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Dissertation
Functional properties of patient-derived human immunodeficiency virus type 1 long terminal repeat and the transactivator protein Tat
Doctor of Philosophy (Ph.D.), Drexel University
Jun 2010
DOI:
https://doi.org/10.17918/00008252
Abstract
The human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) regulates viral gene expression. The viral transactivator protein Tat plays a pivotal role in transcriptional activation via interaction with the transactivation response element (TAR) of viral RNA. Studies in the pre-HAART era demonstrated HIV-1-infected peripheral blood (PB)-derived LTR variants containing a C-to-T change at position 3 of C/EBP site I (3T), or at position 5 of Sp site Ill (5T) were preferentially encountered in late stage disease. The 3T and 5T configurations exhibited low binding affinity for their cognate transcription factors. Our recent studies conducted during the HAART era have identified a number of HIV-1-infected patients within the DREXELM ED HIV/AIDS Genetic Analysis Cohort harboring LTR variants containing 5T Sp III. Transient expression analyses demonstrated that most LTRs containing either the 5T or co-selected 3T/5T configurations exhibited basal, stimulated, and Tat-mediated transcription activities similar to LTRs carrying the conB sequence at these LTR binding sites in Jurkat T cells and monocytic U-937 cells. However, the patient 19 clone 18 5T-containing LTR could not be transactivated by either the laboratory strain IIIB Tat or by Tat derived from the patient 19. When nucleotide +32 (A) of the TAR element of the defective 19-18 LTR was changed to conB (G), Tat-mediated LTR transactivation was only partially restored. However, this could be further enhanced by changing the sequence of the three Sp binding sites to the conB sequence. Results also indicate that selective pressures are likely placed on the virus at least during discrete phases of HIV disease that result in a viral LTR-Tat structural complex that may be more optimized for more effective viral transcription, possibly in specific cellular phenotypes. Furthermore, results are reported that suggest the HIV-1 Tat exon II may contain molecular determinants that play an important role in LTR-directed Tat-mediated transactivation at low concentrations of transactivator protein. The results suggest that genetic variation in Tat exon II may have more impact on Tat-mediated transactivation at low Tat concentrations that may be present during activation from latency, as compared to productive replication in CD4+ T cells.
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Details
- Title
- Functional properties of patient-derived human immunodeficiency virus type 1 long terminal repeat and the transactivator protein Tat
- Creators
- Luna Li
- Contributors
- Ying-Hsiu Su (Advisor) - Drexel University, Drexel University (1970-)Brian Wigdahl (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xxv, 249 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Drexel University
- Other Identifier
- 991021889008104721