RNA Interference Combination Strategy Shows Promise in Laboratory Study

	SUMMARY: Investigators from Johnson and Johnson have devised a set of short hairpin RNA sequences that may be able to inhibit nearly 90% of all known HIV strains, according to findings published in the January 13, 2011 online edition of the open-access journal AIDS Research and Therapy. While HIV can mutate to develop resistance to RNA interference -- as it does to conventional antiretroviral drugs -- combining 4 or more highly conserved hairpin RNA segments may maintain long-term viral suppression.

Below is the text of a media advisory issued by AIDS Research and Therapy publisher BioMed Central describing the research.

Suppression of Entire HIV Subtypes Could Now Be Possible with Multiple shRNAs

The hope of finding new, effective drugs to treat HIV infection by launching a manifold attack on the viral genome has significantly increased, thanks to new research published in BioMed Central's open access journal AIDS Research and Therapy. HIV is a particularly difficult virus to tackle because it mutates very rapidly. Traditional drugs are often swiftly overcome by the virus, which has in part resulted in the many different variants currently circulating.

Australian researchers from Johnson and Johnson Research Pty Ltd have been studying new ways to fight HIV by exploiting the recently discovered a gene-silencing mechanism called RNA interference (RNAi). They have created hundreds of small molecules called "short hairpin RNA" (shRNA), designed against the thousands of HIV variants known to currently exist. shRNA harnesses RNAi such that individual genes can be highly specifically "turned off" at will. It has been known for some time that single shRNAs can attach to the genetic material of HIV and silence the production of certain gene products.

Unfortunately like traditional drugs, the effect of a single shRNA is short-lived as HIV rapidly mutates to escape RNA interference. Using a cocktail of [about] 4 different shRNAs at the same time however, significantly reduces the virus' ability to mutate and escape the genetic attack. By studying thousands of different combinations of shRNAs, the team has identified several combinations to cover all variants commonly found in the USA and Europe.

Principal investigator Glen McIntyre said, "The difficulty in finding a single combination of shRNAs to fight HIV is that there are many different variants that have to be accounted for. The trick is to search for combinations of slightly more shRNAs (than minimally needed for a single variant) so that there will be at least one suitable sub-combination for each different variant likely encountered. Not only did we want our combinations (of shRNA) to cover all currently known subtype variants, but we also aimed for them to actively prevent the emergence of any new, resistant variants."

The team's persistence has paid off and they have created a number of combinations of just 6-7 shRNAs designed to suppress every single variant of HIV belonging to the Clade B subtype; the most common group found in the USA and Europe. "The goal now is to test the best combinations in long-term experiments against different variants to see if they hold up as expected, and particularly in preventing new variants from emerging." Success could one day see an entirely new treatment method for HIV suffers, potentially free of the problems associated with traditional drugs.

Investigator affiliation: Johnson and Johnson Research Pty Ltd, Eveleigh, NSW, Australia.