Minor Genes of HIV May Have a Major Role in its Therapy

By Jeffrey Laurence, M.D., and Rowena Johnston, Ph.D.

April 2007—This has been a very busy month for the amfAR-funded lab of Dr. Ned Landau and his amfAR-supported fellow, Dr. Lei Fang. In the March 2007 issues of Virology and Proceedings of the National Academy of Sciences, Dr. Ned Landau's team describes their research with two so-called accessory or “minor” genes of HIV, Vif and Vpr. Although most anti-HIV drug development efforts have focused on the major enzymes of HIV—reverse transcriptase, protease and, most recently, integrase—less well understood components of the virus, including Vif and Vpr, play important roles as well and should serve as additional drug targets.

One of the most surprising and exciting findings in AIDS research recently has been the identification of proteins that exist in human cells whose evolutionary purpose is to disable and even destroy pieces of genetic material that have the potential to harm the cell, including retroviruses like HIV. In fact, these proteins are more potent killers of HIV than the most effective antiretroviral therapy on the market. So why are humans so vulnerable to HIV infection?

HIV shields itself from the lethal effects of one such normal cell protein, APOBEC3G, by making a small protein called Vif that defuses APOBEC3G. Several amfAR-funded investigators contributed to this discovery, including the finding that other mammals, such as mice and many monkeys, harbor slightly different forms of ABOBEC3G, forms which can prevent Vif from functioning and, in turn, HIV from growing. Might there be a way to give humans the same advantages as mice?

Drs. Fang and Landau describe a test system permitting rapid measurement of Vif activity against human ABOPEC3G. Given such a lab test, it should be possible to screen chemical “libraries,” or large collections of known drugs and random molecules, for anti-Vif activity. In fact, development of similar test systems led to the discovery of the HIV protease inhibitors.

Landau is also studying another HIV accessory gene, Vpr, which arrests cell growth, leading to cell death. But the means by which it functions has been a mystery. In his Proceedings paper, Landau and colleagues identified the likely normal cell protein to which Vpr binds, initiating cell death.

Both studies hold promise for identification of new classes of drugs to combat, and perhaps eventually cure, HIV.

Dr. Laurence is amfAR’s Senior Scientific Consultant.. Dr. Johnston is amfAR's Vice President, Research.