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Johns Hopkins Medicine
Office of Communications and Public Affairs
Media Contact: Joanna Downer

April 23, 2004

Stolen Genetic Material Offers No Benefit to Virus

A hallmark of viruses like HIV is that they evolve and survive in part by "stealing" genetic ideas -- and copying genetic material -- from the human cells they infect, largely to improve their chances of infecting even more cells.

However, Johns Hopkins researchers have discovered an example of this "molecular piracy" between HIV and human cells that seems not to benefit either one. Writing in the April 23 issue of Molecular Cell, the researchers describe an HIV protein that closely matches a protein they've been studying in heart cells. When the two are found together, neither of the proteins can work, the researchers report.

"Classic molecular piracy benefits the virus and is destructive for the host, but here it's negative for both," says Eduardo Marbán, M.D., Ph.D., the Michel Mirowski Professor of Medicine, chief of cardiology and director of the Institute for Molecular Cardiology at Johns Hopkins. "Why HIV would have picked up such a protein is unclear, but it's certain that the proteins' similarity isn't accidental."

While it's unlikely to reveal any new targets for tackling HIV infection, the discovery may help reveal secrets of HIV's effects in different organs, says Marbán, a cardiologist whose research focuses on understanding the molecular basis of heart cells' unique functions.

Graduate student Kate Hsu stumbled across the HIV protein's similarities to their heart cell protein, called TASK-1, while searching databases for proteins that might work like TASK-1, which the researchers believe helps cells send and receive electrical signals.

Moving beyond the structural and sequence similarities, Hsu tested whether the two proteins could interact with one another, and what the effect was if they did. "If the proteins hadn't interacted, or if there'd been no effect, we would have dropped it," says Marbán. "But at each step, the results showed the similarities weren't just coincidence."

Hsu discovered that the two proteins do bind to each other, which then prevents either from doing its job. The HIV protein, called Vpu, normally helps release new copies of the virus from infected cells, and can't when it's tied to TASK-1. TASK-1 normally regulates passage of charged atoms -- in this case potassium -- into and out of the cell, which it can't do when bound to the HIV protein.

"In cells with a lot of TASK-1, the HIV protein is probably shut down completely, and the virus essentially gets stuck inside," says Marbán. "In cells with very little TASK-1, however, there will be extra copies of the HIV protein available to help the virus escape."

Scientists studying HIV already know that the Vpu protein isn't required for the virus to infect cells or survive, which makes it unlikely that Vpu or its activity would be a good target for treatment of HIV infection.

"Blocking the Vpu escape route for HIV might reduce its release from infected cells temporarily, but the benefit would end as soon as the virus could evolve a different route," says Marbán. "Since the virus doesn't need Vpu, it would just be a matter of time -- and probably not much time at that."

But with more study, the proteins' interaction and its effect on their functions could reveal interesting tidbits about how HIV behaves in cells that make a lot of TASK-1, such as heart and brain cells, versus cells that make only a little, such as white blood cells, say the researchers. It could also reveal a lot about how different cells react to or are affected by HIV infection.

For example, Marbán says that while TASK-1 protein in heart and brain cells would outnumber the HIV protein, these cells may still pay a price for having less TASK-1 available to do its job. Down the road, determining those cellular costs -- perhaps disrupted or squelched electrical signals -- may help explain side effects of HIV infection in these tissues, including HIV encephalitis (inflammation of the brain) and AIDS-related cardiomyopathy (a weakened heart muscle), Marbán suggests.

The research was funded by the National Institutes of Health. Authors on the paper are Hsu, Marbán, Jegatheesan Seharaseyon and Peihong Dong, all of Johns Hopkins; and Stephan Bour of the National Institute of Allergy and Infectious Disease.


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