Project: Research project

Project Details


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.
Effective start/end date12/15/9212/14/99


  • National Institutes of Health


  • Medicine(all)


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