Research Breakthrough Opens Door to New Strategy for Battling HIV

By Michele McDonald 

New research showing how the HIV virus 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 Chemistrys October edition and currently is available online.
 
Its 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 bodys immune system by organizing forces to fight off infection. The HIV virus hijacks helper T-cells. When helper T-cell numbers plummet, the body is vulnerable to disease. Not all helper T-cells are the same; some are experienced ones called memory helper T-cells, and others, naive cells or virgin cells, havent encountered an infection. Mason researchers studied why HIV preferentially goes after memory helper T-cells, while shunning their close colleagues. Memory and naive T-cells appear similar.
  
In the body, HIV is able to kill most memory helper cells, says Weifeng Wang, PhD Biosciences 12, the studys 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 its that momentum that attracts the HIV virus and makes the memory cell vulnerable, says Wang, whos currently a research fellow in 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. Its called treadmilling, Wu says. The cytoskeleton or the cells supporting bone is acting like a muscle. The treadmilling of cytoskeleton pushes the cell to migrate.

Thats how it pushes itself. In the past year weve been studying how HIV infects those memory cells. It has to go to the center, into the nucleus. It has to go past the cytoskeleton barriers to go into the center. For many years we didnt understand how the virus could cross such a structure. Its like a wall. It has to cross that wall.

HIV jumps over the wall by exploiting the cells treadmilling process, Wu says. The HIV virus uses a receptor to attach to the cell for entry, he says. When the virus touches that receptor its like someone ringing the doorbell. That triggers a signal someone comes out and opens the door. Now the HIV virus 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 arent 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.
 
HIVs ability to mutate makes it difficult for our 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 the HIV virus. They remember one guy, but this guy changes his face so they dont remember him. Thats 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 dont have an immune system.
 
HIVs 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. Its 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 in that house and then to reduce it or shut it down. The challenge will be if you shut that down, that it doesnt impact normal cell functions. Its 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. Its like when you get lost in the woods at night; its difficult to find the way out.
 
Mentors and colleagues spurred Wang on. Sheer persistence and hours in the lab eventually won out. Its very challenging to do scientific discovery, Wang says. There is no precedent.
 
NYC DC AIDS Research Ride partially funded the research for three years, Wu says. Also, a $1.2 million grant from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, is slated for the project from June 2009 until May 2013.