| Start Date: | 6/7/2016 | Start Time: | 1:00 PM |
| End Date: | 6/7/2016 | End Time: | 3:00 PM |
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Event Description
BIOMED PhD Research Proposal
Title:
Susceptibility of HIV-1 Infected Cells to Transformation of Surface-Exposed Env Spikes by Env-targeting Virus Inhibitors
Speaker:
Charles Ang, PhD Candidate, School of Biomedical Engineering, Science and Health Systems
Advisors:
Ken Barbee, PhD, Professor and Interim Director, School of Biomedical Engineering, Science and Health Systems
Irwin Chaiken, Professor, Department of Biochemistry and Molecular Biology, Drexel University College of Medicine
Abstract:
Although HIV-1 infection has shifted from death via AIDS into a treatable, chronic disease, it remains a burden that is capable of resurgence should a patient’s medication regimen slip, resulting in the refocusing on HIV-1 elimination and prevention. In order to accomplish this, HIV-1 needs to be examined throughout its lifecycle for opportunities, including the infected cell itself.
HIV-1 spreads through two mechanisms from the infected T cell: release of free virion particles and cell-to-cell transmission. Fundamentally, both of these pathways use the same underlying mechanism: virions are assembled and budded off the surface of the infected cell, then either released into the surrounding environment where it will mature, or released directly into contact with a neighboring cell via the immunological/virological synapse. However, the efficiencies of the two processes are very different: in vitro experiments have shown that cell-to-cell transmission of HIV-1 is up to three orders of magnitude more efficient than free virions infecting target cells, in addition to reducing exposure to and the efficacy of antiretroviral treatment. Moreover, in regions rich with target cells, such as lymphoid tissues dense with CD4 T cells, cell-to-cell transmission can result in an explosion of infected cells; often this leads to pyroptotic cell death in non-permissive T cells, largely contributing to the T cell depletion characteristics of AIDS and notably not seen in purely cell-free virion infection. In order to bud infection-competent virions, for either transmission mechanism, the infected T cell must first produce and place the HIV-1 Env glycoprotein on its surface, which should present as a shared target for viral Env-targeting entry inhibitors.
Prior work in the Chaiken Lab has developed the peptide triazole family of Env-targeting HIV-1 entry inhibitors, which has been studied for its effects against cell-free virions in both potency and mechanism. A separate initiative began applying peptide triazole compounds against virion-producer cells, revealing some interesting observations, namely the production of reduced-infectivity virions, denuded of the Env gp120 subunit, and in certain cases, cytotoxicity. This project aims to bridge these two camps, determining if the mechanisms of Env transformations seen in virions are responsible for the effects observed in cells, reacting to the transformations in an analogous, if not identical, manner. This will be accomplished by first demonstrating that peptide triazole compounds produce similar transformation effects as seen in virions, in order to define shared mechanisms intrinsic to Env, independent of location. Next, imaging will be used to provide visual confirmation of the assembly patterns of peptide triazole-treated Env on individual virions, as well as further experiments on Env assembly interactions on the budding virion. Lastly, peptide triazole's potency for inhibition of cell-to-cell transmission will be tested, providing a translational perspective on halting disease progression by targeting virion producer cells. |
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Location:
Bossone Research Center, Room 705, located at 32nd and Market Streets. |
Audience:
Undergraduate StudentsGraduate StudentsFacultyStaff |
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