Feuer, G. (2014). HTLV-1 Infection of Humanized NOD/SCID IL2 γc−/− and BALB/c-Rag2−/−γc−/− Mouse Models. In: Poluektova, L., Garcia, J., Koyanagi, Y., Manz, M., Tager, A. (eds) Humanized Mice for HIV Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1655-9_40
Download citation
DOI: https://doi.org/10.1007/978-1-4939-1655-9_40
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4939-1654-2
Online ISBN: 978-1-4939-1655-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)