Recent research has shown that the human immunodeficiency virus (HIV) is able to infect resting T cells, which are present in large number in the host and generally quite resistant to the virus. This resistance is at least partially provied by a thick layer of actin-based cytoskeleton near the T cell's plasma membrane that usually prevents the viral particles from fully fusing with the host cell and delivering the viral genome into the cell. However, viruses are able to occasionally circumvent this defense through initiation of a cellular signaling cascade that activates the cell's own actin-regulating enzymes to weaken the cytoskeleton layer. The goal of this project is to (1) find exactly which of these enzymes HIV uses to weaken the T cell's actin layer and (2) determine the order that each enzyme is recruited to the site of HIV entry. This knowledge is the foundation that is needed to enable future work on finding a way to strengthen the T cells'own defense as a new type of HIV/AIDS inhibition. To obtain this information, T-cell derived laboratory cell lines and primary T cells wil be imaged with super-resolution fluorescence microscopy. Various cellular proteins that are known or proposed to be involved with the signaling process that HIV uses to dismantle the actin barrier to entry will be labeled with fluorescent tags. The localization of these tagged proteins will be watched in live cells and determined with high resolution using advanced single- molecule based particle tracking and super-resolution imaging techniques.

Public Health Relevance

This project aims to determine the cellular signaling basis of how HIV is able to occasionally enter a subset of host T cells that are usually resistant to infection, but when infected persist in the body for extended periods of time. By understanding this process in detail, it would allow for the development of therapeutic strategies that strengthen these cells'natural resistance to the virus, which could help prevent new HIV infections and slow the progression of existing HIV/AIDS cases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32GM111095-01
Application #
8730420
Study Section
Special Emphasis Panel (ZRG1-AARR-C (22))
Program Officer
Sakalian, Michael
Project Start
2014-03-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$49,850
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biophysics
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109