George Mason University

By Michele McDonald

Yuntao Wu

New research showing how the human immunodeficiency virus (HIV) targets “veterans,” or memory T-cells, could change how drugs are used to stop the virus, Mason researchers say.

The research will appear in the Journal of Biological Chemistry’s October edition and currently is available online.

“It’s a big breakthrough for us,” says Yuntao Wu, an author of the study and professor at the Mason-based National Center for Biodefense and Infectious Diseases. “I think this will impact the field.”

Helper T-cells support the body’s immune system by organizing forces to fight off infection. HIV hijacks helper T-cells, and when helper T-cell numbers plummet, the body is vulnerable to disease.

Not all helper T-cells are the same, although they appear similar. Some are experienced cells that are called memory helper T-cells; others are naive, or “virgin,” cells that haven’t encountered an infection.  Mason researchers studied why HIV preferentially goes after memory helper T-cells, while shunning their close colleagues.

Weifeng Wang

“In the body, HIV is able to kill most memory helper cells in just a few days,” says Weifeng Wang, PhD Biosciences ’12, the study’s main author. “We wanted to pursue what makes the difference between memory and naive T-cells on a molecular level.”

Unlike naive helper T-cells, memory T-cells are on the go and much more mobile. And it’s that momentum that attracts HIV and makes the memory cell vulnerable, says Wang, who is currently a research fellow at the Dana-Farber Cancer Institute at Harvard Medical School.

When a memory cell moves inside the cell, it looks like a waterfall on the moving edge. “It’s called ‘treadmilling,’” Wu says.

“The cytoskeleton, or the cell’s supporting bone, acts like a muscle,” he says. “The treadmilling of cytoskeleton pushes the cell to migrate.” HIV infects memory cells by reaching the nucleus, past the cytoskeleton barriers. “For many years, we didn’t understand how the virus could cross such a structure. It’s like a wall, and it has to cross that wall.”

HIV jumps over the wall by exploiting the cell’s treadmilling process, Wu says. “HIV uses a receptor to attach to the cell for entry,” he says. “When the virus touches that receptor it’s like someone ringing the doorbell. That triggers a signal—someone comes out and opens the door. Now HIV can start the treadmill to ‘walk’ along the cytoskeleton toward the center. If the virus goes to naive cells, it cannot do it. Naive cells aren’t sensitive enough. The cytoskeleton of these virgin cells is different from the memory cells, and it is not easy for the virus to start the treadmilling process.”

HIV’s ability to mutate makes it difficult for the body to control it. “It can mutate very fast,” Wu says. “You may have a lot of memory cell soldiers there, but they are not able to recognize HIV. They remember one guy, but this guy changes his face so they don’t remember him. That’s why our immune system is not effective against HIV. On top of that, the virus kills lots of your memory helper cells. Without sufficient help, your immune system is in complete dysfunction, and now you don’t have an immune system.”

Mason researcher Yuntao Wu and research assistant professor Jia Guo in his lab. Photo by Evan Cantwell.

HIV’s knack for mutating makes it a tough target for drugs, Wang says. By shifting the focus to the cell, away from the virus itself, researchers may find a new way to tackle the virus, he says.

“Basically, our new strategy will be finding a cellular target, something HIV needs to depend on,” Wu says. “It’s as if the virus says ‘give me a house.’ The cell is the house. The house has to have electricity and everything so it can live there. Our approach is to look for something the virus needs to live on in that house and then to reduce it or shut it down. The challenge will be if you shut that down, that it doesn’t impact normal cell functions. It’s a very tricky balance. You want to kill the virus but not healthy cells along with it.”

Wu is looking at existing drugs, including those used for cancer. “There is something shared between cancer cells and HIV-infected cells because cancer cells also like to migrate. So some drugs that are used to slow down cancer migration could also be used to treat HIV.”

As part of his doctoral thesis, Wang spent six years pursuing why HIV attacks memory cells. Failure is a part of research, he says. He had to change the experiment conditions multiple times before finding success. “It’s like when you get lost in the woods at night; it’s difficult to find the way out.”

Mentors and colleagues spurred Wang on. Sheer persistence and hours in the lab eventually won out. “It’s very challenging to do scientific discovery,” Wang says. “There is no precedent.”

Wu’s research is supported by a $1.2 million grant from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, as well as money raised through the NYCDC AIDS Research Ride, an event in which Wu and fellow researchers competed for several years.

This article originally appeared on the university’s News site.

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