Human T-lymphotropic virus type 1 (HTLV-I) is the etiologic agent for both, adult T-cell leukemia/lymphoma (ATLL) and a chronic myelopathy and is an important public health problem in the United States. In contrast to the muted transcription exhibited by the virus during persistent infections, virus replication is increased during neurologic disease states and is necessary for cell transformation. Limited information is known of specific host control mechanisms that regulate HTLV-I expression during activation of the host cell (CD4+ lymphocytes). Further research is needed to define the molecular details of how HTLV-I-infected T- lymphocytes regulate virus transcription when activated through physiologically relevant receptor pathways. The proposed research is based on the following HYPOTHESIS: Signal transduction initiated via the T-cell receptor/CD3 (TCR/CD3) complex and CD2 receptor promote the replication and leukemogenic potential of HTLV-I in infected T- lymphocytes. HTLV-I cell lines, as well as HTLV-I-infected normal lymphocytes during the course of transformation will be used to determine the influence of these receptor-mediated pathways at three sequential levels from cell membrane receptor-binding and generation of secondary cell signals through assessment of cellular proteins which bind viral promoter sequences. Following CD3 and CD2 receptor-mediated activation of HTLV-I-infected CD4+ T-lymphocytes, I postulate that the effects of second signals are mediated by specific cellular proteins which bind viral promoter sequences and enhance virus transcription. Therefore, the long term goal of the proposed research is to molecularly define how these receptor pathways determine the extent of viral replication and cell proliferation in the natural target cell of the virus (CD4+ T lymphocytes).
The Specific Aims of the proposed research are threefold: 1) determine HTLV-I expression and cellular proliferation during CD3 and CD2 receptor-mediated activation of virus infected lymphocytes, 2) analyze the effect of cAMP and protein kinase C activators and inhibitors on HTLV-I expression during CD3 and CD2 receptor-mediated activation, 3) demonstrate that CD3 and CD2 receptor activated CD4+ lymphocytes produce specific cellular proteins which bind HTLV-I promoter sequences and facilitate HTLV-I transcription.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA055185-03
Application #
2096397
Study Section
Experimental Immunology Study Section (EI)
Project Start
1992-12-15
Project End
1997-12-14
Budget Start
1994-12-15
Budget End
1995-12-14
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Ohio State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Newbound, G C; O'Rourke, J P; Collins, N D et al. (2000) Repression of tax-mediated human t-lymphotropic virus type 1 transcription by inducible cAMP early repressor (ICER) protein in peripheral blood mononuclear cells. J Med Virol 62:286-92
Lairmore, M D; Albrecht, B; D'Souza, C et al. (2000) In vitro and in vivo functional analysis of human T cell lymphotropic virus type 1 pX open reading frames I and II. AIDS Res Hum Retroviruses 16:1757-64
Albrecht, B; Collins, N D; Burniston, M T et al. (2000) Human T-lymphotropic virus type 1 open reading frame I p12(I) is required for efficient viral infectivity in primary lymphocytes. J Virol 74:9828-35
Collins, N D; D'Souza, C; Albrecht, B et al. (1999) Proliferation response to interleukin-2 and Jak/Stat activation of T cells immortalized by human T-cell lymphotropic virus type 1 is independent of open reading frame I expression. J Virol 73:9642-9
Newbound, G C; O'Rourke, J P; Collins, N D et al. (1999) Comparison of HTLV-I basal transcription and expression of CREB/ATF-1/CREM family members in peripheral blood mononuclear cells and Jurkat T cells. J Acquir Immune Defic Syndr Hum Retrovirol 20:1-10
Guyot, D J; Newbound, G C; Lairmore, M D (1998) Co-stimulation of human peripheral blood mononuclear cells with IL-2 and anti-CD3 monoclonal antibodies induces phosphorylation of CREB. Immunol Lett 61:45-52
Guyot, D J; Newbound, G C; Lairmore, M D (1998) CD2 signalling induces phosphorylation of CREB in primary lymphocytes. Immunology 95:544-52
Collins, N D; Newbound, G C; Albrecht, B et al. (1998) Selective ablation of human T-cell lymphotropic virus type 1 p12I reduces viral infectivity in vivo. Blood 91:4701-7
Andrews, J M; Oglesbee, M; Lairmore, M D (1998) The effect of the cellular stress response on human T-lymphotropic virus type I envelope protein expression. J Gen Virol 79 ( Pt 12):2905-8
Albrecht, B; Collins, N D; Newbound, G C et al. (1998) Quantification of human T-cell lymphotropic virus type 1 proviral load by quantitative competitive polymerase chain reaction. J Virol Methods 75:123-40

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