HIV Inactivates the Body's Cellular Smart Bomb

July 7, 2003

HIV Inactivates the Body’s Cellular Smart Bomb

July 7, 2003

La Jolla, CA – 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 Munk, and Henrietta Nymark-McMahon, all of the Salk Institute. The study was funded by the National Institutes of Health, the Elizabeth Glaser Pediatric AIDS Foundation, Concerned Parents for AIDS Research, and the American Foundation for AIDS Research.

索尔克生物研究所（Salk Institute for Biological Studies）位于加利福尼亚州拉霍亚，是一个独立的非营利组织，致力于生命科学的基础发现、改善人类健康和条件，以及培养未来几代研究人员。乔纳斯·索尔克医学博士于1960年创立了该研究所，获得了圣地亚哥市政府赠送的土地以及“March of Dimes Birth Defects Foundation”（足迹慈善母婴健康基金会）的财政支持。.