Targeting Hiv Tat-mediated Transcription By Complementary Therapeutic Modalities
Open Access
- Author:
- Narayan, Vivek
- Graduate Program:
- Immunology and Infectious Diseases
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- December 12, 2012
- Committee Members:
- Kumble Sandeep Prabhu, Dissertation Advisor/Co-Advisor
Kumble Sandeep Prabhu, Committee Chair/Co-Chair
Pamela Hankey Giblin, Committee Member
Shantu G Amin, Committee Member
Anthony Paul Schmitt, Committee Member
Andrew Thomas Henderson, Special Member - Keywords:
- HIV transcription
Transactivator of transcription
Selenium
Michael acceptor electrophiles
Thioredoxin reductase - Abstract:
- Human Immunodeficiency Virus (HIV) infection and Acquired Immunodeficiency Syndrome (AIDS) still claim over 2 million lives annually, despite the emergence of Highly Active Anti-Retroviral Therapy (HAART) over 15 years ago. The main cause for this has been the advent of viruses resistant to the HAART therapy. Besides this, there is very irregular adherence to the recommended therapy for HIV/AIDS because of the highly unpleasant side-effects prevalent due to the drugs used in conventional therapy. Due to these reasons, there is a need to establish additional forms of therapy against this disease. There is a considerable amount of epidemiological data suggesting a direct relation between selenium status and the severity of HIV infections. The mechanism underlying this effect has not been studied in detail, although it has been suggested that selenium supplementation alleviates oxidative stress by inhibiting the NF-κB pathway. Selenium exerts its antioxidant effects via incorporation into selenoproteins as selenocysteine. We show here that selenium, via incorporation into the antioxidant selenoenzyme, thioredoxin reductase-1 (TR1), inhibits HIV replication in macrophages by modulating the activity of a crucial HIV transcription factor, Transactivator of transcription (Tat). Our data suggests that TR1 reduces the disulfides in Tat which are important for its activity. Another mechanism by which selenium may inhibit HIV replication, besides incorporation into macrophages, is to cause the inhibition of the lysine acetyltransferase (KAT) activity of the enzyme, p300 (KAT3B). We present data in this thesis suggesting that selenium, via the upregulation of endogenous levels of the cyclopentenone prostaglandin (CyPG) Δ12-PGJ2, inhibits the activity of p300 by covalently modifying a key cysteine residue in the enzyme active site. Furthermore, another CyPG, 15d-PGJ2, which is formed endogenously as a result of selenium supplementation, covalently binds to and inhibits the transactivation activity of Tat. Exogenous addition of 15d-PGJ2 and other Michael acceptor electrophiles such as celastrol, inhibits Tat-mediated transcription and HIV replication in cell culture. Thus, we show here that selenium can inhibit HIV replication by inhibiting the activity of Tat by affecting its modification, and that this inhibition may be enhanced by treatment with compounds of natural origin which covalently modify the Cys-thiols which are highly conserved in the Tat proteins across different HIV strains worldwide.