Although evolutionarily distinct, both the human T-cell leukemia viruses types I (HTLV-I) and II (HTLV-II) and the human immunodeficiency viruses (HIV-1, HIV-2, and SIV) have evolved analogous transacting regulatory mechanisms which may be important in pathogenesis. The rex gene of HTLV-I and HTLV-II, and similarly, the rev gene of HIV-1, have been shown to be required for accumulation of unspliced gag/pol in the cytoplasm of infected cells. In our laboratory, we wish to define the regulatory effects of Rex in the context of HTLV-II. 1. We will study the effects of HTLV-II Rex on subcellular localization of different viral mRNA species expressed from HTLV-II clones, effects of rex mutations on overall mRNA levels, and mechanisms underlying positive and negative regulatory effects of Rex on expression from the viral long terminal repeat (LTR). 2.Cis-acting sequences responsive to Rex will be defined, and direct binding assays employed to identify and purify cellular and/or viral proteins which interact with Rex and/or these regions. 3. Mutagenesis in rex will be performed and correlated with effects in a variety of functional assays to define functional domains within rex. These include assays for nuclear/cytoplasmic levels of spliced versus unspliced mRNA, assays for Rex effects on HTLV-II LTR-linked expression (trans-activation), and assays for Rex-mediated rescue of HIV-1 Rev-deficient mutants. 4. The effects of Rex on cellular gene expression will be investigated, including effects on expression of genes; specifically, trans-activated by Tax, such as the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene, and effects on processing of other cellular mRNAs. This proposal will address the role of Rex in viral gene regulation, in transition from productive to latent infection, and in cellular transformation. A better understanding of Rex may lead to advances in treatment of retroviral infection by HTLV-I, HTLV-II, and possibly HIV-1.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA053632-05
Application #
2095456
Study Section
Special Emphasis Panel (ARR (V1))
Project Start
1990-09-20
Project End
1995-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095