HIV eludes body’s smart bomb

HIV inactivates the body’s cellular smart bomb

HIV eludes one of the body’s key smart bomb defenses against infection, and this finding may lay the groundwork for new drugs to treat AIDS, according to a new Salk Institute study.

Nathaniel Landau, a Salk Institute associate professor, and his team have pinpointed how the body battles HIV, a tremendously complex and relentless virus. Their findings appear in the online issue of Cell and will be published in the July 11 print issue.

“What we have uncovered is a war that is being fought on the molecular level between viruses and cells. The war has been going on for millions of years, but we didn’t know about it until now,” said Landau.

“We have been focusing on an antiviral system that we never knew about-a single protein called APOBEC3G. APOBEC3G would be a powerful inhibitor of viruses such as HIV, except for one problem: the virus has outsmarted it. During the evolutionary war between the virus and the host, the virus developed an effective counter-measure.”

That counter-measure is a gene in HIV called virion infectivity factor (Vif). In an HIV-infected cell, according to Landau, Vif molecules are produced and then attach to the APOBEC3G protein molecules. Once attached, Vif prevents APOBEC3G from getting into the new viruses, and these viruses go on to replicate and spread throughout the body.

Having identified the interaction between Vif and APOBEC3G, Landau and his team then focused on a fundamental question: would it be possible to beat the virus at its own game?

“We found that mice also have the antiviral protein,” said Landau. “But interestingly, HIV can’t recognize the mouse protein. As a result, mouse APOBEC3G is a powerful blocker of HIV replication. The mouse APOBEC3G protein goes into HIV and Vif can’t kick it out.”

The mouse APOBEC3G functions like a smart bomb with a time-delayed fuse. When the virus is produced in an infected cell, APOBEC3G molecules get into the virus. At first, the protein does nothing; however, when the virus infects a new cell, APOBEC3G is activated. As HIV begins to copy its genes into DNA, APOBEC3G attacks the virus, creating massive mutations. APOBEC3G attacks the cytosines in the virus DNA, removing an essential chemical group to make them into uracil. The viral DNA is so badly mutated that the viral genes can’t function.

“Drug companies may be able to use this information to design a novel type of drug to treat HIV infection. They could develop drugs that attach to APOBEC3G, physically blocking Vif from attaching. If Vif can’t bind to APOBEC3G, the process of HIV replication could be halted,” said Landau.

The lead author of the paper was Roberto Mariani, a staff scientist at the Salk Institute. Co-authors of the paper include Darlene Chen, Bärbel Schröfelbauer, Francisco Navarro, Renate König, Brooke Bollman, Carsten Münk, Henrietta and Nymark-McMahon, all of the Salk Institute. The study was funded by the National Institutes of Health, the Elizabeth Glaser Pediatric AIDS Foundation and Concerned Parents for AIDS Research.

The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. Jonas Salk, M.D., founded the institute in 1960 with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.

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More Information:

http://www.salk.edu/

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