Flossie Wong-Staal
e-mail: fwongstaal@ucsd.edu |
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My laboratory continues to focus on the
human retroviruses as model systems to study gene regulation and pathogenesis,
and as targets for genetic intervention. Using techniques to detect
both protein/protein and RNA/protein interactions between viral and
cellular elements, we have uncovered cellular genes that may play important
roles in the function of essential viral regulatory proteins (e.g.,
Tax of HTLV-1 and Rev of HIV). The mechanisms of action of these gene
products are under investigation.
Another major effort of my group is to develop gene therapy for HIV infection. Recent studies of the dynamics of HIV replication in patients under antiviral therapy have reaffirmed the central role of the virus in disease progression and provided a strong rationale for the development of effective, long term antiviral therapy. There are several critical steps in the development of anti-HIV gene therapy: (1) Identification/design of the most potent inhibitory gene(s); (2) Achievement of high level and persistent gene expression in relevant target cells; and (3) Efficient gene transfer into either the mature target cells or hematopoietic progenitor cells. My laboratory has focused on the use of ribozymes (catalytic RNA) to specifically cleave both afferent and efferent viral RNA during the HIV replication cycle. We showed that T-cell lines and primary lymphocytes transduced with retroviral vectors expressing an anti-HIV hairpin ribozyme from a Pol III promoter were resistant to exogenous infection with diverse strains of HIV-1. Furthermore, macrophages derived from primary CD34+ hematopoietic stem/progenitor cells were also resistant to challenge with a macrophage tropic strain of HIV-1. We also developed combinatorial vectors to minimize the chance of viral resistance as well as to increase anti-viral potency.
A clinical trial to test the safety and
feasibility of this therapy in patients has begun. Currently, we are
developing HIV-based gene delivery vectors to specifically target human
CD4+ cells or quiescent, primitive hematopoietic stem cells.
Reddy, T.R., Li, X., Jones, Y., Ellisman, N.H., Chiang, G.Y., Liem, R.K.H. and Wong-Staal, F. (1998). Specific interaction of HTLV-1 Tax protein and a human type IV neuronal intermediate filament proteine. Proc. Natl. Acad. Sci., USA 95: 702-707.
Poeschla, E.M., Wong-Staal, F. and Looney, D. (1998). Efficient transduction of non-binding human cells by feline immunodeficency virus lentiviral vectors. Nat. Med. 4: 354-357
Tang, H., Gaietta, G.M., Fischer, W.H., Ellisman, M.H. and Wong-Staal, F. (1997). The cellualr cofactor for the constitutive transport element of Type D retrovirus. Science 276:1412-1415.
Gervaix, A., Li, X., Kraus, G. and Wong-Staal, F. (1997). Multigene antiviral vectors inhibit diverse HIV-1 clades. J. of Virology 71: 3048-3053.
Gervaix, A., Schwarz, L., Law, P.,
Ho, A.D., Looney, D., Lane, T. and Wong-Staal, F. (1997). Gene therapy
targeting peripheral blood CD34+ hematopoietic stem cells of HIV-infected
indiviuals. Human Gene Therapy 8: 2229-2238.
Flossie Wong-Staal received her Ph.D. in molecular biology from UCLA and conducted postdoctoral work at UCSD. She was a research investigator at the National Cancer Institute and Section Chief of Molecular Genetics of Hematopoietic Cells in the Laboratory of Tumor Cell Biology. Dr. Wong-Staal serves on the editorial board of many journals and is the Florence Riford Professor in AIDS Research.