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Research Finds Possible New Targets for HIV Drugs

By Paul Dalton

January 11, 2008

Researchers at Harvard Medical School have used a promising new technology to newly identify over 200 proteins that HIV needs to live and reproduce inside human cells. While these findings need more research before directly impacting the lives of people living with HIV/AIDS, they offer hope for novel drug targets at a time when such approaches are badly needed.

The research, published in the journal Science, was done by a team of scientists including Drs. Stephen Elledge and Judy Lieberman. Using HIV grown in Lieberman's lab, Elledge used small molecules of RNA (ribonucleic acid) to tease out which human proteins HIV needs to use in order to function. The technology, called RNA interference (RNAi), uses tiny strings of RNA, called small interfering RNA (siRNA), which can turn off a cell's ability to make a particular protein.

Dr. Elledge exposed cells to many thousands of different siRNA molecules to see if HIV was able to survive and reproduce inside them. In all they tested over 20,000 cells and identified 273 human proteins that HIV needs to function. Research using other methods has already found 36 such proteins.

There are potential benefits and risks to targeting human proteins. HIV may be less able to mutate to overcome drugs that target a human protein, making the issue of drug resistance less likely. However, interfering with human proteins runs the risk of disrupting normal cell function. Some drugs used to treat cancer use this approach. Targeting human proteins to combat HIV is a new and largely untested strategy. There is only one HIV drug that works this way -- the CCR5 antagonist Selzentry (maraviroc) -- which was just approved in late 2007.

Researchers are now able to look at each of these proteins to see if it can be safely and successfully targeted to block HIV. This report is very timely, as the pharmaceutical industry has been slow in developing novel types of drugs to treat HIV. With a couple of notable exceptions, most of the recent drug development -- including the candidates now in clinical studies -- are new and probably improved versions of the same kinds of drugs used to treat HIV since 1996. While this has meant significantly better tolerability and convenience, better protease or reverse transcriptase inhibitors are unlikely to fully overcome the limits of their predecessors.

Project Inform wrote about siRNA back in 2003. At the time we focused on siRNA's potential as a drug itself. While this has yet to materialize, the use of the technology to further our understanding of HIV and suggest new drug targets is very welcome. With potent and tolerable HIV drugs keeping many people -- at least those who can access them -- healthy for long periods, there is a growing risk of complacency by scientists and drug companies, who may feel that the problems of living with HIV/AIDS are pretty much solved. Hopefully this research, which Robert Gallo has said was, ' ... destined to be one of the top papers in [HIV/AIDS] for the decade,' can serve to reinvigorate the search for new and more effective treatments for HIV.

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