Oct. 2, 2011 A George Mason University researcher team has revealed the specific process by which the HIV virus infects healthy T cells -- a process previously unknown. The principal investigator, HIV researcher Yuntao Wu, says he hopes this breakthrough will start a new line on inquiry into how researchers can use this knowledge to create drugs that could limit or halt HIV infection.
Wu, a professor of molecular and microbiology at Mason, published these findings in an April 2011 edition of the Journal of Biological Chemistry, along with researchers Paul J. Vorster, Jia Guo, Alyson Yoder, Weifeng Wang, Yanfang Zheng, Dongyang Yu and Mark Spear from Mason's National Center for Biodefense and Infectious Diseases and the Department of Molecular and Microbiology and Xuehua Xu from Georgetown University School of Medicine's Department of Oncology.
This paper outlined a new understanding on how T cells -- which are the target cells that the HIV virus infects -- move and migrate when hijacked by the virus.
"The discovery adds to our understanding of how HIV initiates the infection of human T cells, which leads to their eventual destruction and the development of AIDS," Wu says.
Researchers and doctors have known for some time that the HIV virus, rather than directly killing healthy T cells, actually hijacks them. This eventually leads to their destruction. So the virus essentially turns the infected T cells (also known as CD4T cells or helper T cells) into a factory for creating even more HIV. Learning more about how the cells are infected could be a key step toward figuring out how to stop infection altogether.
Wu's latest discovery builds upon his previous work, published in the journal Cell in 2008, which described the basic process of how HIV infects T cells. After discovering that cofilin -- a protein used to cut through a cell's outer layer, or cytoskeleton -- is involved in HIV infection, Wu's new research provides the detailed framework for this process.
This new factor is called LIM domain kinase, or LIMK. The researchers discovered that LIMK triggers a cell to move, almost acting like a propeller. This cell movement is essential for HIV infection. This discovery marks the first time that a research team has uncovered the involvement of LIMK in HIV infection.
Building upon these results, the researchers then used a drug to trigger similar LIMK activation and found that it increased infection of T cells. Of course, the researchers ultimately want to decrease the infection of T cells -- so they worked backwards and found something very promising.
"When we engineered the cell to inhibit LIMK activity, the cell became relatively resistant to HIV infection," says Wu. In other words, the researchers engineered human T cells that were not easily infected by HIV. This finding suggests that, in the future, drugs could be developed based on LIMK inhibition.
And while there are currently no medical drugs available to inhibit LIMK, Wu hopes this is a developing area in potential new therapeutic targets. One advantage of using this kind of therapy over the current medication available to those with HIV is that it's more difficult for the HIV virus to generate resistance to treatment, Wu explains.
Wu's team continues its work on decoding this complicated process, and he stresses that there is still much to be done.
"These findings are certainly exciting, and are an emerging research field that we are proud to have established three years ago with the publication of our Cell paper," he says. "We will continue to study the molecular details and to use those discoveries to develop new diagnostic and therapeutic tools to monitor and treat HIV-mediated CD4 T cell dysfunction and depletion."
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- P. J. Vorster, J. Guo, A. Yoder, W. Wang, Y. Zheng, X. Xu, D. Yu, M. Spear, Y. Wu. LIM Kinase 1 Modulates Cortical Actin and CXCR4 Cycling and Is Activated by HIV-1 to Initiate Viral Infection. Journal of Biological Chemistry, 2011; 286 (14): 12554 DOI: 10.1074/jbc.M110.182238
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