October 14, 2009

Progress in Finding a New Class of HIV Drugs

Scientists have discovered a method for screening an entirely new class of drugs, targeted against the HIV protein Nef, according to an article published online October 6 in ACS Chemical Biology and reported by ScienceDaily.

HIV’s Nef protein has an important indirect influence on how well HIV functions in the body. The presence of Nef inhibits HIV-infected cells from signaling to other cells that they are infected. This means that other immune system cells responsible for seeking out and destroying diseased or damaged cells aren’t able to respond effectively, thus allowing HIV-infected cells to continue producing new virus. Nef also activates uninfected CD4 cells nearby, increasing the likelihood that they too will become infected.

Researchers learned long ago that people infected with a strain of HIV containing a disabled form of Nef typically have much slower disease progression than people infected with Nef-functional HIV. Unfortunately, the protein is very difficult to study, as its effects don’t show up well in test tube studies.

Now, however, Lori Emert-Sedlak, PhD, from the University of Pittsburgh School of Medicine, along with department chair Thomas Smithgall, PhD, and other colleagues, has found a way to measure the effect of drugs on Nef. They’ve done so by looking at a cellular protein that Nef partners with, called Hck, to perform vital functions. Emert-Sedlak and her team developed an automated screening tool to test the effect of various chemical compounds on Hck, and thus presumably on Nef as well.

After screening 10,000 compounds, they found three that appear not only to disable Nef, but also to have a measurable effect on HIV replication. One, in particular, was able to completely stop all HIV replication in test tubes.

“We now have a way to rapidly and efficiently screen for inhibitors of Nef signaling through Hck,” Smithgall said. “But the surprise was that some of those inhibitors also showed strong antiviral activity in cell culture models.”

As with all early discoveries, the team’s method will have to be validated, and promising compounds will have to be studied in animals to determine whether they function as desired and are safe.

NEW! Scroll down to comment on this story.

Previous Comments:

Steve, Morristown, 2009-10-21 16:41:04
Kudos to Emert-Sedlak, Smithgall and their colleagues for their incredibly remarkable diligence (3 out of 10,000 compounds?), and especially for having the vision to go outside the box in fighting (and hopefully completely stopping the progression of) hiv in a brand-new way. Guarded hope and optimism are definitely called for, and I wish them the very best in achieving that goal.