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Turning the tables on HIV

February 14, 2011


John Albin.

John Albin led a team that discovered what a difference one amino acid can make in fighting AIDS.

Researchers find a clue to protecting a major anti-HIV protein

By Deane Morrison

A battle rages inside white blood cells of persons infected with HIV. The struggle pits many human and viral proteins against each other, but the fight between just two of them may become a focal point for tipping the balance. 

On the human side is a protein, made by white cells, that produces mutations in DNA of the HIV virus. Its name is a mouthful--APOBEC3F--so we'll call it “Apo” here for short.

On the HIV side is a protein that is made by the virus in cells during infection. Its name is Vif, and it attacks Apo.

Medical researchers would like to give Apo the advantage in this conflict, and a recent discovery by University of Minnesota researchers may lead to a drug that will help do that.

Leading the research was John Albin, a doctoral student in the laboratory of Reuben Harris, an associate professor of biochemistry, molecular biology and biophysics. Their discovery was published in the Dec. 24, 2010 issue of the Journal of Biological Chemistry.

Here’s how the battle goes:

Close encounters of the hostile kind

When HIV infects a human white blood cell, the first thing the virus does is produce DNA. Left to its own devices, this DNA will move into the nucleus of the cell, insert itself into chromosomes, and start directing the production of new virus particles.

Reuben Harris.Reuben Harris studies mechanisms that generate mutations and how they may be harnessed to destroy pathogens.

But Apo attacks the viral DNA as soon as it comes off the assembly line and starts sticking it full of mutations; this has the potential to cripple the HIV.

HIV counterattacks with Vif, which attaches to Apo. Somehow, this attachment makes Apo susceptible to destruction by the cell's own machinery that normally breaks down defective proteins. (Until then, however, Apo can go right on attacking viral DNA.) A way to stave off destruction of Apo could, therefore, mean greater damage to HIV.

Albin and his team found that Apo could be protected from destruction by changing the amino acid glutamate at just one of the many positions where it occurs in the protein. That’s one out of the almost 400 amino acid building blocks in Apo.

"Changing this one amino acid doesn't seem to dislodge Vif," explains Albin. "It's that somehow, if this amino acid is missing or changed, the interaction is altered in such a way that Apo isn't destroyed." Thus, Apo could continue the fight.

Albin and his colleagues are now experimenting to find out exactly how Apo and Vif interact.

"Once you have that information, you can work toward designing drugs to interrupt that interaction specifically," he says.

Too much of a good thing?

Even as researchers seek to help Apo inactivate HIV through mutations, they realize this may have a downside: It could help HIV mutate so fast that the immune system can't fight it.

Model of APOBEC3F.On this model of the APOBEC3F protein molecule, the red area indicates the location of the key amino acid involved in its interaction with Vif.

This idea stems from the fact that HIV is notorious for mutating into new strains too rapidly for the human immune system to evolve defenses. It's possible that the mutations produced by Apo contribute to this phenomenon.

So what to do? Help Apo mutate HIV even faster, so the virus will suffer more damage? Or muzzle Apo to slow down the rate of HIV mutation and give our immune systems time to evolve resistance to it?

The consensus, says Albin, leans toward finding ways to unfetter Apo, such as the aforementioned search for a drug to alter its interaction with Vif. But research into the potential for HIV to adapt by using Apo mutations is ongoing.

Tipping the balance of this battle could be a delicate affair.
 

 

 

 

Tags: College of Biological Sciences, Academic Health Center

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Reuben Harris's page

Department of Biochemistry, Molecular Biology and Biophysics

College of Biological Sciences