As outlined in RFA 90-CA10 (""""""""Human T-Cell Lymphotropic Viruses in Human Neoplasia""""""""), retroviruses have been implicated as causative agents in a diverse range of malignancies and degenerative neurologic disorders. Despite the isolation of retroviral agents from patients suffering from these disorders, only the human T-cell lymphotropic virus (HTLV) type I (HTLV-I) and human immunodeficiency virus (HIV) have been accepted as etiological agents of human disease. Although HTLV-I has been implicated in the etiology of an aggressive form of leukemia referred to as adult T-cell leukemia (ATL) as well as a progressive neurologic disorder known as tropical spastic paraparesis (TSP), little is known concerning the role of specific host and viral factors involved in the oncogenic process or during the course of neurologic dysfunction. In addition, the increasing prevalence of HTLV-like viruses world-wide and the demonstration that the virus can be transmitted from an infected mother to her offspring suggests a need for additional information concerning the interaction of HTLVlike viruses with human tissues with respect to oncogenic and neuropathogenic processes that may be operative during early human development. In response to RFA 90-CA-10, we propose to utilize this in vitro human fetal neural cell culture system to examine the role of HTLV-I-specific nucleic acid sequences and gene products in the neuropathogenic and oncogenic processes associated with virus infection.
The specific aims of the proposed research are to (1) identify human fetal neural cell populations that are susceptible to HTLV-I infection; (2) characterize the HTLV-I expression program in susceptible human fetal neural cell populations; (3) characterize the final outcome of the interaction of HTLV-I with specific susceptible human fetal and neural cell populations (cell death, persistence or latency, induction of a transformed or oncogenic phenotype); (4) examine the potential effects of HTLV-I infection on specific fetal neuronal and glial cell functions; (5) characterize the role of HTLV-I long terminal repeat (LTR) and regulatory gene products in neurotropism; and (6) characterize the role of the HTLV-I env gene product and corresponding receptor in neurotropism. The long-range goal of these studies is to improve our understanding of HTLV-I neuropathogenesis and oncogenesis with emphasis on characterizing the role of both viral and cellular factors involved in these processes. This information will be essential in the design of HTLV-I-specific therapies to prevent or treat HTLV-I-specific disorders.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA054559-03
Application #
2096031
Study Section
Special Emphasis Panel (SRC (44))
Project Start
1991-04-01
Project End
1995-03-31
Budget Start
1993-04-01
Budget End
1995-03-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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