Attacking HIV Genetically

Jeffrey Laurence, M.D.

July 15, 2008—A small piece of genetically engineered material bearing the exotic name, “hammerhead ribozyme,” forms the basis of a promising gene therapy approach to suppressing HIV. Recently, amfAR fellow Dr. Hoshang Unwalla, working in the laboratory of Dr. John Rossi at The City of Hope in Duarte, California, uncovered a means to rapidly discover and ultimately design the most potent anti-HIV hammerhead ribozymes.

Hammerhead ribozymes, so named because of their physical appearance, work by attacking specific RNA targets via their intrinsic enzyme activities. The targeted RNA forms the transition stage between the beginning of viral production and the final product, HIV. To an appropriately designed ribozyme, this HIV-in-the-making is simply a piece of RNA to be destroyed.

Writing in the June 2008 issue of the journal Molecular Therapy, Dr. Unwalla and colleagues first described the construction of a collection, or “library,” of randomly prepared genetic sequences encoding some 20 million hammerhead ribozymes. This library was then tested against cells infected with HIV, searching for those sequences with the greatest ability to block HIV activity. Only about one in 100,000 ribozymes looked promising initially, and two were finally chosen for further testing. Both were capable of inhibiting HIV growth by at least 95 percent.

The value of such a large library of ribozymes is that it permits a scientist to search rapidly for a specific activity in a living cell without having to rely on computer models and educated guesses to choose the most potent players. With the aim of ultimately curing a cell of HIV, and then the entire body, scientists need to achieve a complete suppression (or, in the parlance of genetic research, knockdown) of virus production. Approaches such as those being pioneered by Dr. Unwalla, along with other types of gene therapies, bring us closer to that goal.

Dr. Laurence is amfAR’s senior scientific consultant.