Human T Lymphotropic Virus Type 1 (HTLV-I) was the first human retrovirus discovered. Infection is endemic in parts of the United States, Japan and the tropics and it is considered the etiologic agent of two disease syndromes, an aggressive adult T cell leukemia and an immune-mediated chronic progressive myelopathy. An estimated 1-4% of infected individuals will develop HTLV-I-related discase, often decades after the initial infection. The immunopathogenic mechanism by which the virus is released from its latent state and induces cellular transformation is not understood. We hypothesize that signal transduction initiated via normal cell-signaling pathways, the TCR/CD3 complex and the CD2 receptor promotes viral replication and leukemogenesis. The HTLV-I long terminal repeat contains sequences responsive to both cyclic adenosine monophosphate (CANT) and protein kinase C (PKC). It is postulated that differential stimulation of these second messenger systems may co-regulate viral expression and cellular activation or transformation. To investigate this hypothesis I intend to manipulate protein kinase pathways using CAMP and PKC analogues and inhibitors in HTLV-I infected peripheral blood lymphocytes. This will be followed by receptor-mediated activation using monoclonal antibodies to cluster determinants (CD2, CD3, CD4 and CD8). Viral expression and cellular activation will be evaluated using complementary techniques to identify soluble and cell-associated viral antigens, HTLV-I mRNA and proviral DNA; intracellular calcium flux, phenotypic expression of membrane receptors and cell proliferation. It is anticipated that such manipulations will help clarify mechanisms of latency and cellular transformation associated with HTLV-I infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Physician Scientist Award (K11)
Project #
5K11AI001111-03
Application #
2057157
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Project Start
1992-09-15
Project End
1997-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
3
Fiscal Year
1994
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
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; Trask, O J; Andrews, J M et al. (1996) Stimulation of the CD2 receptor pathway induces apoptosis in human T lymphotropic virus type I-infected cell lines. J Acquir Immune Defic Syndr Hum Retrovirol 11:317-25