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Novel Antiviral Strategies Targeting the Human Immunodeficiency Virus Type 1 (HIV-1) Viral Protein R and Its Cellular Partner, the Glucocorticoid Receptor

Schafer, Elizabeth Ann (2005) Novel Antiviral Strategies Targeting the Human Immunodeficiency Virus Type 1 (HIV-1) Viral Protein R and Its Cellular Partner, the Glucocorticoid Receptor. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Most highly active anti-retroviral treatment (HAART) regimens eventually fail to provide complete and long-term suppression of virus replication due to the inability to fully clear virus from cellular reservoirs. The HIV-1 viral protein R, Vpr, increases virus replication in T cells and is necessary for the optimal infection of primary monocytes/macrophages and other non-dividing cells. In this essay, it is demonstrated that Vpr interacts with the cellular Glucocorticoid Receptor (GR) and transactivates the HIV-1 LTR through GRE and that this event can be blocked by the GR antagonist, mifepristone. Based on these observations, it is shown that targeting Vpr-mediated virus transcription with the glucocorticoid antagonist, mifepristone, can demonstrate a potent anti-retroviral therapy. Results demonstrated that Vpr-induced transactivation of both autologous and heterologous promoters was inhibited by mifepristone in a dose-dependent manner by >90% at a 1 µM concentration. Infectivity assays using T-tropic, dual-tropic, and macrophage-tropic viruses demonstrated antiviral effects on a dose-dependent regimen of mifepristone. The effects of mifepristone were also tested in HIV-1 latent cells that could be activated with extracellular viral protein and results exhibited a greater than 90% inhibition of re-activation in the presence of this antagonist. Cytotoxic effects of mifepristone demonstrated a CT50 from 10 to 100 µM in normal human primary cells, HeLa, HEK293, and CV-1 cells. Statement of Public Health Relevance: By utilizing the interaction between Vpr and the glucocortoicoid receptor, glucocorticoid antagonists such as mifepristone hold promise for anti-retroviral therapy by both preventing viral transactivation in currently-infected cell populations as well as preventing the reactivation of latent virus.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Schafer, Elizabeth Annels102@pitt.edu, elizabethschafer@hotmail.comELS102
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairAyyavoo, Velpandivelpandi@pitt.eduVELPANDI
Committee MemberKarol, Merylmhk@pitt.eduMHK
Committee MemberGupta, Phalgunipgupta1@pitt.eduPGUPTA1
Date: 29 September 2005
Date Type: Completion
Defense Date: 13 July 2005
Approval Date: 29 September 2005
Submission Date: 29 July 2005
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Antiviral; Glucocorticoid Receptor; HIV-1; Mifepristone; Vpr
Other ID: http://etd.library.pitt.edu/ETD/available/etd-07292005-211913/, etd-07292005-211913
Date Deposited: 10 Nov 2011 19:54
Last Modified: 15 Nov 2016 13:47
URI: http://d-scholarship.pitt.edu/id/eprint/8701

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