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HIV protein find
February 2008
by David Hutton  |  Email the author
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BOSTONóResearchers at the Harvard Medical School have used RNAi to screen thousands of genes and identify 273 human proteins required for HIV propagation. The vast majority had not been connected to the virus by previous studies.Of the proteins identified, only 36 had previously been implicated in the HIV lifecycle.The ripple effect emanating from the discovery could soon circulate through the drug discovery industry, with myriad commercial opportunities for the findings to be applied to new R&D efforts.Harvard Medical School Professor and senior author Stephen Elledge, who holds primary appointments in the Department of Genetics and at Brigham and Women's Hospital, says Harvard holds the patent on most of the screened genes, but he is hopeful drug companies will take up the work to develop new therapies. "I think there needs to be more research, but the proteins we identified are potential drug targets and some of them already have drugs," Elledge says. "Quite possibly, new drugs could be developed for these proteins. If people can tolerate them, they should become new HIV therapies."Drugs currently used to treat the viral infection interact directly with the virus itself, and it's quite simple for the rapidly mutating virus to avoid destruction by altering how it interacts with these therapies. "Antiviral drugs are currently doing a good job of keeping people alive, but these therapeutics all suffer from the same problem, which is that you can get resistance, so we decided to take a different approach centered on the human proteins exploited by the virus," says Elledge. "The virus would not be able to mutate to overcome drugs that interact with these proteins."During the research, Elledge picked three of the other 237 proteins, and subjected them to a host of genetic experiments, proving they too truly play a role in HIV propagation. "I think the list of 36 was a generous evaluation," Elledge says, adding there probably are more proteins beyond the 273 listed. "First, anything that was toxic to the cells, we threw out. That probably makes them lousy drug targets, but they can be toxic for a variety of reasons. There are probably more than we actually reported because if you start killing the cells, you never replicate HIV and you don't know what happens."Elledge adds the research is closing in on a systems level understanding of HIV, which opens new therapeutic avenues. "We might be able to tweak various parts of the system to disrupt viral propagation without making our own cells sick," he says.To create the list, postdoctoral researcher and first author Abraham Brassóworking with Derek Dyxkhoorn and Nan Yan from Harvard Medical School Professor Judy Lieberman's labóbegan with a library of siRNAs targeting specific human genes. With the help of the staff at the Institute of Chemistry and Cell Biology at Longwood, Brass placed the siRNAs on thousands of human cells, with just one gene being targeted in each well of cells. Thus each well contained cells lacking a particular protein. Next, he unleashed HIV on the cells. If HIV replication was inhibited in a given well, it suggested the missing protein was involved. "The expanded list is a hypothesis generation machine," explains Elledge, who is also a member of the HMS-Partners Health Care Center for Genetics and Genomics and investigator with the Howard Hughes Medical Institute. "Scientists can look at the list, predict why HIV needs a particular protein, and then test their hypothesis."The research, according to Elledge, could lead to the discovery of other proteins that play a role in HIV propagation. The method also could be applied to other diseases, including cancer. ddn
 
Code: E020803

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