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“Many of the proteins identified in this study would probably be good candidates for screening to find new anti-HIV drugs,” notes David Baltimore, a leading HIV authority at the California Institute of Technology, who agrees that the virus will have a harder time developing resistance to drugs that target cellular proteins. “However,” he adds, “for the same reason, the drugs will have to be carefully characterized for toxicity.”
Elledge acknowledges that starving viruses of required host proteins could have unintended effects. “The cells do need the proteins,” he says. “That needs to be worked out.”
For Elledge, who is best known for his DNA cell cycle work, this new study is a first, if dramatic, foray into HIV biology. His lab also has ongoing gene discovery projects focused on other viral pathogens, as well as cancer, stem cells, and diabetes. He plunged into HIV to spur HIV drug development by industry, which he says is lagging: “I wanted to point out using genetics that there are real targets in cells and get [drug developers] thinking about mining those pathways.” 
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It's not just HIV that Steve Elledge is probing for weaknesses. He's taken on cancer too. In a paper published in Science on February 1, 2008, Elledge and his collaborator, HHMI investigator Gregory J. Hannon of Cold Spring Harbor Laboratory, revealed a new screening technique to probe tumors for genes that help them thrive.
Elledge and his colleagues generated about 8,000 bits of short hairpin RNAs (shRNA)—single strands of RNA that fold back on themselves—that can be inserted into retroviruses. When the altered retroviruses infect either normal or cancerous cells, the shRNA binds to corresponding stretches of RNA in the cells, preventing their translation into proteins.
If the shRNA knocks down production of a protein essential to keeping the cells alive, then the abundance of that particular shRNA quickly diminishes as cells die. If the shRNA corresponds to a gene involved in dampening cell growth, then the cells that carry that shRNA will multiply and thrive.
By tracking the abundance of each shRNA from the total pool and comparing breast and colon cancers with normal tissues, Elledge and his colleagues were able to identify genes critical to tumors' growth.
“The overall idea behind this is that cancer cells reprogram their [molecular] networks,” says Elledge. “We're interested in finding what components in these new networks are controlling proliferation.”
While his studies on HIV rely on a slightly different method, in both HIV and cancer Elledge hopes that full-genome scanning will reveal new target proteins for drugs.
“HIV is a lot like a cancer cell—cancer cells also mutate, so it's hard to get drugs to them that kill them,” he says. Both HIV and cancer are so complicated that selecting genes one at a time to test for importance would likely miss other vital ones, he says. “This is a way to take the guesswork out, because we're testing everything.”
—Sarah C.P. Williams
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