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(Unpublished)
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Unpublished |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: |
|
| ETD Committee: |
| Title | Member | Email Address | Pitt Username | ORCID |
|---|
| Thesis Advisor | Sluis-Cremer, Nicolas | | | | | Committee Member | Mailliard, Robbie | | | | | Committee Member | Gupta, 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: |
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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