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Chemical-biology approach to delineate the mechanism of action of HIV-1 latency reversing agents

Han, Feng (2017) Chemical-biology approach to delineate the mechanism of action of HIV-1 latency reversing agents. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Prostratin exhibits potent HIV-1 latency reversing activity, yet its molecular mechanism of action has not been defined in detail. Here, we used a novel chemical biology approach which revealed that the protein kinase C-mitogen activated protein kinase kinase (PKC-Mel) pathway is essential for prostratin-induced reactivation of latent HIV-1 provirus. We identified 7 different Mek inhibitors using our approach that constantly impaired prostratin-induced reactivation. We also identified PKC inhibitors, Raf kinase inhibitors, and extracellular signal-regulated kinases (Erk) inhibitors that blocked prostratin-induced reversal of HIV-1 latency. Consistent with these observations, the PKC-Ras-Mek-Erk pathway plays an essential role in the mechanism by which prostratin reactivates latent HIV-1. In addition, we identified several kinase inhibitors that activated HIV-1 latent genes in a significant level individually, including CUDC-101, XMD8-92, PD173074, Quizartinib, and CUDC-907. Therefore, this chemical biology approach provides new methods of revealing the molecular mechanism of LRAs into the HIV-1 eradication research.
The work represented by this thesis holds public health significances lying mainly in enriching the knowledge of HIV-1 latency reversing agents, contributing to the translational study, and the overall advancement of HIV eradication in public health.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Han, Fengfeh21@pitt.edufeh21
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorSluis-Cremer, Nicolas
Committee MemberMailliard, Robbie
Committee MemberGupta, Phalguni
Date: 29 June 2017
Date Type: Publication
Defense Date: 21 April 2017
Approval Date: 29 June 2017
Submission Date: 28 April 2017
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 48
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: HIV-1 eradication, Prostratin, LRAs, chemical biology approach
Date Deposited: 29 Jun 2017 23:11
Last Modified: 29 Jun 2017 23:11
URI: http://d-scholarship.pitt.edu/id/eprint/31631

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