Small change shields anti-HIV protein

U. MINNESOTA (US) — The battle inside white blood cells of people infected with HIV may come down to a fight between two proteins.

New research finds that on the human side is APOBEC3F, or the Apo protein, made by white cells that produces mutations in DNA of the HIV virus. On the HIV side is Vif, a protein made by the virus in cells during infection that attacks Apo.

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

But Apo attacks the viral DNA as soon as it comes off the assembly line and starts sticking it full of mutations, potentially crippling 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, mean greater damage to HIV.

Researchers 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,” says John Albin, a doctoral student in the lab of Reuben Harris, associate professor of biochemistry, molecular biology, and biophysics at the University of Minnesota.

“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.

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

The research was reported recently in the Journal of Biological Chemistry.

Too much of a good thing?

Even as researchers seek to help Apo inactivate HIV through mutations, there may be a downside, Albin says.

It could help HIV mutate so fast that the immune system can’t fight it.

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.

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

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