It is estimated that 15 to 25 million people worldwide are infected with human T-cell leukemia virus type 1 (HTLV-1) or type 2 (HTLV-2). HTLV-1 infection is associated primarily with leukemia and neurological disease in a small percentage of infected patients, whereas HTLV-2 disease association is less clear. Although infected patients develop antibody and cytotoxic T-lymphocyte (CTL) responses to many of the viral proteins, HTLV manages to persist throughout life. In the previous funding period we generated and characterized distinct Tax-2 mutants that failed to activate NFkB/Rel or CREB/ATF cellular activation pathways and developed a HTLV-2 infectious virus that replicates independently of Tax. These reagents provided us with the unique tools to directly implicate Tax in the transformation of primary T-cells. Furthermore, we showed that Tax deregulation of NFkB/Rel was absolutely critical for cellular transformation, and that Tax activation of CREB/ATF also contributed, but at a later step in the process. We also observed that the in vitro transformation tropism of HTLV-1 and HTLV-2 is preferential for CD4+ and CD8+ T-cells, respectively, and the first successful recombinant virus studies between HTLV-1 and HTLV-2 indicated that this distinct transformation tropism is not encoded by Tax or Rex. Our long-range goal is to understand the molecular basis of T-lymphocyte transformation and induction of leukemia/lymphoma by HTLV. We continue to feel that the best way to ultimately understand the pathogenesis of HTLV is to use infectious molecular clones of HTLV-1 and the related less pathogenic HTLV-2, manipulate these clones to contain specific alterations or gene mutations, and compare and contrast their biological properties in primary human T-cells in vitro and our reproducible rabbit model in vivo.
In Aim 1 of this proposal we will test the hypothesis that additional documented activities of Tax that include the induction of micronuclei/DNA damage and direct interaction with tumor suppressor and cell cycle regulatory proteins are critical for viral replication and HTLV-mediated cellular transformation and IL-2 independent growth.
In Aim 2 we will extend our novel HTLV-1 and HTLV-2 tropism studies to determine the viral genetic basis for the distinct transformation tropisms of HTLV-1 (preference for CD4+ T-cells) and HTLV-2 (preference for CD8+ Tcells). Lastly, the rabbit model will be used to assess early infectivity tropism in a newly infected host and evaluate key Tax virus mutants and HTLV-1 and HTLV-2 recombinants for tropism, viral replication kinetics, immune response, and viral persistence. These studies will provide important new information about mechanisms by which HTLV Tax mediates cellular transformation and provide a greater understanding of the distinct biological properties of HTLV-1 and HTLV-2.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077556-09
Application #
7386053
Study Section
Virology - B Study Section (VIRB)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1997-09-15
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
9
Fiscal Year
2008
Total Cost
$271,103
Indirect Cost
Name
Ohio State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Kannian, Priya; Yin, Han; Doueiri, Rami et al. (2012) Distinct transformation tropism exhibited by human T lymphotropic virus type 1 (HTLV-1) and HTLV-2 is the result of postinfection T cell clonal expansion. J Virol 86:3757-66
Satou, Yorifumi; Yasunaga, Jun-Ichirou; Zhao, Tiejun et al. (2011) HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo. PLoS Pathog 7:e1001274
Zhao, Tiejun; Satou, Yorifumi; Sugata, Kenji et al. (2011) HTLV-1 bZIP factor enhances TGF-? signaling through p300 coactivator. Blood 118:1865-76
Jones, Kathryn S; Green, Patrick L (2010) Cloaked virus slips between cells. Nat Med 16:25-7
Li, Min; Kesic, Matthew; Yin, Han et al. (2009) Kinetic analysis of human T-cell leukemia virus type 1 gene expression in cell culture and infected animals. J Virol 83:3788-97
Matsuoka, Masao; Green, Patrick L (2009) The HBZ gene, a key player in HTLV-1 pathogenesis. Retrovirology 6:71
Li, Min; Green, Patrick L (2007) Detection and quantitation of HTLV-1 and HTLV-2 mRNA species by real-time RT-PCR. J Virol Methods 142:159-68
Ishioka, Kojiro; Higuchi, Masaya; Takahashi, Masahiko et al. (2006) Inactivation of tumor suppressor Dlg1 augments transformation of a T-cell line induced by human T-cell leukemia virus type 1 Tax protein. Retrovirology 3:71
Niinuma, Akiko; Higuchi, Masaya; Takahashi, Masahiko et al. (2005) Aberrant activation of the interleukin-2 autocrine loop through the nuclear factor of activated T cells by nonleukemogenic human T-cell leukemia virus type 2 but not by leukemogenic type 1 virus. J Virol 79:11925-34

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