HTLV-I is the etiologic agent of adult T-cell leukemia (ATL) and neurologic diseases termed tropical spastic paraparesis/ HTLV-I-associated myelopathy (TSP/HAM). We have constructed an infectious molecular clone of HTLV-I and have shown that it transforms primary human lymphocytes in vitro. We have also identified a fetal rhesis lung cell line that can be productively and persistently infected by HTLV-I. This cell-virus system provides new opportunities to examine the functions and mechanisms of viral structural, enzymatic, and regulatory proteins in the context of a well defined, infectious virus. Mutant proviruses have been constructed with deletions of the open reading frames designated ORF X1 and ORF X2; these genes were entirely dispensable for expression and replication of the virus and for T-cell transformation in vitro. Mutations of the nucleocapsid and post-protease genes abolished virus propagation in vitro but had no effect on virus protein synthesis, assembly, or virion release from transfected cells. These structural proteins may thus have functions at early steps of the infection process. Mutant viruses with changes in the viral transcriptional transactivator, tax, are under examination to identify pathways involved in T cell transformation. Alterations in the expression and activities of signal transduction proteins in HTLV-I transformed T cell lines are also under study. We are also examining the Rev proteins encoded by HIV-1 and other lentiviruses. Rev is essential for virus gene expression and mediates nuclear export of intron-containing mRNAs that are usually sequestered in the nucleus. We demonstrated that the Rev encoded by equine infectious anemia virus induces exon skipping in virus pre-mRNA. This effect was also seen with a Rev mutant defective for nuclear export, indicating a direct action of Rev on the spliceosome. UV-crosslinking studies revealed that Rev bound to RNA near a purine-rich splicing enhancer element which is also recognized by specific SR-protein accessory splicing factors, suggesting that Rev interferes with functions essential for pre-mRNA splicing reactions. Finally, the SIVmne Nef protein was shown to interact with specific cellular protein kinases and to inhibit cell proliferation. SIV Nef amino acid sequence variation was monitored after experimental infections of animals with a cell culture-adapted virus clone. Specific, recurrent changes occurred in the nef sequence in vivo that were distinct from cell culture-adapted viruses.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010003-01
Application #
2463805
Study Section
Special Emphasis Panel (LLB)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1996
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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