Research Team Uncovers New Factor in HIV Infection

Posted: August 29, 2011 at 1:00 am, Last Updated: August 29, 2011 at 8:12 am

By Leah Kerkman Fogarty

Yuntao Wu. Photo by Evan Cantwell

One of the most troubling issues with HIV research is also the most promising: There is simply still so much to learn about how this devastating disease works. Thankfully, there are researchers like Yuntao Wu who are making key discoveries every day that could eventually lead to the cure for this epidemic, which affects more than 33 million people worldwide.

Recently, Wu, professor of molecular and microbiology in the College of Science, and his team experienced one of the breakthroughs that he hopes will start a new line of inquiry into how the HIV virus infects cells and, more important, how researchers can use that knowledge to create drugs that will limit or halt HIV infection.

Understanding the T Cell

In an April 2011 edition of the Journal of Biological Chemistry, Wu and his fellow researchers published a study that revealed this new understanding on how T cells — 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.

Other researchers on the study were 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 the Georgetown University School of Medicine’s Department of Oncology.

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 CD4 T 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.

Understanding this, what Wu and his research team discovered was the actual factor that allows the infection of T cells to happen. This discovery builds upon his previous work, published in the journal Cell in 2008, which outlined the basic process of how HIV infects T cells. Read more on this foundational research here and here.

After discovering that cofilin — a protein used to cut through a cell’s outer layer, or cytoskeleton — is involved in HIV infection, Wu’s latest finding provides the detailed framework for this process.

“We went on to figure out the details of all of the cellular proteins that regulate cofilin,” Wu explains. “This led us to discover the role of LIMK in this process.”

The New LIMK Factor

Wu’s team will continue its work on decoding this complicated process. Photo by Evan Cantwell

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.

“In this study, we found that HIV sends a signal into the cell when it touches the cell surface,” explains Wu. This signal, in turn, activates LIMK, which allows the virus to enter the cell. Building upon this discovery, 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 backward 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 to carry an inhibitor that suppressed LIMK, called LIMK knockdown.

What they found was that LIMK knockdown cells 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.

“Current drugs largely inhibit HIV viral proteins,” Wu says. “Our study is oriented to find new cellular targets for HIV infection.” One advantage of using this kind of therapy over the current medication 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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